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Polymeric nanoparticles

Polymeric nanoparticles ReVIew Human Vaccines & Immunotherapeutics 10:2, 321–332; February 2014; © 2014 Landes Bioscience Potent vectors for vaccine delivery targeting cancer and infectious diseases 1, 1,2 3 2 1 Azam Bolhassani *, Shabnam Javanzad , Tayebeh Saleh , Mehrdad Hashemi , Mohammad Reza Aghasadeghi , and Seyed Mehdi Sadat 1 2 Department of Hepatitis and AIDs; Pasteur Institute of Iran; Tehran, Iran; Department of genetics; Islamic Azad University; Tehran Medical Branch; Tehran, Iran; Department of Nanobiotechnology; Faculty of Biological Sciences; Tarbiat Modares University; Tehran, Iran Keywords: non-viral vectors, natural polymer, synthetic polymer, gene therapy, vaccine delivery may be in a condensed or non-condensed form, depending on the Nanocarriers with various compositions and biological prop- nature of the polymer and the method used for formulating the erties have been extensively applied for in vitro/in vivo drug and vector system. Recently, researchers have focused on biodegrad- gene delivery. The family of nanocarriers includes polymeric able carrier systems. The potential advantage of biodegradable nanoparticles, lipid-based carriers (liposomes/micelles), den- carriers compared with their non-degradable counterparts is their drimers, carbon nanotubes, and gold nanoparticles (nanoshells/ reduced toxicity and the prevention of the polymer accumula- nanocages). Among different delivery systems, polymeric car- riers have several properties such as: easy to synthesize, inex- tion in the cells after repeated administration. Furthermore, the pensive, biocompatible, biodegradable, non-immunogenic, degradation of the polymer can be used as a tool to release the non-toxic, and water soluble. In addition, cationic polymers plasmid DNA into the cytosol. Efficient non-viral gene delivery seem to produce more stable complexes led to a more protec- based on cationic polymers as DNA condensing agents is depen- tion during cellular trafficking than cationic lipids. dent on a variety of factors such as complex size, complex stability, Nanoparticles often show significant adjuvant effects in toxicity, immunogenicity, protection against DNase degradation vaccine delivery since they may be easily taken up by antigen and intracellular trafficking, and processing of the DNA. presenting cells (APCs). Natural polymers such as polysac- The nanoparticles (size <1000 nm) such as virus-like particles, charides and synthetic polymers have demonstrated great liposomes, the immuno-stimulating complexes (ISCOMs), poly- potential to form vaccine nanoparticles. The development of meric, and non-degradable nanospheres have received attention new adjuvants or delivery systems for DNA and protein immu- nization is an expanding research field. This review describes as potential delivery vehicles for vaccine antigens which can both polymeric carriers especially PLGA, chitosan, and PeI as vaccine stabilize vaccine antigens and act as adjuvants. Importantly, some delivery systems. of these nanoparticles are able to enter antigen presenting cells (APCs) by different pathways, thereby modulating the immune response to the antigen. This may be critical for the induction of protective Th1-type immune responses to intracellular patho- Introduction gens. Different polymers were used in solid particulate vaccine delivery. The vaccine antigen is either encapsulated within or Nanoparticles (NPs) are solid colloidal particles with diam- decorated onto the surface of the NP. By encapsulating antigenic eters ranging from 1–1000 nm. They consist of macromolecular material, NPs provide a method for delivering antigens which materials and can be used therapeutically as adjuvant in vaccines may otherwise degrade rapidly upon injection or induce a short- 1,2 or as drug carriers. Polymers are the most common materials lived, localized immune response. Conjugation of antigens onto for constructing nanoparticle-based drug carriers. One of the NPs can allow presentation of the immunogen to the immune earliest reports of their use for cancer therapy dates back to 1979 systems at the same way that it would be presented by the patho- when adsorption of anticancer drugs to polyalkylcyanoacrylate gen, thereby generating a similar response. nanoparticles was studied. Polymers used to form nanoparticles Generally, there are obstacles in manufacturing, formulation can be both synthetic and natural polymers. These nanocarriers and stability of polymers, in vitro and problems of extracellu- have been demonstrated for a variety of applications such as drug lar nonspecific interactions and intracellular trafficking to the 3 9 delivery, imaging, and detection of apoptosis. nucleus, in vivo. Recent efforts include the development of new Many cationic polymers have been studied both in vitro and polymers for gene delivery, the modification of traditional poly- in vivo for gene delivery. The DNA encapsulated in polymers cations with hydrophilic polymers for salt and serum stability and the addition of bioactive molecules to polymers for enhanced intracellular trafficking. Herein, we describe the roles of poly- *Correspondence to: Azam Bolhassani; Email: [email protected] meric constructs in vaccine delivery as well as gene and drug Submitted: 06/25/2013; Revised: 10/06/2013; Accepted: 10/12/2013; delivery in vitro and in vivo. Published Online: 10/15/2013; http://dx.doi.org/10.4161/hv.26796 www.landesbioscience.com Human Vaccines & Immunotherapeutics 321 ©2014 Landes Bioscience. Do not distribute. Figure 1. Schematic illustration on different vectors-mediated gene delivery. Polymeric Nanoparticles in Vaccine Delivery into the nucleus through nuclear pore complexes can be medi- ated by the presence of nuclear localization sequences (NLS) on Polymeric microparticles or nanoparticles have applied to proteins. If the vector contains one or several NLS, either as deliver genes especially in vaccine design (e.g., DNA vaccines). covalently or non-covalently DNA-linked peptides, a competi- Moreover, gene therapy has shown an excellent potential to help tion may take place between the rate of dissociation of the DNA- patients in a variety of disease conditions. Various strategies can vector complexes and the rate of loading of the complexes to be used in cancer gene therapy. Some of the gene therapy strat- the NLS-mediated nucleus importation machinery. Moreover, egies to kill or slow down growth of cancer cells are included since the cytosolic release of heterologous DNA is a prerequisite (1) Immunomodulation; (2) Prodrug activation; (3) Anti-sense/ for nuclear translocation, entrapment, and degradation of plas- RNAi, and (4) Induction of apoptosis. However, the lack of mid DNA in endolysosomes constitute a major barrier to effi- suitable vectors for the delivery of nucleic acids (e.g., DNA and cient gene transfer. siRNA), especially in vaccine development, represents a major The polyplexes which are formed between cationic polymers problem to their therapeutic application. Gene delivery systems and DNA through electrostatic interactions and thus known as include viral vectors, cationic liposomes, polycation complexes, polycation/DNA complexes are widely used as non-viral gene and microencapsulated systems. The failure of viral gene therapy delivery vectors. Many factors such as molecular weight (MW), in clinical trials due to toxicity, immunogenicity, and carcinoge- surface charge, charge density, hydrophilicity, and the structure nicity strongly motivates a non-viral approach. Synthetic vectors of cationic polymers affect gene transfection eff iciency of cationic based on polycations are promising vectors for gene delivery as polymers. Therefore, optimization of cationic polymers is nec- they are relatively safe and can be modified by the incorporation essary to improve the gene transfection efficiency. Currently, of ligands for targeting to specific cell types. However, the levels several important cationic polymers were used for gene delivery of gene expression mediated by synthetic vectors are low com- such as Polyethylenimine (PEI), PLL, Chitosan, and PAMAM. pared with viral vectors. Several vectors have been developed in Some strategies including PEGylation, combination, and mul- order to target genes to specific cells as shown in Figure 1. tifunctional modification were developed in the cationic poly- As known, a perfect gene vector includes four conditions: meric vectors. (1) be able to condense DNA effectively; (2) be stable in body Polyethylenimine (PEI) and DNA/ RNA transfection fluid; (3) be able to target the specific cells, and (4) be able to PEI is a cationic polymer widely used for nucleic acid deliv- 16 21 cross membranes and release efficiently. Strategies for over- ery. It is particularly promising vector with relatively high level of coming some of these barriers have resulted in polymer/DNA transfection in a number of target organs. The high charge density complexes with increased stability and delivery efficiencies. of PEI is thought to be a key factor that contributes to its high In addition, trafficking of nuclear proteins from the cytoplasm transfection efficiency. On the other hand, the polycationic nature 322 Human Vaccines & Immunotherapeutics Volume 10 Issue 2 ©2014 Landes Bioscience. Do not distribute. Figure 2. Functions of two important examples of current cationic polymers (PeI and chitosan) as non-viral gene delivery vectors. of PEI also appears to be the main origin of its toxicity, similar to Adsorption of nucleic acid onto cationic nanoparticles is one of many other polycations (e.g., polylysine). This toxicity has limited the approaches used for DNA or RNA delivery. This technique its use as a gene delivery vector in vivo. Therefore, the success of facilitates the immediate release of DNA or RNA at target site. gene transfection is dependent on the development of vectors that Furthermore, the preparations of polymer and DNA/RNA can efficiently deliver a gene to cells with minimum toxicity. The complexes by adsorption can avoid the chemical effects used studies have shown that PEI derivatives obtained by cross-linking in other approaches such as encapsulation. For example, PEI low-molecular weight PEI with degradable materials display higher possesses very high positive charges from amines in molecules transfection efficiency and lower cytotoxicity. For example, in which can form complexes with phosphate groups of nucleic order to develop new polymeric gene vectors with low cytotoxicity acids through electrostatic interaction. The complexes can be and high gene transfection efficiency, a cationic polymer was com- later delivered into the cell through endocytosis. PEI is consid- posed of low molecular weight PEI (MW ~600 Da) cross-linked ered to be the most effective cationic polymer due to its buffering by 2-hydroxypropyl-g-cyclodextrin (HP-g-CD) and then coupled capacity via the proton sponge effect. Its high proton-buffering to MC-10 oligopeptide containing a sequence of Met-Ala-Arg-Ala- capacity results in rapid osmolysis of the endosomes and the PEI/ Lys-Glu at a molar ratio of 1:3.3:1.2. DNA complexes escape into the cytosol and are subsequently This new gene vector was able to target delivery of genes to transported into the nucleus (Fig. 2). HER2 positive cancer cells for gene therapy. Furthermore, water- In a study, Heparin-PEI (HPEI) nanoparticles were used to soluble lipopolymer (WSLP) consisting of a low molecular weight deliver plasmid-expressing mouse survivin-T34A (ms-T34A) PEI and cholesterol was employed for in vivo gene therapy of can- to treat C-26 carcinoma in vitro and in vivo. According to the cer or ischemic myocardium. The Preformed PEI/DNA complexes in vitro studies, HPEI nanoparticle-mediated ms-T34A could were encapsulated in PEG stabilized liposomes resulting in the so- efficiently inhibit the proliferation of C-26 cells by induction of called “pre-condensed stable plasmid lipid particle” (pSPLP). apoptosis. Moreover, intra-tumoral injection of HPEI nanoparti- Currently, cell penetrating peptides (CPPs) have also been cle-mediated ms-T34A significantly inhibited growth of subcu- used to enhance the intracellular delivery of DNA by PEI and/ taneous C-26 carcinoma in vivo by induction of apoptosis and 24 29 or dendrimers. Our group showed that two delivery systems inhibition of angiogenesis. including PEI 25 kDa and PEI600-Tat conjugates are efficient Chitosan and DNA transfection tools for HPV16 E7 gene transfection. Although the level of Chitosan, produced by deacetylation of chitin, is a non- transfected COS-7 cells is higher using PEI 25 kDa in com- toxic and hydrophilic polysaccharide. Commercially, chitin and parison with PEI600-Tat, but its toxicity was obstacle in vivo. chitosan are obtained from shellfish sources such as crabs and Transfection experiments demonstrated that the use of PEI600- shrimps. Chitosan and its derivatives could accelerate wound Tat conjugates was more effective than the two compounds with- healing by enhancing the functions of inflammatory cells and out chemical conjugation. Furthermore, the newly developed repairing cells. Recent studies further indicated that chitosan conjugates maintain the desirable property of low cytotoxicity and its derivatives are used as a carrier of DNA for gene deliv- displayed by lower molecular weight PEI polymers and Tat pep- ery applications. It is able to condense nucleic acid into stable tides. It has been confirmed that a type of low molecular weight complexes (100 –250 nm in diameter), which protects DNA from polymer, so-called PEI (MW <2000 Da), covalently coupled to degradation by nuclease. The DNA/polymer complexes are Tat was able to improve Tat peptide mediated gene delivery as taken up into the cells via endocytosis into the endosomes, fol- 26,27 chloroquine. lowing with burst release of complexes fraction in endosomes and www.landesbioscience.com Human Vaccines & Immunotherapeutics 323 ©2014 Landes Bioscience. Do not distribute. 32 the DNA translocates into the nucleus (Fig. 2). Chitosan could The researchers have analyzed the production of pro-inflam- be a useful oral gene carrier because of its adhesive and transport matory cytokines (TNF-α, IFN-γ, IL-6, IL-12/IL-23, IFN-β, properties in the GI tract. Although most chitosans are able to and IL-1β) and hepatic enzyme levels (alanine aminotransferase, form polyplexes, the transfection efficiency of chitosans depends aspartate aminotransferase, lactate dehydrogenase, and alkaline on structural variables such as the fraction of acetylated units, phosphatase) in the blood serum of mice after systemic injec- the degree of polymerization, the chain architecture and chemi- tion of DNA or siRNAs delivered with L-PEI. The data showed cal modifications. On the other hand, the researchers found no major production of pro-inflammatory cytokines or hepatic that in vitro chitosan-mediated transfection depends on the cell enzymes after injection of DNA or oligonucleotides active for type, serum concentration, pH, and molecular weight of chito- RNA interference (siRNAs or sticky siRNAs) complexed with san. For example, Hela cells were efficiently transfected by this L-PEI. Only a slight induction of IFN-γ was detected after system even in the presence of 10% serum. In contrast, chitosan DNA delivery, which is probably induced by the CpG mediated has not been able to transfect HepG2 human hepatoma cells and response. Altogether, the results highlighted that linear PEI is a BNLCL2 murine hepatocytes. The transfection efficiency was delivery reagent of choice for nucleic acid therapeutics. found to be higher at pH 6.9 than that at pH 7.6. Indeed, at Using nanoparticles to deliver antigens, the efficiency of pH < 7, amine groups of chitosan are protonated which facilitate uptake into dendritic cells is significantly increased compared the binding between complexes and negatively charged cell sur- with soluble antigen alone. Particle shape and surface charge face. Moreover, transfection efficiency mediated by chitosan of are also important physicochemical factors playing critical roles high molecular weight (MW) > 100 kDa is less than that of low in the interaction between particles and antigen-presenting cells MW ~15 and 52 kDa. (APCs). Generally, cationic particles are taken up into cells much Although, chitosan successfully transfected cells in vitro, the more readily than those with an overall negative surface charge transfection efficiency showed to be lower than that of other cat- due to the anionic nature of cell membranes. When NPs as poly 1,28 ionic polymer vehicles such as PEI. One of the primary causes (amino acid) with encapsulated ovalbumin were used to immu- of poor gene delivery eff iciency is the insuff icient release of chito- nize mice, significantly higher levels of total IgG, IgG1, and sans from endosomes into the cytoplasm. Two approaches have IgG2a as well as IFN-gamma (stimulator of Ig class switching to been developed to increase transfection efficiency of chitosan IgG2a) were induced as compared with those in soluble ovalbu- nanoparticles: (1) Enhancement of chitosan solubility and (2) min, suggesting the particles have the ability to prime humoral 1 7 Attachment of cell targeting ligands to the chitosan particles. As and cellular immune responses. In this line, chitosan could act known, chitosan is insoluble at physiological pH and also it lacks on tumor cells directly to interfere with cell metabolism, inhibit charge. Thus, for development of an efficient gene vector with cell growth, and induce cell apoptosis. Chitosan induced apop- high transfection and low cytotoxicity, amphiphilic chitosan tosis of bladder tumor cells via caspase-3 activation. In addi- was linked with low-molecular weight PEI. In addition, a liver tion, it showed an anti-tumor role through improving the body’s cancer-targeted specific peptide (FQHPSF sequence) was bound immune function. Indeed, hydrophilic polysaccharide poly- with chitosan-linked PEI (CP) to form a new targeted gene deliv- mers are also good candidates for vaccine delivery with both dex- ery vector called CPT (CP/peptide). The vector showed low tran and chitosan being chosen for preparing NPs. On the other cytotoxicity and strong targeting specificity to liver tumors in hand, PEI /DNA complexes (“polyplexes”) conjugated with the vitro. The in vivo results showed that IL-12 delivered by CPT cell-binding ligand transferrin (Tf ) or epidermal growth factor (CPT/DNA) significantly enhanced the antitumor effects on (EGF) were used to achieve receptor-mediated endocytosis. The ascites tumor bearing mice as compared with PEI 25 kDa and surface charge of the complexes was masked by covalently linking CP as a control. PEI to polyethylene glycol (PEG). Intravenous injection of Tf– PEI and chitosan as immune stimulators PEG-coated polyplexes resulted in gene transfer to subcutane- Vaccination is cost-effective and the best prophylactic strategy ous neuroblastoma tumors of syngeneic A/J mice. Furthermore, against most diseases. Vaccines are the preparations given to EGF-PEG coated polyplexes were intravenously applied for patients to stimulate immune responses leading to the production targeting human hepatocellular carcinoma xenografts in SCID of humoral or cell-mediated responses that will combat infectious mice. In this line, our group showed that the mixture of a agents or non-infectious conditions such as tumors. Vaccines DNA vaccine expressing HPV16 E7 with PEI600-Tat cojugate may be prophylactic (e.g., to prevent the effects of a future infec- is immunologically more potent than E7 alone. Indeed, binding tion by pathogens) or therapeutic (e.g., vaccines against cancer). of cationic peptide (Tat)-polymer (PEI) to plasmid DNA encod- Attempts are being made to deliver vaccines through carriers as ing an antigen (E7) enhanced the uptake of the plasmid DNA they control the presentation of antigens to immune system thus and consequently induced both humoral and cellular immune leading to their prolonged release and targeting. Thus, lower responses in vaccinated mice. Our observations illustrated the doses of weak immunogens can be effectively directed to stimu- ability of PEI-Tat conjugate to augment immune responses in late immune responses and eliminate the need for the admin- vivo. Herein, the ratio of PEI600-Tat/E7DNA complex forma- istration of prime and booster doses as a part of conventional tion has significant influence on the level of protein expression 8 39 vaccination regimen. and consequently immune responses in C57BL/6 mice model. The previous studies demonstrated that the linear PEI (L-PEI) Generally, interactions of cationic polymers with the immune is being more efficient in vivo than the branched PEI (B-PEI). systems are rarely studied. Agonists of toll like receptors (TLRs) 324 Human Vaccines & Immunotherapeutics Volume 10 Issue 2 ©2014 Landes Bioscience. Do not distribute. are potential therapeutic reagents for cancer immunotherapy. the ability to activate innate immune cells and induce cytokine Cationic polymers have signif icant immunological activity medi- and chemokine production. The cell surface receptors include ated by TLRs. The studies indicated that cationic polymers macrophage mannose receptor, TLR-2, C-type lectin receptor including PEI, polylysine, cationic dextran and cationic gelatin Dectin-1 and leukotriene B4 receptor (BLT1). In addition, intra- specifically stimulate the macrophage to secrete IL-12 which is peritoneal injection of chitin particles induced adaptive Th2, one of the main Th1-inducing cytokines. Cationic polymers Th1, and Th17 immune responses. TLR-2, MyD88, and IL-17A could interact with macrophages through TLR-4 which is the have been proved to play important roles in the adjuvant proper- receptor of LPS. The stimulation ability of cationic polymer was ties of chitin and chitosan. It is believed that chitosan enhances related with their cationic degree and molecular weight. Larger both humoral and cell-mediated immune responses e.g., in sub- molecular weight and higher positive charge of polymers exhib- cutaneous vaccination. In addition, recombinant granulocyte- ited stronger stimulation ability. Additionally, the cationic macrophage colony-stimulating factor (rGM-CSF) accelerates polymers such as PEI and cationic dextran could reverse tumor- neutrophil recovery in cancer patients receiving chemotherapy. associated macrophages (TAMs) polarization and promote IL-12 When it co-formulated with chitosan, local rGM-CSF retention expression both in vitro and in vivo. Indeed, these cationic at a subcutaneous injection site was increased in mice for up to 9 polymers exerted direct tumoricidal activity by promoting Th1 d. In contrast, when delivered in a saline vehicle, rGM-CSF was and NK cell infiltration, suppressing tumor angiogenesis, and undetectable in 12–24 h. This indicated that chitosan helped to 41 44 prolonging the survival of sarcoma-bearing wild-type mice. control the distribution of rGM-CSF. As known, IL-12 is a potent anti-tumor cytokine that exhibits Poly (lactic-co-glycolic acid) and immunity significant clinical toxicities following systemic administration. Biodegradable polymers such as poly (lactic-co-glycolic acid) A study showed that intra-tumoral administration of IL-12 co- (PLGA) are also being developed for matrix antigen delivery. formulated with the biodegradable polysaccharide chitosan could PLGA microspheres are rapidly taken up by M-cells and trans- enhance the anti-tumor activity of IL-12 in mice bearing estab- located toward the underlying lymphatic tissue within 1 h. For lished colorectal (MC32a) and pancreatic (Panc02) tumors while instance, the loading of Hepatitis B core antigen into PLGA limiting its systemic toxicity. Chitosan/IL-12 is a well-tolerated, NPs (300 nm) induced a stronger cellular immune response as effective immunotherapy with considerable potential for clinical compared with Hepatitis B core antigen alone in a mouse model. trials. Vaccine immunotherapy using a specific antigen, such as Particle size plays an important role in directing the immune prostate specific antigen (PSA) led to stimulate both the innate response. Immunization with PLGA NPs (200–600 nm) was and adaptive immune systems to destroy tumor cells in the body. associated with higher levels of IFN-γ production related to a An adenovirus encoding PSA (Ad-PSA), as a viral gene delivery Th1 response. In contrast, immunization with PLGA mic- system could stimulate anti-tumor activity. To enhance trans- roparticles (2–8 μm) promoted IL-4 secretion related to a Th2 fection efficiency, the combination of this system with a cationic response. The studies have indicated that both PLGA NPs and polymer such as PEI or chitosan was applied. In fact, cationic liposomes are efficiently phagocytosed by dendritic cells in cul- polymers could complex with the negatively charged adenovirus ture, resulting in their intracellular localization. However, the to form nanoparticles. To further augment immune response, use of PLGA can be limited by acid hydrolytic degradation prod- CpG sequences were used as an adjuvant delivered in particulate ucts detrimental to the entrapped protein and loss of immunoge- form. In this line, the studies demonstrated that the adenovirus nicity on storage. Also, organic solvents used to load the antigen encoding OVA (AdOVA) as a model antigen, coupled with PEI, onto the polymer can be detrimental to the antigen. increased tumor protection in vivo compared with AdOVA alone. Formulation of DNA into both liposomal and polymeric cat- In addition, AdOVA + CpG showed the best tumor protection ionic nanoparticles completely blocks vaccination-induced anti- in therapeutic studies. In other set of experiments, AdOVA + gen expression in mice and ex vivo human skin. Furthermore, this chitosan + CpG represented a decrease in protective levels and negative effect of cationic nanoparticle formulation is associated antigen-specific immune responses. Indeed, the kinetic stud- with a complete block in vaccine immunogenicity. The reports ies showed that peak levels of effector T cells were present 14 d showed that shielding of the surface charge of the nanoparticles later in AdPSA + CpG immunized mice than in AdPSA alone. by PEGylation improves in vivo antigen expression more than 55 This delayed effect may explain the increased levels of protec- fold. Furthermore, this shielding of cationic surface charge results tion in AdPSA + CpG mice against AdPSA + chitosan + CpG. in antigen-specific T cell responses similar to those induced by The data are useful in vaccine design concerning the timing of naked DNA for both lipoplex and polyplex DNA carrier systems. peak response. Recently, cancer vaccine has become a novel These observations suggest that charge shielding forms a useful modality for cancer treatment and the important role of adju- strategy for the development of dermally vaccine formulations. vant has been realized. Chitin, chitosan, and their derivatives are Polymeric Vaccine Delivery Systems in Clinical Trials important adjuvants for immunotherapy. Based on their prin- cipal mechanisms of action, adjuvants can be generally divided into two classes: (1) vaccine delivery systems such as mineral The considerable research on microparticle-based vaccines salts, emulsions, liposomes, and virosomes; (2) immunostimula- has generated a number of strategies based on optimizing antigen tory adjuvants including toll-like receptor (TLR) agonists (e.g., release rates to produce single dose delivery systems. For exam- monophosphoryl lipid A), saponins and cytokines. Chitin has ple, pulse release of antigen from biodegradable microparticles is www.landesbioscience.com Human Vaccines & Immunotherapeutics 325 ©2014 Landes Bioscience. Do not distribute. Table 1. DNA vaccine delivery system Delivery system Disease Administration Status Ref. Polymeric microparticle-based platforms PLGA HIV IM Novartis, phase I 53 PLGA Solid tumors IM Preclinical 54, 55 PLGA (amolimogene/ZYC101a) HPV cervical neoplasia IM MGI pharma, phase II/III 56–58 Measles virus IM Preclinical 59 PLGA w/cetyltrimethylammonium FMDV ID, I M, IN Veterinary use 60 bromide (CTAB) HCV IM Preclinical 61 PLGA microspheres w/ PeI nanoparticles Model antigens Oral/IM Preclinical 62, 63 PLGA w/PeI coating B cell lymphoma ID, IM Preclinical 64, 65 PLGA w/PBAe Tumor antigen ID Preclinical 66 Polymeric nanoparticle-based platforms Allergy, RSV, Chitosan IN, Oral, Pulm Preclinical 67–69 tuberculosis Genetic Immunity, PeI-mannose HIV Transdermal 70 phase I/II IN, intranasal; IM, intramuscular; ID, intradermal; Pulm, pulmonary. considered advantageous for simulating the conventional, multi- (IM) and ID PLGA–PEI vaccination routes provided protection dose vaccine delivery regime. However, most microparticulate against lymphoma tumor challenge, IM vaccination was more delivery systems are considered to function on the principles of efficient among vaccination routes. On the other hand, PLGA efficient phagocytosis and transport to the lymph nodes and sus- can also be used to encapsulate and release pre-formed PEI–DNA tained antigen release over extended time periods which may pres- nanoparticles. Microspheres release DNA in PEI–DNA nanopar- 46,47 ent a continuous leakage of antigen to the immune system. ticle with kinetics similar to that of simple PLGA microparti- Cationic polymers and DNA vaccines cles and also efficiently transfect non-phagocytic cells as well as Within a decade, a myriad of potential applications of DNA APCs. It was demonstrated that PLGA-PEI-DNA microspheres vaccines developed targeting infectious agents, various cancers, increase humoral responses compared with naked DNA follow- allergy and immune dysfunction and by 1998 early clinical tri- ing IM vaccination and can induce efficient CTL responses at als reported induction of immune responses against HIV and doses lower than that obtained with naked DNA vaccination. malaria in humans. The only licensed and approved DNA-based Almost 100 Phase I and II clinical trials have confirmed the 48 49 vaccines are for animal use. One targets flavivirus (West Nile safety of DNA vaccines in humans. PLGA is one of the most virus) infection in horses and has also been used to protect wild widely studied polymers of interest in the vaccine field. For Californian condors; the other has been used to protect com- instance, to increase the efficacy of DNA-based vaccines, DNA mercial salmon against infectious hematopoietic necrosis virus. encoding hepatitis B surface antigen (HBsAg)-encapsulated for- Surface DNA loading can be facilitated by supplementation mulation of PLGA nanoparticles could induce enhanced immu- with the cationic surfactant cetyltrimethylammonium bromide nity in mice. In addition, PLG encapsulated DNA encoding (CTAB) as well as by the incorporation of PEI either into the human papillomavirus antigen has been tested in phase I and matrix of the microsphere or at the surface. Many other materi- II human clinical trials. PLGA microspheres containing DNA als such as DOTAP, DEAM, and PLL have been used to absorb encoding for the E6 and E7 genes of human papillomavirus virus DNA to PLGA microparticles. PLGA/CTAB microparticles (HPV) 16 and 18 have been developed into clinical trials by MGI were recently developed into stage I clinical trials by Novartis Pharma, Inc. to treat advanced pre-cancerous cervical intraepi- for HIV-1 DNA vaccination. Incorporating PEI into PLGA thelial neoplasia (CIN) by inducing CTL-mediated responses microspheres has also been developed as a method for avoiding to HPV-infected pre-cancerous epithelial cells. A phase I trial of the problems associated with internal encapsulation of plasmid PLGA microparticles encapsulating plasmid DNA encoding only DNA. PEI imparts a positive charge to the PLGA microsphere. HPV-16 E7 antigen (ZYC101, Eisai Pharmaceuticals) established Unlike CTAB, which by itself is not a transfection agent, PEI has T-cell immunologic responses in 11/15 participants and complete intrinsic ability to form nanoparticles with DNA and increase clinical response in 5/15 patients following three intramuscular transfection efficiency. In addition, PLGA–PEI microspheres (IM) vaccinations. In a phase II study, patients with CIN grade improved in vitro transfection and caused upregulation of co- 2/3 were injected IM with DNA encoding for both the E6 and stimulatory signals on APCs. Increased survival against a lethal E7 antigens in PLGA microspheres (ZYC101a/Amolimogene). dose of lymphoma tumor challenge was observed following These two trials demonstrate the clinical potential of DNA vac- 53-70 intradermal (ID) vaccination with PLGA microspheres prepared cines delivered by PLGA microspheres (Table 1). A phase with branched PEI on the surface. While both intramuscular II/III trial of ZYC101a is currently underway. Tumor antigen 326 Human Vaccines & Immunotherapeutics Volume 10 Issue 2 ©2014 Landes Bioscience. Do not distribute. (ZYC300)-encoding plasmid DNA encapsulated in biodegrad- the mice were protected against a syngenic challenge with PSA- able polymer microparticles was evaluated in cancer patients and expressing tumor cells. Then, the safety, feasibility, and Biological was shown to induce detectable immune responses and clinical efficacy of PSA/DNA vaccine was evaluated in a phase I clinical improvement. PLG microparticles with adsorbed DNA encod- trial in patients with hormone-refractory PC. No adverse effects ing HIV antigens have recently entered human clinical trials in (WHO grade > 2) were observed in any patients. PSA-specific healthy volunteers. cellular responses and an increase in anti-PSA antibodies were Moreover, PEI is also under clinical study for DNA vaccine detected after vaccination with the highest vaccine dose (900 delivery. Mannose–PEI was originally used for the ex vivo trans- μ g). However, new adjuvants and/or delivery systems need to be fection of dendritic cells (DCs), which successfully generated explored to enhance the anti-tumor immune responses activated 71,72 effector and memory CTL responses following subcutaneous by DNA vaccines in humans. (SC) injection in non-human primates mediated by transfection Polymeric nanoparticles in clinical trials of Langerhans cells in vivo. Interestingly, these robust cell-medi- Nowadays, the use of polymeric materials to elicit DNA vac- 48 47 ated responses were not accompanied by antibody production. cine responses seems promise. The use of available polymers DermaVir is an intradermal administration of linear PEI conju- such as PLGA, chitosan, and PEI has shown much promise in gated to mannose for the purpose of generating HIV immunity pre-clinical and clinical studies. Polymers used for gene deliv- and is currently in phase I/II studies (Table 1). ery including POEs, PAMAMs, and PBAEs have only recently Poloxamers (Pluronics) are a well-studied group of copolymers emerged as promising strategies for DNA vaccine delivery. The used as surfactants in a variety of pharmaceutical applications improvement of oral bioavailability of several other therapeutic including vaccine delivery and as adjuvants for DNA vaccines. peptides by encapsulation in polymeric nanoparticles was also Poloxamers are thought to act as adjuvants by recruiting and studied. Immunization with DNA encoding HLA-A2-restricted activating APCs. Poloxamers consist of blocks of poly (ethylene epitopes from the HPV16 E7 protein, encapsulated in biodegrad- oxide) (PEO) flanking a central poly(propylene oxide) (POP) able polymer microparticles, could induce HPV-specific T-cell core, and CRL1005 is a triblock copolymer that has a POP core responses in 10/12 patients which were still elevated after 6 mo. of 12 kDa flanked with 350 Da PEO. CRL1005 forms mic- Currently, vaccines are certainly the most promising applications roparticles spontaneously above a phase transition temperature, for orally delivered nanoparticulate systems. Indeed, immunolog- though formulation with the cationic surfactant benzalkonium ical stimulation does not require a dose as high as those required chloride (BAK) reduces particle sizes into the nanometer range obtaining a pharmacologic effect and control of time release (200–300 nm). Without BAK, DNA does not associate with profile could be less critical. In addition, several nanoparticle- CRL1005. However, adding plasmid DNA to BAK-CRL1005 siRNA therapies are in human clinical trials to assess their safety particles increases the size to 300 nm, indicating CRL1005- and efficiency. Since the initial discovery of RNAi, there have BAK-DNA particle formation, and these ternary nanoparticles been over 30 clinical trials assessing the potential of siRNA as a were shown to increase cell-mediated immune responses in non- novel therapeutic. human primates. Alternatives of Natural or Synthetic Polymers While the mechanism of CRL1005 without BAK as a DNA vaccine adjuvant is poorly understood, there is some evidence that CRL1005 enhances delivery of DNA in vivo. CRL1005 Natural polymers such as chitosan, albumin, and heparin has also been shown to be safe and practical. In pre-clinical tri- have been used for the delivery of oligonucleotides, DNA, and als, CRL1005-BAK-DNA nanoparticles increased cell-mediated protein, as well as drugs. An albumin-paclitaxel nanoconjugate and humoral responses to cytomegalovirus (CMV) antigens. has been studied in the treatment of metastatic breast cancer In addition, CRL1005-BAK-DNA induced cell-mediated and during phase III clinical trials. Different in vitro and in vivo humoral CMV responses in humans in phase I clinical trials, and research studies have focused on the use of conjugated poly- this formulation is now in phase II clinical trials. Poloxamer was meric nanoparticles with chemotherapeutic drugs to reduce the also mixed with PLGA to form nanoparticles for nasal delivery of damaging effects of the free drug administration. Currently, DNA to elicit a strong humoral response. more than 20 nano-particle therapeutics, are in clinical use, Since the beginning of year 2000, several phase I clini- validating the ability of nanoparticles to improve the therapeu- cal trials investigating DNA vaccination against cancer have tic index of drugs. evaluated DNA delivery to patients with colorectal carcinoma, Anticancer drugs often have poor solubility in water and thus HPV16-associated anal dysplasia, B-cell lymphoma, metastatic need to use organic solvents or detergents for clinical applica- melanoma, and prostate cancer. All studies demonstrated that tions, resulting in undesirable side effects such as venous inf lam- repetitive DNA administration is well tolerated, with no dose- mation and respiratory distress. Therefore, designing a distinct limiting toxicities even at doses of 2 mg per injection. The first carrier system that encapsulates a large quantity of drugs and study of Prostate-Specific Antigen (PSA)/DNA vaccine dem- specially targets tumor cells is essential for successful cancer ther- onstrated that PSA-specific cytotoxic T lymphocytes could be apy. To date, at least 12 polymer-drug conjugates have entered induced in mice. When two cytokine adjuvants, granulocyte Phase I and II clinical trials and are especially useful for target- macrophage-colony stimulating factor (GM-CSF) and interleu- ing blood vessels in tumors. Examples include anti-endothelial kin-2 (IL-2), were co-delivered with the DNA vaccine, 80% of immune-conjugates, fusion proteins, and caplostatin, the first www.landesbioscience.com Human Vaccines & Immunotherapeutics 327 ©2014 Landes Bioscience. Do not distribute. 3 76 polymer- angiogenesis inhibitor conjugates. Recently, water- loaded with methotrexate and conjugated to apo-transferrin. soluble polymers have been proposed due to simple preparation The authors demonstrated that the conjugated microgels exhib- methods without the use of organic solvent. ited a significant increase in mortality of Hela cells, compared Polymeric NPs have attracted much attention for their abil- with non-conjugated microgels. This was ascribed not only to ity to deliver drugs as well as being biodegradable. Among cat- receptor-mediated endocytosis of the conjugated microgels, but ionic water-soluble polymers available, chitosan is one of the most also to pH-mediated release of methotrexate from the microgels 1 76 extensively studied polymers. Recently, further studies have been by their swelling at the intracellular level. focused on using nanoparticles in cell culture. Chitosan showed The benefits of chitosan-based vectors include their avail- significantly lower toxicity than poly-l -lysine and PEI. For ther- ability, ease of modification, and unique biological properties apeutic applications, drugs can either be integrated in the matrix related to their polycationic nature. Chitosan nano-particles are of the particle or attached to the particle surface. A drug target- capable of passing through biological barriers in vivo (e.g., the ing system should be able to control the fate of a drug entering blood-brain barrier) and delivering drugs to the lesion site due to 77 36 the biological environment. Chitosan microsphere have several their small size. Evidence has shown that chitosan nanoparticles applications in novel drug delivery systems such as GI-delivery may exert differential bactericidal and pharmacological effects on systems, colon and intestinal drug delivery, opthalmic drug prokaryotic and eukaryotic cells in culture. In vitro anti-tumor delivery, oral, buccal and sublingual drug delivery, nasal and testing of chitosan nano-particles indicated that inhibition rate transdermal drug delivery, and vaginal drug delivery. of 500 mg/L chitosan nano-particles was 27% on Hela cells of Chitosan and its derivatives can be covalently cross-linked to cervical cancer, 23% on liver SMMC-7721 cells, 29% on gastric 78 30 prepare nano-sized particles as the drug carriers. The chemi- cancer BGC-823 cells, and 55% on breast cancer MCF-7 cells. cal cross-linkers that have been widely used for chitosan include The studies have shown that cancer treatments consisting of bifunctional agents such as PEG dicarboxylic acid, glutaralde- a combination of chemotherapy and immunotherapy have been hyde or mono-functional agents such as epichlorohydrin. The exploited to further improve the efficacy of cancer therapies. In release kinetics of loaded drugs from polymeric NPs can be con- a study, a chitosan hydrogel (CH) system loaded with GM-CSF trolled by compositional changes to the copolymer. This class and a cancer drug was utilized as a chemo-immunotherapeutic of NP can be prepared from a range of polymers including poly agent in an effort to assess the anti-tumor effects in mice model. (α-hydroxy acids), poly (amino acids), or polysaccharides to cre- The growth of TC-1 tumors was signif icantly reduced in mice ate a vesicle which can either accommodate or display antigens. treated with a CH harboring a cancer drug (doxorubicin: DOX), Chitosan can be formulated in a variety of forms such as pow- cisplatin (CDDP) or cyclophosphamide (CTX), and GM-CSF der, film, sphere, gel, and fiber. Chitosan nanoparticles showed (CH-a cancer drug + GM-CSF), as compared with other groups selectivity for tumor cells. Studies have indicated significant that were treated with CH containing only a cancer drug (CH-a differences in antitumor activity of nanoparticles prepared by cancer drug) or GM-CSF (CH-GM-CSF). chitosan from different producers. Nanogels are nanosized Curcumin, a polyphenolic compound found in the spice tur- hydrogel particles formed by physical or chemical cross-linked meric, has been found to exert preventive and therapeutic effects 79 81 polymer networks. The materials used for the preparation of in various cancers. It is able to inhibit the growth of breast can- nanogels ranged from natural polymers like ovalbumin, pullu- cer cell lines in a dose dependent manner and induces an increase lan, hyaluronic acid, methacrylated chondroitin sulfate and chi- in the percentage of cells in sub-G0 phase, representing the apop- tosan, to synthetic polymers like poly (N-isopropylacrylamide), totic cell population. Curcumin is being applied to a number poly (N-isopropylacrylamide-co-acrylic acid), and poly (ethylene of patients with breast cancer, rheumatoid arthritis, Alzheimer 79 83 glycol)-b-poly (methacrylic acid). disease, colorectal cancer, and psoriatic. Various basic and The mechanism of nano-particles formation is based on elec- clinical studies elucidated curcumin’s limited efficacy due to its trostatic interaction between amine group of chitosan and nega- low solubility, high rate of metabolism, poor bioavailability, and tively charge group of polyanion such as tripolyphosphate. This pharmacokinetics. technique offers a simple preparation method in the aqueous Recently, the polymeric nanoparticle encapsulated curcumin environment. In order to improve targeting and bioavailability (nanocurcumin) is under development for cancer therapy and of chitosan nano-particles, an increasing number of studies are also to overcome these challenges. In addition, curcumin focusing on modification of chitosan. Modified chitosan nano- loaded biodegradable self-assembled polymeric micelles have particles are characterized by pH sensitivity, thermosensitivity, been developed to overcome poor water solubility of curcumin 36 86 and targeting accuracy. and to meet the requirement of intravenous administration. Generally, chitosan possesses some ideal properties of poly- In an experiment, our group tested tumor inhibition rates of a meric carriers for nanoparticles such as biocompatible, biode- chitosan hydrogel system loaded with curcumin (nanocurcumin) gradable, nontoxic, and inexpensive. Furthermore, it possesses on breast cancer MCF-7 cells. Cytotoxicity study showed that positively charge and exhibits absorption enhancing effect. The the encapsulated curcumin remained its potent anti-tumor reports mentioned the preparation of pH-responsive chitosan- effect. IC-50 was calculated 23% and 44% after 48 h and 72 h, based microgels (<200 nm diameter) by ionically cross-linking respectively (unpublished data, 2013). The studies showed that N-[(2-hydroxy-3-trimethylammonium) propyl] chitosan chlo- curcumin treatment could display anti-proliferative and pro- ride in the presence of tripolyphosphate. These microgels were apoptotic activities and induce cell cycle arrest at G2/M phase. 328 Human Vaccines & Immunotherapeutics Volume 10 Issue 2 ©2014 Landes Bioscience. Do not distribute. Brief ly, polymeric nano-particles have long been chosen as carri- safe. Furthermore, the immunosuppressive microenvironment of ers for systemic and targeted drug delivery. The ability of these tumor should be blocked by inhibitors using different delivery sys- particles to circulate in the bloodstream for a prolonged period of tems, as a promising application in cancer immunotherapy. time is often a prerequisite for successful targeted delivery. The Future and Alternative Directions present results suggest that a combinational coating of PEG and chitosan may represent a significant step in the development of long-circulating drug delivery carriers for tumor drug delivery. Nanoparticles can be engineered to either avoid immune sys- PLGA nanoparticles are widely used for the delivery of vari- tem recognition or specifically inhibit or enhance the immune ous chemotherapeutic agents (especially hydrophobic drugs) responses. Some formulations are already in clinical trials, to the target site. However, rapid opsonization by cells of the whereas many others are in various phases of preclinical develop- phagocytic system is a major limitation for achieving effective ment. Although in recent years, our understanding of nanopar- drug targeting to the site of action by PLGA nanoparticles. Thus, ticle interaction with components of the immune system has to maximize the therapeutic benefits of drug loaded nanopar- improved; many questions still require being clear. Further mech- ticles, they should be able to evade the reticuloendothelial sys- anistic studies investigating particle immunomodulatory effects tem (RES). This can be done through the use of various surface (immunostimulatory and immunosuppression) are required to coatings of hydrophilic polymers, as opsonization of hydrophobic improve our understanding of the physicochemical parameters nanoparticles may occur more quickly in comparison to hydro- of nanoparticles that define their effects on the immune system. philic nanoparticles due to the enhanced adsorption of opsonins Development of delivery system remains a critical area for on their surfaces. future research. Important areas for future research include modifying viral vectors to reduce toxicity and immunogenic- Perspectives: Myths and Facts ity, increasing the transduction efficiency of non-viral vectors, enhancing vector targeting and specificity, regulating gene Different NP delivery systems have been described, each expression, and identifying synergies between gene-based agents offering advantages over current methods of vaccine delivery. and other cancer therapeutics. As known, DNA vaccination indi- Nanotechnology platforms are being investigated as vaccine car- cates great potential for combating a variety of diseases. Initial riers, adjuvants, and drug delivery systems to target inflamma- results are promising and some technologies have advanced to tory and inf lammation-associated disorders. Recently, researchers clinical trials. However, safe and efficient delivery of plasmid started to understand the effects of particle size, surface charac- DNA to initiate immune responses remains a major barrier in teristics, and material interactions with the innate immune sys- bringing DNA vaccination into human medicine. Development tem. Investigating of the underlying biological mechanisms of of novel nonviral delivery strategies for DNA vaccines must con- DNA vaccination requires strategies that can isolate one polymer tinue to serve as both methods of biological insight and clini- function from another, such as DNA release kinetics and trans- cally relevant outcomes. Specific concerns include the observed fection efficiency. Future development of polymeric and other difficulty in transfecting DCs, methods to target APC uptake synthetic materials must focus on these considerations for DNA and lymph node trafficking, and providing strong danger signals vaccination. without sacrificing biocompatibility. Rather than conventional vaccines which use whole microbes In addition, self-assembling synthetic vectors for DNA deliv- (live or killed), this new generation of vaccines use components ery are designed to perform several biological functions. They of microbes to elicit an immune response and mimic the way in must be able to deliver their genetic load specifically to the tar- which these antigens would be delivered during a natural infec- get tissue in a site-specific manner, while protecting the genetic tion. Often these antigens are poor immunogens on their own material from degradation by metabolic or immune pathways. and thus require an adjuvant to boost the immune response. NPs Furthermore, they must exhibit minimal toxicity and be proven provide an alternate method for antigen delivery which not only safe enough for therapeutic use. Ultimately, they must have the activates different elements of the immune system but also have capability to express a therapeutic gene for a limited period of good biocompatibility. Delivering antigens in different ways also time in an appropriate fashion. The whole process presents many has a profound effect on the resulting immune response, whether barriers at both tissue and cellular levels. Overcoming these hur- the antigen is decorated on the NP surface for presentation to anti- dles is the principal objective for efficient polymer-based DNA gen-presenting cells or encapsulated for slow release and prolonged therapeutics. exposure to the immune system. Recently, the enhancement of Many nanoparticles appear to show some toxicity in various vaccine potency through the use of different delivery systems (e.g., cell types. Regarding to the use of nanoparticles in pharmaceuti- NPs) is underway. However, this novel and promising approach cal and other biomedical applications, the putative cytotoxicity of (polymeric NPs) should be improved as an efficient delivery system such particles should be eliminated. As the active antitumor com- for gene, drug, and vaccine in future as well as focusing on the ponents of plant drugs are being constantly discovered, develop- modification of their structures to reduce toxicity and overcome ment of targeted polymeric carriers (e.g., chitosan) for controlled in vivo barriers. Recent preclinical and clinical studies reflect the release plant drugs is also an area of future studies. effects of immunotherapy in combination with chemotherapy as a Brief ly, cationic polymers are the subject of critical research as potential approach to specifically target cancer leaving normal cells non-viral gene delivery systems, due to their flexible properties, www.landesbioscience.com Human Vaccines & Immunotherapeutics 329 ©2014 Landes Bioscience. Do not distribute. simple synthesis, and proven gene delivery efficiency. However, hydrophobic modif ications of the cationic polymers are receiving low transfection efficiency and undesirable cytotoxicity remain more attention. the most challenging aspects of these cationic polymers. To over- Disclosure of Potential Conf licts of Interest come the disadvantages, various modifications have been made to improve their gene and vaccine delivery eff icacy. Among them, No potential conf licts of interest were disclosed. 18. Hébert E. Improvement of exogenous DNA nuclear 31. Shi C, Zhu Y, Ran X, Wang M, Su Y, Cheng T. References importation by nuclear localization signal-bearing Therapeutic potential of chitosan and its derivatives 1. Tiyaboonchai W. Chitosan nanoparticles: A prom- vectors: a promising way for non-viral gene therapy? in regenerative medicine. J Surg Res 2006; 133:185- ising system for drug delivery. 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Yallapu MM, Jaggi M, Chauhan SC. Curcumin org/10.1016/j.vaccine.2003.09.044 PMID:14754702; http://dx.doi.org/10.1097/01. nanomedicine: a road to cancer therapeutics. Curr 68. Roy K, Mao HQ, Huang SK, Leong KW. Oral gene AOG.0000110246.93627.17 Pharm Des 2013; 19:1994-2010 ; PMID:23116309 delivery with chitosan--DNA nanoparticles generates immunologic protection in a murine model of peanut allergy. Nat Med 1999; 5:387-91; PMID:10202926 ; http://dx.doi.org/10.1038/7385 www.landesbioscience.com Human Vaccines & Immunotherapeutics 331 ©2014 Landes Bioscience. Do not distribute. 85. Zou P, Helson L, Maitra A, Stern ST, McNeil SE. 87. Jiang M, Huang O, Zhang X, Xie Z, Shen A, Liu Polymeric curcumin nanoparticle pharmacokinetics H, Geng M, Shen K. Curcumin induces cell death and metabolism in bile duct cannulated rats. Mol and restores tamoxifen sensitivity in the anties- Pharm 2013; 10:1977-87; PMID:23534919; http:// trogen-resistant breast cancer cell lines MCF-7/ dx.doi.org/10.1021/mp4000019 LCC2 and MCF-7/LCC9. Molecules 2013; 18:701- 20 ; PMID:23299550 ; http://dx.doi.org/10.3390/ 86. Liu L, Sun L, Wu Q, Guo W, Li L, Chen Y, Li Y, molecules18010701 Gong C, Qian Z, Wei Y. Curcumin loaded polymeric micelles inhibit breast tumor growth and spontaneous 88. Parveen S, Sahoo SK. Long circulating chitosan/PEG pulmonary metastasis. Int J Pharm 2013; 443:175- blended PLGA nanoparticle for tumor drug delivery. 82; PMID:23287774; http://dx.doi.org/10.1016/j. Eur J Pharmacol 2011; 670 :372-83 ; PMID :21951969; ijpharm.2012.12.032 http://dx.doi.org/10.1016/j.ejphar.2011.09.023 332 Human Vaccines & Immunotherapeutics Volume 10 Issue 2 ©2014 Landes Bioscience. Do not distribute. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Human Vaccines & Immunotherapeutics Taylor & Francis

Polymeric nanoparticles

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Abstract

ReVIew Human Vaccines & Immunotherapeutics 10:2, 321–332; February 2014; © 2014 Landes Bioscience Potent vectors for vaccine delivery targeting cancer and infectious diseases 1, 1,2 3 2 1 Azam Bolhassani *, Shabnam Javanzad , Tayebeh Saleh , Mehrdad Hashemi , Mohammad Reza Aghasadeghi , and Seyed Mehdi Sadat 1 2 Department of Hepatitis and AIDs; Pasteur Institute of Iran; Tehran, Iran; Department of genetics; Islamic Azad University; Tehran Medical Branch; Tehran, Iran; Department of Nanobiotechnology; Faculty of Biological Sciences; Tarbiat Modares University; Tehran, Iran Keywords: non-viral vectors, natural polymer, synthetic polymer, gene therapy, vaccine delivery may be in a condensed or non-condensed form, depending on the Nanocarriers with various compositions and biological prop- nature of the polymer and the method used for formulating the erties have been extensively applied for in vitro/in vivo drug and vector system. Recently, researchers have focused on biodegrad- gene delivery. The family of nanocarriers includes polymeric able carrier systems. The potential advantage of biodegradable nanoparticles, lipid-based carriers (liposomes/micelles), den- carriers compared with their non-degradable counterparts is their drimers, carbon nanotubes, and gold nanoparticles (nanoshells/ reduced toxicity and the prevention of the polymer accumula- nanocages). Among different delivery systems, polymeric car- riers have several properties such as: easy to synthesize, inex- tion in the cells after repeated administration. Furthermore, the pensive, biocompatible, biodegradable, non-immunogenic, degradation of the polymer can be used as a tool to release the non-toxic, and water soluble. In addition, cationic polymers plasmid DNA into the cytosol. Efficient non-viral gene delivery seem to produce more stable complexes led to a more protec- based on cationic polymers as DNA condensing agents is depen- tion during cellular trafficking than cationic lipids. dent on a variety of factors such as complex size, complex stability, Nanoparticles often show significant adjuvant effects in toxicity, immunogenicity, protection against DNase degradation vaccine delivery since they may be easily taken up by antigen and intracellular trafficking, and processing of the DNA. presenting cells (APCs). Natural polymers such as polysac- The nanoparticles (size <1000 nm) such as virus-like particles, charides and synthetic polymers have demonstrated great liposomes, the immuno-stimulating complexes (ISCOMs), poly- potential to form vaccine nanoparticles. The development of meric, and non-degradable nanospheres have received attention new adjuvants or delivery systems for DNA and protein immu- nization is an expanding research field. This review describes as potential delivery vehicles for vaccine antigens which can both polymeric carriers especially PLGA, chitosan, and PeI as vaccine stabilize vaccine antigens and act as adjuvants. Importantly, some delivery systems. of these nanoparticles are able to enter antigen presenting cells (APCs) by different pathways, thereby modulating the immune response to the antigen. This may be critical for the induction of protective Th1-type immune responses to intracellular patho- Introduction gens. Different polymers were used in solid particulate vaccine delivery. The vaccine antigen is either encapsulated within or Nanoparticles (NPs) are solid colloidal particles with diam- decorated onto the surface of the NP. By encapsulating antigenic eters ranging from 1–1000 nm. They consist of macromolecular material, NPs provide a method for delivering antigens which materials and can be used therapeutically as adjuvant in vaccines may otherwise degrade rapidly upon injection or induce a short- 1,2 or as drug carriers. Polymers are the most common materials lived, localized immune response. Conjugation of antigens onto for constructing nanoparticle-based drug carriers. One of the NPs can allow presentation of the immunogen to the immune earliest reports of their use for cancer therapy dates back to 1979 systems at the same way that it would be presented by the patho- when adsorption of anticancer drugs to polyalkylcyanoacrylate gen, thereby generating a similar response. nanoparticles was studied. Polymers used to form nanoparticles Generally, there are obstacles in manufacturing, formulation can be both synthetic and natural polymers. These nanocarriers and stability of polymers, in vitro and problems of extracellu- have been demonstrated for a variety of applications such as drug lar nonspecific interactions and intracellular trafficking to the 3 9 delivery, imaging, and detection of apoptosis. nucleus, in vivo. Recent efforts include the development of new Many cationic polymers have been studied both in vitro and polymers for gene delivery, the modification of traditional poly- in vivo for gene delivery. The DNA encapsulated in polymers cations with hydrophilic polymers for salt and serum stability and the addition of bioactive molecules to polymers for enhanced intracellular trafficking. Herein, we describe the roles of poly- *Correspondence to: Azam Bolhassani; Email: [email protected] meric constructs in vaccine delivery as well as gene and drug Submitted: 06/25/2013; Revised: 10/06/2013; Accepted: 10/12/2013; delivery in vitro and in vivo. Published Online: 10/15/2013; http://dx.doi.org/10.4161/hv.26796 www.landesbioscience.com Human Vaccines & Immunotherapeutics 321 ©2014 Landes Bioscience. Do not distribute. Figure 1. Schematic illustration on different vectors-mediated gene delivery. Polymeric Nanoparticles in Vaccine Delivery into the nucleus through nuclear pore complexes can be medi- ated by the presence of nuclear localization sequences (NLS) on Polymeric microparticles or nanoparticles have applied to proteins. If the vector contains one or several NLS, either as deliver genes especially in vaccine design (e.g., DNA vaccines). covalently or non-covalently DNA-linked peptides, a competi- Moreover, gene therapy has shown an excellent potential to help tion may take place between the rate of dissociation of the DNA- patients in a variety of disease conditions. Various strategies can vector complexes and the rate of loading of the complexes to be used in cancer gene therapy. Some of the gene therapy strat- the NLS-mediated nucleus importation machinery. Moreover, egies to kill or slow down growth of cancer cells are included since the cytosolic release of heterologous DNA is a prerequisite (1) Immunomodulation; (2) Prodrug activation; (3) Anti-sense/ for nuclear translocation, entrapment, and degradation of plas- RNAi, and (4) Induction of apoptosis. However, the lack of mid DNA in endolysosomes constitute a major barrier to effi- suitable vectors for the delivery of nucleic acids (e.g., DNA and cient gene transfer. siRNA), especially in vaccine development, represents a major The polyplexes which are formed between cationic polymers problem to their therapeutic application. Gene delivery systems and DNA through electrostatic interactions and thus known as include viral vectors, cationic liposomes, polycation complexes, polycation/DNA complexes are widely used as non-viral gene and microencapsulated systems. The failure of viral gene therapy delivery vectors. Many factors such as molecular weight (MW), in clinical trials due to toxicity, immunogenicity, and carcinoge- surface charge, charge density, hydrophilicity, and the structure nicity strongly motivates a non-viral approach. Synthetic vectors of cationic polymers affect gene transfection eff iciency of cationic based on polycations are promising vectors for gene delivery as polymers. Therefore, optimization of cationic polymers is nec- they are relatively safe and can be modified by the incorporation essary to improve the gene transfection efficiency. Currently, of ligands for targeting to specific cell types. However, the levels several important cationic polymers were used for gene delivery of gene expression mediated by synthetic vectors are low com- such as Polyethylenimine (PEI), PLL, Chitosan, and PAMAM. pared with viral vectors. Several vectors have been developed in Some strategies including PEGylation, combination, and mul- order to target genes to specific cells as shown in Figure 1. tifunctional modification were developed in the cationic poly- As known, a perfect gene vector includes four conditions: meric vectors. (1) be able to condense DNA effectively; (2) be stable in body Polyethylenimine (PEI) and DNA/ RNA transfection fluid; (3) be able to target the specific cells, and (4) be able to PEI is a cationic polymer widely used for nucleic acid deliv- 16 21 cross membranes and release efficiently. Strategies for over- ery. It is particularly promising vector with relatively high level of coming some of these barriers have resulted in polymer/DNA transfection in a number of target organs. The high charge density complexes with increased stability and delivery efficiencies. of PEI is thought to be a key factor that contributes to its high In addition, trafficking of nuclear proteins from the cytoplasm transfection efficiency. On the other hand, the polycationic nature 322 Human Vaccines & Immunotherapeutics Volume 10 Issue 2 ©2014 Landes Bioscience. Do not distribute. Figure 2. Functions of two important examples of current cationic polymers (PeI and chitosan) as non-viral gene delivery vectors. of PEI also appears to be the main origin of its toxicity, similar to Adsorption of nucleic acid onto cationic nanoparticles is one of many other polycations (e.g., polylysine). This toxicity has limited the approaches used for DNA or RNA delivery. This technique its use as a gene delivery vector in vivo. Therefore, the success of facilitates the immediate release of DNA or RNA at target site. gene transfection is dependent on the development of vectors that Furthermore, the preparations of polymer and DNA/RNA can efficiently deliver a gene to cells with minimum toxicity. The complexes by adsorption can avoid the chemical effects used studies have shown that PEI derivatives obtained by cross-linking in other approaches such as encapsulation. For example, PEI low-molecular weight PEI with degradable materials display higher possesses very high positive charges from amines in molecules transfection efficiency and lower cytotoxicity. For example, in which can form complexes with phosphate groups of nucleic order to develop new polymeric gene vectors with low cytotoxicity acids through electrostatic interaction. The complexes can be and high gene transfection efficiency, a cationic polymer was com- later delivered into the cell through endocytosis. PEI is consid- posed of low molecular weight PEI (MW ~600 Da) cross-linked ered to be the most effective cationic polymer due to its buffering by 2-hydroxypropyl-g-cyclodextrin (HP-g-CD) and then coupled capacity via the proton sponge effect. Its high proton-buffering to MC-10 oligopeptide containing a sequence of Met-Ala-Arg-Ala- capacity results in rapid osmolysis of the endosomes and the PEI/ Lys-Glu at a molar ratio of 1:3.3:1.2. DNA complexes escape into the cytosol and are subsequently This new gene vector was able to target delivery of genes to transported into the nucleus (Fig. 2). HER2 positive cancer cells for gene therapy. Furthermore, water- In a study, Heparin-PEI (HPEI) nanoparticles were used to soluble lipopolymer (WSLP) consisting of a low molecular weight deliver plasmid-expressing mouse survivin-T34A (ms-T34A) PEI and cholesterol was employed for in vivo gene therapy of can- to treat C-26 carcinoma in vitro and in vivo. According to the cer or ischemic myocardium. The Preformed PEI/DNA complexes in vitro studies, HPEI nanoparticle-mediated ms-T34A could were encapsulated in PEG stabilized liposomes resulting in the so- efficiently inhibit the proliferation of C-26 cells by induction of called “pre-condensed stable plasmid lipid particle” (pSPLP). apoptosis. Moreover, intra-tumoral injection of HPEI nanoparti- Currently, cell penetrating peptides (CPPs) have also been cle-mediated ms-T34A significantly inhibited growth of subcu- used to enhance the intracellular delivery of DNA by PEI and/ taneous C-26 carcinoma in vivo by induction of apoptosis and 24 29 or dendrimers. Our group showed that two delivery systems inhibition of angiogenesis. including PEI 25 kDa and PEI600-Tat conjugates are efficient Chitosan and DNA transfection tools for HPV16 E7 gene transfection. Although the level of Chitosan, produced by deacetylation of chitin, is a non- transfected COS-7 cells is higher using PEI 25 kDa in com- toxic and hydrophilic polysaccharide. Commercially, chitin and parison with PEI600-Tat, but its toxicity was obstacle in vivo. chitosan are obtained from shellfish sources such as crabs and Transfection experiments demonstrated that the use of PEI600- shrimps. Chitosan and its derivatives could accelerate wound Tat conjugates was more effective than the two compounds with- healing by enhancing the functions of inflammatory cells and out chemical conjugation. Furthermore, the newly developed repairing cells. Recent studies further indicated that chitosan conjugates maintain the desirable property of low cytotoxicity and its derivatives are used as a carrier of DNA for gene deliv- displayed by lower molecular weight PEI polymers and Tat pep- ery applications. It is able to condense nucleic acid into stable tides. It has been confirmed that a type of low molecular weight complexes (100 –250 nm in diameter), which protects DNA from polymer, so-called PEI (MW <2000 Da), covalently coupled to degradation by nuclease. The DNA/polymer complexes are Tat was able to improve Tat peptide mediated gene delivery as taken up into the cells via endocytosis into the endosomes, fol- 26,27 chloroquine. lowing with burst release of complexes fraction in endosomes and www.landesbioscience.com Human Vaccines & Immunotherapeutics 323 ©2014 Landes Bioscience. Do not distribute. 32 the DNA translocates into the nucleus (Fig. 2). Chitosan could The researchers have analyzed the production of pro-inflam- be a useful oral gene carrier because of its adhesive and transport matory cytokines (TNF-α, IFN-γ, IL-6, IL-12/IL-23, IFN-β, properties in the GI tract. Although most chitosans are able to and IL-1β) and hepatic enzyme levels (alanine aminotransferase, form polyplexes, the transfection efficiency of chitosans depends aspartate aminotransferase, lactate dehydrogenase, and alkaline on structural variables such as the fraction of acetylated units, phosphatase) in the blood serum of mice after systemic injec- the degree of polymerization, the chain architecture and chemi- tion of DNA or siRNAs delivered with L-PEI. The data showed cal modifications. On the other hand, the researchers found no major production of pro-inflammatory cytokines or hepatic that in vitro chitosan-mediated transfection depends on the cell enzymes after injection of DNA or oligonucleotides active for type, serum concentration, pH, and molecular weight of chito- RNA interference (siRNAs or sticky siRNAs) complexed with san. For example, Hela cells were efficiently transfected by this L-PEI. Only a slight induction of IFN-γ was detected after system even in the presence of 10% serum. In contrast, chitosan DNA delivery, which is probably induced by the CpG mediated has not been able to transfect HepG2 human hepatoma cells and response. Altogether, the results highlighted that linear PEI is a BNLCL2 murine hepatocytes. The transfection efficiency was delivery reagent of choice for nucleic acid therapeutics. found to be higher at pH 6.9 than that at pH 7.6. Indeed, at Using nanoparticles to deliver antigens, the efficiency of pH < 7, amine groups of chitosan are protonated which facilitate uptake into dendritic cells is significantly increased compared the binding between complexes and negatively charged cell sur- with soluble antigen alone. Particle shape and surface charge face. Moreover, transfection efficiency mediated by chitosan of are also important physicochemical factors playing critical roles high molecular weight (MW) > 100 kDa is less than that of low in the interaction between particles and antigen-presenting cells MW ~15 and 52 kDa. (APCs). Generally, cationic particles are taken up into cells much Although, chitosan successfully transfected cells in vitro, the more readily than those with an overall negative surface charge transfection efficiency showed to be lower than that of other cat- due to the anionic nature of cell membranes. When NPs as poly 1,28 ionic polymer vehicles such as PEI. One of the primary causes (amino acid) with encapsulated ovalbumin were used to immu- of poor gene delivery eff iciency is the insuff icient release of chito- nize mice, significantly higher levels of total IgG, IgG1, and sans from endosomes into the cytoplasm. Two approaches have IgG2a as well as IFN-gamma (stimulator of Ig class switching to been developed to increase transfection efficiency of chitosan IgG2a) were induced as compared with those in soluble ovalbu- nanoparticles: (1) Enhancement of chitosan solubility and (2) min, suggesting the particles have the ability to prime humoral 1 7 Attachment of cell targeting ligands to the chitosan particles. As and cellular immune responses. In this line, chitosan could act known, chitosan is insoluble at physiological pH and also it lacks on tumor cells directly to interfere with cell metabolism, inhibit charge. Thus, for development of an efficient gene vector with cell growth, and induce cell apoptosis. Chitosan induced apop- high transfection and low cytotoxicity, amphiphilic chitosan tosis of bladder tumor cells via caspase-3 activation. In addi- was linked with low-molecular weight PEI. In addition, a liver tion, it showed an anti-tumor role through improving the body’s cancer-targeted specific peptide (FQHPSF sequence) was bound immune function. Indeed, hydrophilic polysaccharide poly- with chitosan-linked PEI (CP) to form a new targeted gene deliv- mers are also good candidates for vaccine delivery with both dex- ery vector called CPT (CP/peptide). The vector showed low tran and chitosan being chosen for preparing NPs. On the other cytotoxicity and strong targeting specificity to liver tumors in hand, PEI /DNA complexes (“polyplexes”) conjugated with the vitro. The in vivo results showed that IL-12 delivered by CPT cell-binding ligand transferrin (Tf ) or epidermal growth factor (CPT/DNA) significantly enhanced the antitumor effects on (EGF) were used to achieve receptor-mediated endocytosis. The ascites tumor bearing mice as compared with PEI 25 kDa and surface charge of the complexes was masked by covalently linking CP as a control. PEI to polyethylene glycol (PEG). Intravenous injection of Tf– PEI and chitosan as immune stimulators PEG-coated polyplexes resulted in gene transfer to subcutane- Vaccination is cost-effective and the best prophylactic strategy ous neuroblastoma tumors of syngeneic A/J mice. Furthermore, against most diseases. Vaccines are the preparations given to EGF-PEG coated polyplexes were intravenously applied for patients to stimulate immune responses leading to the production targeting human hepatocellular carcinoma xenografts in SCID of humoral or cell-mediated responses that will combat infectious mice. In this line, our group showed that the mixture of a agents or non-infectious conditions such as tumors. Vaccines DNA vaccine expressing HPV16 E7 with PEI600-Tat cojugate may be prophylactic (e.g., to prevent the effects of a future infec- is immunologically more potent than E7 alone. Indeed, binding tion by pathogens) or therapeutic (e.g., vaccines against cancer). of cationic peptide (Tat)-polymer (PEI) to plasmid DNA encod- Attempts are being made to deliver vaccines through carriers as ing an antigen (E7) enhanced the uptake of the plasmid DNA they control the presentation of antigens to immune system thus and consequently induced both humoral and cellular immune leading to their prolonged release and targeting. Thus, lower responses in vaccinated mice. Our observations illustrated the doses of weak immunogens can be effectively directed to stimu- ability of PEI-Tat conjugate to augment immune responses in late immune responses and eliminate the need for the admin- vivo. Herein, the ratio of PEI600-Tat/E7DNA complex forma- istration of prime and booster doses as a part of conventional tion has significant influence on the level of protein expression 8 39 vaccination regimen. and consequently immune responses in C57BL/6 mice model. The previous studies demonstrated that the linear PEI (L-PEI) Generally, interactions of cationic polymers with the immune is being more efficient in vivo than the branched PEI (B-PEI). systems are rarely studied. Agonists of toll like receptors (TLRs) 324 Human Vaccines & Immunotherapeutics Volume 10 Issue 2 ©2014 Landes Bioscience. Do not distribute. are potential therapeutic reagents for cancer immunotherapy. the ability to activate innate immune cells and induce cytokine Cationic polymers have signif icant immunological activity medi- and chemokine production. The cell surface receptors include ated by TLRs. The studies indicated that cationic polymers macrophage mannose receptor, TLR-2, C-type lectin receptor including PEI, polylysine, cationic dextran and cationic gelatin Dectin-1 and leukotriene B4 receptor (BLT1). In addition, intra- specifically stimulate the macrophage to secrete IL-12 which is peritoneal injection of chitin particles induced adaptive Th2, one of the main Th1-inducing cytokines. Cationic polymers Th1, and Th17 immune responses. TLR-2, MyD88, and IL-17A could interact with macrophages through TLR-4 which is the have been proved to play important roles in the adjuvant proper- receptor of LPS. The stimulation ability of cationic polymer was ties of chitin and chitosan. It is believed that chitosan enhances related with their cationic degree and molecular weight. Larger both humoral and cell-mediated immune responses e.g., in sub- molecular weight and higher positive charge of polymers exhib- cutaneous vaccination. In addition, recombinant granulocyte- ited stronger stimulation ability. Additionally, the cationic macrophage colony-stimulating factor (rGM-CSF) accelerates polymers such as PEI and cationic dextran could reverse tumor- neutrophil recovery in cancer patients receiving chemotherapy. associated macrophages (TAMs) polarization and promote IL-12 When it co-formulated with chitosan, local rGM-CSF retention expression both in vitro and in vivo. Indeed, these cationic at a subcutaneous injection site was increased in mice for up to 9 polymers exerted direct tumoricidal activity by promoting Th1 d. In contrast, when delivered in a saline vehicle, rGM-CSF was and NK cell infiltration, suppressing tumor angiogenesis, and undetectable in 12–24 h. This indicated that chitosan helped to 41 44 prolonging the survival of sarcoma-bearing wild-type mice. control the distribution of rGM-CSF. As known, IL-12 is a potent anti-tumor cytokine that exhibits Poly (lactic-co-glycolic acid) and immunity significant clinical toxicities following systemic administration. Biodegradable polymers such as poly (lactic-co-glycolic acid) A study showed that intra-tumoral administration of IL-12 co- (PLGA) are also being developed for matrix antigen delivery. formulated with the biodegradable polysaccharide chitosan could PLGA microspheres are rapidly taken up by M-cells and trans- enhance the anti-tumor activity of IL-12 in mice bearing estab- located toward the underlying lymphatic tissue within 1 h. For lished colorectal (MC32a) and pancreatic (Panc02) tumors while instance, the loading of Hepatitis B core antigen into PLGA limiting its systemic toxicity. Chitosan/IL-12 is a well-tolerated, NPs (300 nm) induced a stronger cellular immune response as effective immunotherapy with considerable potential for clinical compared with Hepatitis B core antigen alone in a mouse model. trials. Vaccine immunotherapy using a specific antigen, such as Particle size plays an important role in directing the immune prostate specific antigen (PSA) led to stimulate both the innate response. Immunization with PLGA NPs (200–600 nm) was and adaptive immune systems to destroy tumor cells in the body. associated with higher levels of IFN-γ production related to a An adenovirus encoding PSA (Ad-PSA), as a viral gene delivery Th1 response. In contrast, immunization with PLGA mic- system could stimulate anti-tumor activity. To enhance trans- roparticles (2–8 μm) promoted IL-4 secretion related to a Th2 fection efficiency, the combination of this system with a cationic response. The studies have indicated that both PLGA NPs and polymer such as PEI or chitosan was applied. In fact, cationic liposomes are efficiently phagocytosed by dendritic cells in cul- polymers could complex with the negatively charged adenovirus ture, resulting in their intracellular localization. However, the to form nanoparticles. To further augment immune response, use of PLGA can be limited by acid hydrolytic degradation prod- CpG sequences were used as an adjuvant delivered in particulate ucts detrimental to the entrapped protein and loss of immunoge- form. In this line, the studies demonstrated that the adenovirus nicity on storage. Also, organic solvents used to load the antigen encoding OVA (AdOVA) as a model antigen, coupled with PEI, onto the polymer can be detrimental to the antigen. increased tumor protection in vivo compared with AdOVA alone. Formulation of DNA into both liposomal and polymeric cat- In addition, AdOVA + CpG showed the best tumor protection ionic nanoparticles completely blocks vaccination-induced anti- in therapeutic studies. In other set of experiments, AdOVA + gen expression in mice and ex vivo human skin. Furthermore, this chitosan + CpG represented a decrease in protective levels and negative effect of cationic nanoparticle formulation is associated antigen-specific immune responses. Indeed, the kinetic stud- with a complete block in vaccine immunogenicity. The reports ies showed that peak levels of effector T cells were present 14 d showed that shielding of the surface charge of the nanoparticles later in AdPSA + CpG immunized mice than in AdPSA alone. by PEGylation improves in vivo antigen expression more than 55 This delayed effect may explain the increased levels of protec- fold. Furthermore, this shielding of cationic surface charge results tion in AdPSA + CpG mice against AdPSA + chitosan + CpG. in antigen-specific T cell responses similar to those induced by The data are useful in vaccine design concerning the timing of naked DNA for both lipoplex and polyplex DNA carrier systems. peak response. Recently, cancer vaccine has become a novel These observations suggest that charge shielding forms a useful modality for cancer treatment and the important role of adju- strategy for the development of dermally vaccine formulations. vant has been realized. Chitin, chitosan, and their derivatives are Polymeric Vaccine Delivery Systems in Clinical Trials important adjuvants for immunotherapy. Based on their prin- cipal mechanisms of action, adjuvants can be generally divided into two classes: (1) vaccine delivery systems such as mineral The considerable research on microparticle-based vaccines salts, emulsions, liposomes, and virosomes; (2) immunostimula- has generated a number of strategies based on optimizing antigen tory adjuvants including toll-like receptor (TLR) agonists (e.g., release rates to produce single dose delivery systems. For exam- monophosphoryl lipid A), saponins and cytokines. Chitin has ple, pulse release of antigen from biodegradable microparticles is www.landesbioscience.com Human Vaccines & Immunotherapeutics 325 ©2014 Landes Bioscience. Do not distribute. Table 1. DNA vaccine delivery system Delivery system Disease Administration Status Ref. Polymeric microparticle-based platforms PLGA HIV IM Novartis, phase I 53 PLGA Solid tumors IM Preclinical 54, 55 PLGA (amolimogene/ZYC101a) HPV cervical neoplasia IM MGI pharma, phase II/III 56–58 Measles virus IM Preclinical 59 PLGA w/cetyltrimethylammonium FMDV ID, I M, IN Veterinary use 60 bromide (CTAB) HCV IM Preclinical 61 PLGA microspheres w/ PeI nanoparticles Model antigens Oral/IM Preclinical 62, 63 PLGA w/PeI coating B cell lymphoma ID, IM Preclinical 64, 65 PLGA w/PBAe Tumor antigen ID Preclinical 66 Polymeric nanoparticle-based platforms Allergy, RSV, Chitosan IN, Oral, Pulm Preclinical 67–69 tuberculosis Genetic Immunity, PeI-mannose HIV Transdermal 70 phase I/II IN, intranasal; IM, intramuscular; ID, intradermal; Pulm, pulmonary. considered advantageous for simulating the conventional, multi- (IM) and ID PLGA–PEI vaccination routes provided protection dose vaccine delivery regime. However, most microparticulate against lymphoma tumor challenge, IM vaccination was more delivery systems are considered to function on the principles of efficient among vaccination routes. On the other hand, PLGA efficient phagocytosis and transport to the lymph nodes and sus- can also be used to encapsulate and release pre-formed PEI–DNA tained antigen release over extended time periods which may pres- nanoparticles. Microspheres release DNA in PEI–DNA nanopar- 46,47 ent a continuous leakage of antigen to the immune system. ticle with kinetics similar to that of simple PLGA microparti- Cationic polymers and DNA vaccines cles and also efficiently transfect non-phagocytic cells as well as Within a decade, a myriad of potential applications of DNA APCs. It was demonstrated that PLGA-PEI-DNA microspheres vaccines developed targeting infectious agents, various cancers, increase humoral responses compared with naked DNA follow- allergy and immune dysfunction and by 1998 early clinical tri- ing IM vaccination and can induce efficient CTL responses at als reported induction of immune responses against HIV and doses lower than that obtained with naked DNA vaccination. malaria in humans. The only licensed and approved DNA-based Almost 100 Phase I and II clinical trials have confirmed the 48 49 vaccines are for animal use. One targets flavivirus (West Nile safety of DNA vaccines in humans. PLGA is one of the most virus) infection in horses and has also been used to protect wild widely studied polymers of interest in the vaccine field. For Californian condors; the other has been used to protect com- instance, to increase the efficacy of DNA-based vaccines, DNA mercial salmon against infectious hematopoietic necrosis virus. encoding hepatitis B surface antigen (HBsAg)-encapsulated for- Surface DNA loading can be facilitated by supplementation mulation of PLGA nanoparticles could induce enhanced immu- with the cationic surfactant cetyltrimethylammonium bromide nity in mice. In addition, PLG encapsulated DNA encoding (CTAB) as well as by the incorporation of PEI either into the human papillomavirus antigen has been tested in phase I and matrix of the microsphere or at the surface. Many other materi- II human clinical trials. PLGA microspheres containing DNA als such as DOTAP, DEAM, and PLL have been used to absorb encoding for the E6 and E7 genes of human papillomavirus virus DNA to PLGA microparticles. PLGA/CTAB microparticles (HPV) 16 and 18 have been developed into clinical trials by MGI were recently developed into stage I clinical trials by Novartis Pharma, Inc. to treat advanced pre-cancerous cervical intraepi- for HIV-1 DNA vaccination. Incorporating PEI into PLGA thelial neoplasia (CIN) by inducing CTL-mediated responses microspheres has also been developed as a method for avoiding to HPV-infected pre-cancerous epithelial cells. A phase I trial of the problems associated with internal encapsulation of plasmid PLGA microparticles encapsulating plasmid DNA encoding only DNA. PEI imparts a positive charge to the PLGA microsphere. HPV-16 E7 antigen (ZYC101, Eisai Pharmaceuticals) established Unlike CTAB, which by itself is not a transfection agent, PEI has T-cell immunologic responses in 11/15 participants and complete intrinsic ability to form nanoparticles with DNA and increase clinical response in 5/15 patients following three intramuscular transfection efficiency. In addition, PLGA–PEI microspheres (IM) vaccinations. In a phase II study, patients with CIN grade improved in vitro transfection and caused upregulation of co- 2/3 were injected IM with DNA encoding for both the E6 and stimulatory signals on APCs. Increased survival against a lethal E7 antigens in PLGA microspheres (ZYC101a/Amolimogene). dose of lymphoma tumor challenge was observed following These two trials demonstrate the clinical potential of DNA vac- 53-70 intradermal (ID) vaccination with PLGA microspheres prepared cines delivered by PLGA microspheres (Table 1). A phase with branched PEI on the surface. While both intramuscular II/III trial of ZYC101a is currently underway. Tumor antigen 326 Human Vaccines & Immunotherapeutics Volume 10 Issue 2 ©2014 Landes Bioscience. Do not distribute. (ZYC300)-encoding plasmid DNA encapsulated in biodegrad- the mice were protected against a syngenic challenge with PSA- able polymer microparticles was evaluated in cancer patients and expressing tumor cells. Then, the safety, feasibility, and Biological was shown to induce detectable immune responses and clinical efficacy of PSA/DNA vaccine was evaluated in a phase I clinical improvement. PLG microparticles with adsorbed DNA encod- trial in patients with hormone-refractory PC. No adverse effects ing HIV antigens have recently entered human clinical trials in (WHO grade > 2) were observed in any patients. PSA-specific healthy volunteers. cellular responses and an increase in anti-PSA antibodies were Moreover, PEI is also under clinical study for DNA vaccine detected after vaccination with the highest vaccine dose (900 delivery. Mannose–PEI was originally used for the ex vivo trans- μ g). However, new adjuvants and/or delivery systems need to be fection of dendritic cells (DCs), which successfully generated explored to enhance the anti-tumor immune responses activated 71,72 effector and memory CTL responses following subcutaneous by DNA vaccines in humans. (SC) injection in non-human primates mediated by transfection Polymeric nanoparticles in clinical trials of Langerhans cells in vivo. Interestingly, these robust cell-medi- Nowadays, the use of polymeric materials to elicit DNA vac- 48 47 ated responses were not accompanied by antibody production. cine responses seems promise. The use of available polymers DermaVir is an intradermal administration of linear PEI conju- such as PLGA, chitosan, and PEI has shown much promise in gated to mannose for the purpose of generating HIV immunity pre-clinical and clinical studies. Polymers used for gene deliv- and is currently in phase I/II studies (Table 1). ery including POEs, PAMAMs, and PBAEs have only recently Poloxamers (Pluronics) are a well-studied group of copolymers emerged as promising strategies for DNA vaccine delivery. The used as surfactants in a variety of pharmaceutical applications improvement of oral bioavailability of several other therapeutic including vaccine delivery and as adjuvants for DNA vaccines. peptides by encapsulation in polymeric nanoparticles was also Poloxamers are thought to act as adjuvants by recruiting and studied. Immunization with DNA encoding HLA-A2-restricted activating APCs. Poloxamers consist of blocks of poly (ethylene epitopes from the HPV16 E7 protein, encapsulated in biodegrad- oxide) (PEO) flanking a central poly(propylene oxide) (POP) able polymer microparticles, could induce HPV-specific T-cell core, and CRL1005 is a triblock copolymer that has a POP core responses in 10/12 patients which were still elevated after 6 mo. of 12 kDa flanked with 350 Da PEO. CRL1005 forms mic- Currently, vaccines are certainly the most promising applications roparticles spontaneously above a phase transition temperature, for orally delivered nanoparticulate systems. Indeed, immunolog- though formulation with the cationic surfactant benzalkonium ical stimulation does not require a dose as high as those required chloride (BAK) reduces particle sizes into the nanometer range obtaining a pharmacologic effect and control of time release (200–300 nm). Without BAK, DNA does not associate with profile could be less critical. In addition, several nanoparticle- CRL1005. However, adding plasmid DNA to BAK-CRL1005 siRNA therapies are in human clinical trials to assess their safety particles increases the size to 300 nm, indicating CRL1005- and efficiency. Since the initial discovery of RNAi, there have BAK-DNA particle formation, and these ternary nanoparticles been over 30 clinical trials assessing the potential of siRNA as a were shown to increase cell-mediated immune responses in non- novel therapeutic. human primates. Alternatives of Natural or Synthetic Polymers While the mechanism of CRL1005 without BAK as a DNA vaccine adjuvant is poorly understood, there is some evidence that CRL1005 enhances delivery of DNA in vivo. CRL1005 Natural polymers such as chitosan, albumin, and heparin has also been shown to be safe and practical. In pre-clinical tri- have been used for the delivery of oligonucleotides, DNA, and als, CRL1005-BAK-DNA nanoparticles increased cell-mediated protein, as well as drugs. An albumin-paclitaxel nanoconjugate and humoral responses to cytomegalovirus (CMV) antigens. has been studied in the treatment of metastatic breast cancer In addition, CRL1005-BAK-DNA induced cell-mediated and during phase III clinical trials. Different in vitro and in vivo humoral CMV responses in humans in phase I clinical trials, and research studies have focused on the use of conjugated poly- this formulation is now in phase II clinical trials. Poloxamer was meric nanoparticles with chemotherapeutic drugs to reduce the also mixed with PLGA to form nanoparticles for nasal delivery of damaging effects of the free drug administration. Currently, DNA to elicit a strong humoral response. more than 20 nano-particle therapeutics, are in clinical use, Since the beginning of year 2000, several phase I clini- validating the ability of nanoparticles to improve the therapeu- cal trials investigating DNA vaccination against cancer have tic index of drugs. evaluated DNA delivery to patients with colorectal carcinoma, Anticancer drugs often have poor solubility in water and thus HPV16-associated anal dysplasia, B-cell lymphoma, metastatic need to use organic solvents or detergents for clinical applica- melanoma, and prostate cancer. All studies demonstrated that tions, resulting in undesirable side effects such as venous inf lam- repetitive DNA administration is well tolerated, with no dose- mation and respiratory distress. Therefore, designing a distinct limiting toxicities even at doses of 2 mg per injection. The first carrier system that encapsulates a large quantity of drugs and study of Prostate-Specific Antigen (PSA)/DNA vaccine dem- specially targets tumor cells is essential for successful cancer ther- onstrated that PSA-specific cytotoxic T lymphocytes could be apy. To date, at least 12 polymer-drug conjugates have entered induced in mice. When two cytokine adjuvants, granulocyte Phase I and II clinical trials and are especially useful for target- macrophage-colony stimulating factor (GM-CSF) and interleu- ing blood vessels in tumors. Examples include anti-endothelial kin-2 (IL-2), were co-delivered with the DNA vaccine, 80% of immune-conjugates, fusion proteins, and caplostatin, the first www.landesbioscience.com Human Vaccines & Immunotherapeutics 327 ©2014 Landes Bioscience. Do not distribute. 3 76 polymer- angiogenesis inhibitor conjugates. Recently, water- loaded with methotrexate and conjugated to apo-transferrin. soluble polymers have been proposed due to simple preparation The authors demonstrated that the conjugated microgels exhib- methods without the use of organic solvent. ited a significant increase in mortality of Hela cells, compared Polymeric NPs have attracted much attention for their abil- with non-conjugated microgels. This was ascribed not only to ity to deliver drugs as well as being biodegradable. Among cat- receptor-mediated endocytosis of the conjugated microgels, but ionic water-soluble polymers available, chitosan is one of the most also to pH-mediated release of methotrexate from the microgels 1 76 extensively studied polymers. Recently, further studies have been by their swelling at the intracellular level. focused on using nanoparticles in cell culture. Chitosan showed The benefits of chitosan-based vectors include their avail- significantly lower toxicity than poly-l -lysine and PEI. For ther- ability, ease of modification, and unique biological properties apeutic applications, drugs can either be integrated in the matrix related to their polycationic nature. Chitosan nano-particles are of the particle or attached to the particle surface. A drug target- capable of passing through biological barriers in vivo (e.g., the ing system should be able to control the fate of a drug entering blood-brain barrier) and delivering drugs to the lesion site due to 77 36 the biological environment. Chitosan microsphere have several their small size. Evidence has shown that chitosan nanoparticles applications in novel drug delivery systems such as GI-delivery may exert differential bactericidal and pharmacological effects on systems, colon and intestinal drug delivery, opthalmic drug prokaryotic and eukaryotic cells in culture. In vitro anti-tumor delivery, oral, buccal and sublingual drug delivery, nasal and testing of chitosan nano-particles indicated that inhibition rate transdermal drug delivery, and vaginal drug delivery. of 500 mg/L chitosan nano-particles was 27% on Hela cells of Chitosan and its derivatives can be covalently cross-linked to cervical cancer, 23% on liver SMMC-7721 cells, 29% on gastric 78 30 prepare nano-sized particles as the drug carriers. The chemi- cancer BGC-823 cells, and 55% on breast cancer MCF-7 cells. cal cross-linkers that have been widely used for chitosan include The studies have shown that cancer treatments consisting of bifunctional agents such as PEG dicarboxylic acid, glutaralde- a combination of chemotherapy and immunotherapy have been hyde or mono-functional agents such as epichlorohydrin. The exploited to further improve the efficacy of cancer therapies. In release kinetics of loaded drugs from polymeric NPs can be con- a study, a chitosan hydrogel (CH) system loaded with GM-CSF trolled by compositional changes to the copolymer. This class and a cancer drug was utilized as a chemo-immunotherapeutic of NP can be prepared from a range of polymers including poly agent in an effort to assess the anti-tumor effects in mice model. (α-hydroxy acids), poly (amino acids), or polysaccharides to cre- The growth of TC-1 tumors was signif icantly reduced in mice ate a vesicle which can either accommodate or display antigens. treated with a CH harboring a cancer drug (doxorubicin: DOX), Chitosan can be formulated in a variety of forms such as pow- cisplatin (CDDP) or cyclophosphamide (CTX), and GM-CSF der, film, sphere, gel, and fiber. Chitosan nanoparticles showed (CH-a cancer drug + GM-CSF), as compared with other groups selectivity for tumor cells. Studies have indicated significant that were treated with CH containing only a cancer drug (CH-a differences in antitumor activity of nanoparticles prepared by cancer drug) or GM-CSF (CH-GM-CSF). chitosan from different producers. Nanogels are nanosized Curcumin, a polyphenolic compound found in the spice tur- hydrogel particles formed by physical or chemical cross-linked meric, has been found to exert preventive and therapeutic effects 79 81 polymer networks. The materials used for the preparation of in various cancers. It is able to inhibit the growth of breast can- nanogels ranged from natural polymers like ovalbumin, pullu- cer cell lines in a dose dependent manner and induces an increase lan, hyaluronic acid, methacrylated chondroitin sulfate and chi- in the percentage of cells in sub-G0 phase, representing the apop- tosan, to synthetic polymers like poly (N-isopropylacrylamide), totic cell population. Curcumin is being applied to a number poly (N-isopropylacrylamide-co-acrylic acid), and poly (ethylene of patients with breast cancer, rheumatoid arthritis, Alzheimer 79 83 glycol)-b-poly (methacrylic acid). disease, colorectal cancer, and psoriatic. Various basic and The mechanism of nano-particles formation is based on elec- clinical studies elucidated curcumin’s limited efficacy due to its trostatic interaction between amine group of chitosan and nega- low solubility, high rate of metabolism, poor bioavailability, and tively charge group of polyanion such as tripolyphosphate. This pharmacokinetics. technique offers a simple preparation method in the aqueous Recently, the polymeric nanoparticle encapsulated curcumin environment. In order to improve targeting and bioavailability (nanocurcumin) is under development for cancer therapy and of chitosan nano-particles, an increasing number of studies are also to overcome these challenges. In addition, curcumin focusing on modification of chitosan. Modified chitosan nano- loaded biodegradable self-assembled polymeric micelles have particles are characterized by pH sensitivity, thermosensitivity, been developed to overcome poor water solubility of curcumin 36 86 and targeting accuracy. and to meet the requirement of intravenous administration. Generally, chitosan possesses some ideal properties of poly- In an experiment, our group tested tumor inhibition rates of a meric carriers for nanoparticles such as biocompatible, biode- chitosan hydrogel system loaded with curcumin (nanocurcumin) gradable, nontoxic, and inexpensive. Furthermore, it possesses on breast cancer MCF-7 cells. Cytotoxicity study showed that positively charge and exhibits absorption enhancing effect. The the encapsulated curcumin remained its potent anti-tumor reports mentioned the preparation of pH-responsive chitosan- effect. IC-50 was calculated 23% and 44% after 48 h and 72 h, based microgels (<200 nm diameter) by ionically cross-linking respectively (unpublished data, 2013). The studies showed that N-[(2-hydroxy-3-trimethylammonium) propyl] chitosan chlo- curcumin treatment could display anti-proliferative and pro- ride in the presence of tripolyphosphate. These microgels were apoptotic activities and induce cell cycle arrest at G2/M phase. 328 Human Vaccines & Immunotherapeutics Volume 10 Issue 2 ©2014 Landes Bioscience. Do not distribute. Brief ly, polymeric nano-particles have long been chosen as carri- safe. Furthermore, the immunosuppressive microenvironment of ers for systemic and targeted drug delivery. The ability of these tumor should be blocked by inhibitors using different delivery sys- particles to circulate in the bloodstream for a prolonged period of tems, as a promising application in cancer immunotherapy. time is often a prerequisite for successful targeted delivery. The Future and Alternative Directions present results suggest that a combinational coating of PEG and chitosan may represent a significant step in the development of long-circulating drug delivery carriers for tumor drug delivery. Nanoparticles can be engineered to either avoid immune sys- PLGA nanoparticles are widely used for the delivery of vari- tem recognition or specifically inhibit or enhance the immune ous chemotherapeutic agents (especially hydrophobic drugs) responses. Some formulations are already in clinical trials, to the target site. However, rapid opsonization by cells of the whereas many others are in various phases of preclinical develop- phagocytic system is a major limitation for achieving effective ment. Although in recent years, our understanding of nanopar- drug targeting to the site of action by PLGA nanoparticles. Thus, ticle interaction with components of the immune system has to maximize the therapeutic benefits of drug loaded nanopar- improved; many questions still require being clear. Further mech- ticles, they should be able to evade the reticuloendothelial sys- anistic studies investigating particle immunomodulatory effects tem (RES). This can be done through the use of various surface (immunostimulatory and immunosuppression) are required to coatings of hydrophilic polymers, as opsonization of hydrophobic improve our understanding of the physicochemical parameters nanoparticles may occur more quickly in comparison to hydro- of nanoparticles that define their effects on the immune system. philic nanoparticles due to the enhanced adsorption of opsonins Development of delivery system remains a critical area for on their surfaces. future research. Important areas for future research include modifying viral vectors to reduce toxicity and immunogenic- Perspectives: Myths and Facts ity, increasing the transduction efficiency of non-viral vectors, enhancing vector targeting and specificity, regulating gene Different NP delivery systems have been described, each expression, and identifying synergies between gene-based agents offering advantages over current methods of vaccine delivery. and other cancer therapeutics. As known, DNA vaccination indi- Nanotechnology platforms are being investigated as vaccine car- cates great potential for combating a variety of diseases. Initial riers, adjuvants, and drug delivery systems to target inflamma- results are promising and some technologies have advanced to tory and inf lammation-associated disorders. Recently, researchers clinical trials. However, safe and efficient delivery of plasmid started to understand the effects of particle size, surface charac- DNA to initiate immune responses remains a major barrier in teristics, and material interactions with the innate immune sys- bringing DNA vaccination into human medicine. Development tem. Investigating of the underlying biological mechanisms of of novel nonviral delivery strategies for DNA vaccines must con- DNA vaccination requires strategies that can isolate one polymer tinue to serve as both methods of biological insight and clini- function from another, such as DNA release kinetics and trans- cally relevant outcomes. Specific concerns include the observed fection efficiency. Future development of polymeric and other difficulty in transfecting DCs, methods to target APC uptake synthetic materials must focus on these considerations for DNA and lymph node trafficking, and providing strong danger signals vaccination. without sacrificing biocompatibility. Rather than conventional vaccines which use whole microbes In addition, self-assembling synthetic vectors for DNA deliv- (live or killed), this new generation of vaccines use components ery are designed to perform several biological functions. They of microbes to elicit an immune response and mimic the way in must be able to deliver their genetic load specifically to the tar- which these antigens would be delivered during a natural infec- get tissue in a site-specific manner, while protecting the genetic tion. Often these antigens are poor immunogens on their own material from degradation by metabolic or immune pathways. and thus require an adjuvant to boost the immune response. NPs Furthermore, they must exhibit minimal toxicity and be proven provide an alternate method for antigen delivery which not only safe enough for therapeutic use. Ultimately, they must have the activates different elements of the immune system but also have capability to express a therapeutic gene for a limited period of good biocompatibility. Delivering antigens in different ways also time in an appropriate fashion. The whole process presents many has a profound effect on the resulting immune response, whether barriers at both tissue and cellular levels. Overcoming these hur- the antigen is decorated on the NP surface for presentation to anti- dles is the principal objective for efficient polymer-based DNA gen-presenting cells or encapsulated for slow release and prolonged therapeutics. exposure to the immune system. Recently, the enhancement of Many nanoparticles appear to show some toxicity in various vaccine potency through the use of different delivery systems (e.g., cell types. Regarding to the use of nanoparticles in pharmaceuti- NPs) is underway. However, this novel and promising approach cal and other biomedical applications, the putative cytotoxicity of (polymeric NPs) should be improved as an efficient delivery system such particles should be eliminated. As the active antitumor com- for gene, drug, and vaccine in future as well as focusing on the ponents of plant drugs are being constantly discovered, develop- modification of their structures to reduce toxicity and overcome ment of targeted polymeric carriers (e.g., chitosan) for controlled in vivo barriers. Recent preclinical and clinical studies reflect the release plant drugs is also an area of future studies. effects of immunotherapy in combination with chemotherapy as a Brief ly, cationic polymers are the subject of critical research as potential approach to specifically target cancer leaving normal cells non-viral gene delivery systems, due to their flexible properties, www.landesbioscience.com Human Vaccines & Immunotherapeutics 329 ©2014 Landes Bioscience. Do not distribute. simple synthesis, and proven gene delivery efficiency. However, hydrophobic modif ications of the cationic polymers are receiving low transfection efficiency and undesirable cytotoxicity remain more attention. the most challenging aspects of these cationic polymers. To over- Disclosure of Potential Conf licts of Interest come the disadvantages, various modifications have been made to improve their gene and vaccine delivery eff icacy. Among them, No potential conf licts of interest were disclosed. 18. Hébert E. Improvement of exogenous DNA nuclear 31. Shi C, Zhu Y, Ran X, Wang M, Su Y, Cheng T. References importation by nuclear localization signal-bearing Therapeutic potential of chitosan and its derivatives 1. Tiyaboonchai W. Chitosan nanoparticles: A prom- vectors: a promising way for non-viral gene therapy? in regenerative medicine. J Surg Res 2006; 133:185- ising system for drug delivery. 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Journal

Human Vaccines & Immunotherapeutics – Taylor & Francis

Published: Feb 1, 2014

Keywords: non-viral vectors; natural polymer; synthetic polymer; gene therapy; vaccine delivery

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