Advanced Therapeutics

Wu, Ye; Fu, Li; Li, Qianqian; Gao, Xiang; Zhang, Yingjun; Jin, Chuanfei; Ding, Feiqing; Hong, Sheng; Cai, Hui; Li, Yiliang

doi: 10.1002/adtp.202300181pmid: N/A

Alzheimer's disease (AD) is a neurodegenerative disease and the most common cause of dementia. Although it is discovered more than 100 years ago and is the subject of many scientific studies, much is yet to be discovered about many aspects of this disease, including the precise biological changes that cause it, the best approach to its early diagnosis, and effective therapeutic interventions to slow or stop the progression. This article briefly reviews the disease progression, risk factors, and pathogenesis of the disease. In addition, the current early diagnostic and therapeutical strategies for AD are presented.

Li, Mingxun; Wu, Yibin; He, Chunfeng; Li, Xinxin; Tao, Ji; Qu, Chunrong; Chen, Wen‐Hua; Cheng, Zhen

doi: 10.1002/adtp.202300151pmid: N/A

Mitochondrial membrane potential (ΔΨm)‐targeting molecular probes play an essential role in diagnosing and treating diseases. Recently, the second near‐infrared window (NIR‐II, 1000–1700 nm) fluorescent imaging has been actively studied as an attractive imaging modality. However, small molecule ΔΨm‐targeting NIR‐II probes are rarely reported, especially for highly efficient imaging and treatment of tumors. Herein, a small molecule probe named TQPTPP is designed and synthesized by conjugation of a novel D‐A type dye TQT1009 with ΔΨm‐targeting molecule alkyl triphenylphosphine (TPP) through a polyethylene glycol‐8 (PEG8) linker. The conventional ICG dye is also coupled with TPP through PEG8 to produce ICGTPP as a comparison. TQPTPP showed a fluorescence quantum yield of 0.041% and excellent photothermal conversion efficiency (61.4%). It can be self‐assembled into nanoparticles and still preserve ΔΨm‐targeting capability. Tumor imaging is further performed, and results showed a long tumor retention time of TQPTPP (maximum tumor signal on day five and signal‐to‐noise ratio up to nine). As a comparison, ICGTPP remained a single molecule with ΔΨm‐targeting capability. But it has shorter tumor retention and lower photostability. These results suggested the novel D‐A small molecule ΔΨm‐targeting NIR‐II probe TQPTPP provided a new tool for diagnosing and treating tumors.

Marple, April S. T.; Jesmer, Alexander H.; Lake, Ben P. M.; Rullo, Anthony F.; Wylie, Ryan G.

doi: 10.1002/adtp.202300124pmid: N/A

Immunotherapeutics, such as bispecific T cell engagers (BiTEs), have shown promise in cancer therapies, however their efficacy against solid tumors is hindered by transport barriers. Local therapies are being investigated to improve solid tumor immunotherapies and minimize systemic toxicity. Because local therapies bypass the circulatory system, drug properties can be optimized to further enhance local efficacy. Herein, the use of a larger BiTE‐like antibody‐oligomer conjugate is investigated, modular T cell engagers (MoTEs), to extend the duration of activity within local tissue mimics. Specifically, an anti‐CD3 antibody is modified with heterobifunctional ethylene oxide ((EO)4‐12) linkers, which are subsequently modified with cancer targeting ligands (CTLs). The (EO)x molecular weight and CTL grafting densities are optimized to achieve targeted cytotoxicity within in vitro co‐cultures against prostate‐specific membrane antigen (PSMA) positive and human epidermal growth factor receptor 2 (HER2) positive cancer cells. In local tissue models comprised of embedded PSMA positive spheroids in collagen‐hyaluronic acid hydrogels with T cells, it is demonstrated that MoTEs resulted in ≈2.5‐fold greater cytotoxicity toward cancer spheroids than a PSMA targeting BiTE at longer 12‐day timepoints. MoTEsmay therefore prove beneficial for local therapies by extending the duration of action after single‐dose administration and establishing simple synthetic protocols to target various cancer antigens.

Zou, Benkun; Jiang, Haohua; Liu, Hongyu; Lu, Jun; Qiang, Huiping; Lu, Mingfang; Yu, Lian; Zhong, Hua; Chu, Tianqing; Han, Baohui

doi: 10.1002/adtp.202300141pmid: N/A

The combination therapy of targeted drugs and immune checkpoint inhibitors has shown prominent success. In addition to blocking mutated oncogene downstream signaling, the immunological mechanism(s) underlying the anti‐tumor effect of targeted‐immuno‐therapy is not clear. In this study, anlotinib, a novel pan‐targeted tyrosine kinase receptor inhibitor (pTKI), is combined with anti‐PD1 (αPD1) as a therapeutic regimen applying to an immunocompetent mouse tumor model. Anlotinib induces immunogenic cell death (ICD), elicits anti‐tumor inflammation and infiltration, and activation of DCs and CD8+ T cells, which are enhanced by αPD1. Furthermore, anlotinib reduces KC/MCP‐1 secretion by attenuating educational effect that cancer cells imposed on tumor‐associated macrophages (TAMs) and prevents their M2 polarization by inhibiting AKT/mTORC1 and Pparδ pathways. Importantly, anlotinib plus αPD1 prolongs median progression‐free survival time compared with standard chemotherapy plus pembrolizumab as the 1st line treatment in non‐small cell lung cancer (NSCLC) patients. Thus, anlotinib treatment elicits both innate and adaptive anti‐tumor immune responses while αPD1 enhances its potency. This study provides strong evidence that combination of targeted therapy and immunotherapy is a promising regimen for treating NSCLC.

Biancacci, Ilaria; De Santis, Daniele; Rama, Elena; Benderski, Karina; Momoh, Jeffrey; Pohlberger, Robert; Moeckel, Diana; Kaps, Leonard; Rijcken, Cristianne J. F.; Prakash, Jai; Thewissen, Marielle; Kiessling, Fabian; Shi, Yang; Peña, Quim; Sofias, Alexandros Marios; Consolino, Lorena; Lammers, Twan

Kapat, Kausik; Semwal, Nitesh; Chillarge, Anjali; Aswani, Arja

doi: 10.1002/adtp.202300189pmid: N/A

Carbon nanodots (CNDs) are an emerging class of zero dimensional (0D) carbon nanomaterials that accumulated immense interest from researchers in the past two decades due to their facile synthesis and unique photo‐physical and ‐chemical properties. In particular, their long wavelength fluorescence emission, enhanced tissue penetration depth, excellent water dispersibility, tunable surface chemistry, charge transfer properties, and biocompatibility have unveiled newer avenues for advanced application in therapeutics, diagnostics, theranostics, and tissue regeneration. The review typically emphasizes CNDs, excluding the other members of the carbon dots (CDs) family, which has not been covered before. After introducing CNDs in the carbon nanomaterial hierarchy, their synthesis, general properties, functionalization, and characterization are subsequently discussed. The following section elaborates on mechanisms of CNDs fluorescence, quenching, and associated factors based on the latest theories and models. The diagnostic, theranostic, and therapeutic applications of red/NIR‐emitting CNDs are thoroughly reviewed to cover the latest developments, including in vitro/in vivo bioimaging, thermoelectric and piezoelectric biosensing, and various soft and hard tissue regeneration. Overall, this work will enlighten passionate readers about the present status and futuristic aspects of CNDs in healthcare management, besides reported toxicities and challenges associated with their bench‐to‐bedside translation.

Mauser, Ava; Quevedo, Daniel F.; Zhang, Boya; Hernandez, Yazmin; Berardi, Anthony; Brown, William; Lee, Sophia; Miki, Rikako; Raymond, Jeffery; Lahann, Joerg; Greineder, Colin F.

doi: 10.1002/adtp.202300007pmid: 41049273

Protein‐based drug delivery systems have gained popularity due to their biocompatibility, straightforward surface modification, and potential for intrinsic therapeutic activity. Among therapeutic proteins, enzymes are particularly attractive because of their specificity, efficient reaction rates, regeneration after substrate turnover, and proven track record in the treatment of diseases ranging from cancer to inherited metabolic and lysosomal storage disorders. Herein, previous work on electrohydrodynamic jetting is expanded upon by developing a novel class of protein nanoparticles that features therapeutic enzymes. In particular, nanoparticles incorporating the antioxidant enzyme, catalase, at weight fractions as high as 50% are reported. Catalase‐based synthetic protein nanoparticles (CAT‐SPNPs) demonstrate sustained antioxidative activity, retain significantly enhanced enzymatic activity compared to its solute form, and overall demonstrate good structural stability. Moreover, surface functionalization of CAT‐SPNPs with targeting antibodies results in ≈12.5‐fold increase in uptake over unmodified control particles. Importantly, CAT‐SPNPs exert protection from oxidative stress, as indicated by significant increase in viability and reduction in LDH release compared to equivalent amounts of free catalase. Taken together, the work establishes targeted enzyme‐based SPNPs as a platform for enhancing the drug‐like properties of therapeutic enzymes.

Paramio, Irene; Salazar, Ainhoa; Jordà‐Redondo, Mireia; Nonell, Santi; Torres, Tomás; de la Torre, Gema

doi: 10.1002/adtp.202300116pmid: N/A

In this work, the ability of amphiphilic Phthalocyanine (Pc) photosensitizers (PS) (Zn(II)Pcs PS1, PS2, and PS3) to assemble into cationic nanoparticles in water and to photo‐inactivate bacterial strains is demonstrated. All the synthesized Zn(II)Pcs exhibit an AABB functionalization pattern, having a binaphthyloxy‐linked bisisoindole (AA) functionalized at the chiral binaphthol core with branched (PS1) or linear (PS2 and PS3) poly‐ammonium chains, and two non‐functionalized isoindole rings (BB). The aggregation behavior and the stability of the nanoparticles formed by the three PS in water is studied by UV–vis, fluorescence and circular dichroism (CD) spectroscopies, and their shape and size is determined by transmission electron microscopy (TEM) and dynamic light scattering (DLS). The PS nanoparticles prove efficient in the photoinactivation of S. aureus and E. coli. Although PS2 and PS3 present better photophysical features in their monomeric form (i.e., improved singlet oxygen quantum yield), PS1 is more effective in killing both types of strains, especially the gram‐negative E. coli. This observation may derive from the low stability found for PS1 nanoparticles, which easily disassemble after binding to the bacteria surface, recovering the photophysical properties of the non‐aggregated species.

doi: 10.1002/adtp.202370032pmid: N/A

Vaezzadeh, Mahsa; Kachooei, Ehsan; Krishnamurthy, Shivani; Manandhar, Preeti; Nadort, Annemarie; Guillemin, Gilles J; Di Ieva, Antonio; Santiago, Marina; Heng, Benjamin; Guller, Anna

doi: 10.1002/adtp.202300197pmid: N/A

Combination drug therapy addresses the auxiliary cancer pathways of the tumor progression unaffected by the standard adjuvant treatments such as radio‐ and chemotherapy. It is a particularly attractive strategy to improve the treatment outcomes and the quality of life in patients with the deadliest brain cancer, glioblastoma (GB). Testing of combination drug treatment protocols requires reliable, efficient, and biologically accurate preclinical testbeds applicable before the transition to clinical trials. The 3D in vitro models of GB are a promising platform for pharmacological research. However, there is notable methodological uncertainty and a highly scattered data landscape regarding drug testing in 3D in vitro models of GB. In particular, it is not completely clear how to mimic clinically relevant dozing and schedule of the main chemotherapy drug for GB, temozolomide (TMZ) in 3D in vitro GB models. Here, the authors carefully explore the available literature on the application of TMZ in 3D in vitro models of GB, both as a sole agent and in combination with other medications. The joint analysis of the tumor modeling approaches, the employed assays, and the obtained treatment responses provided in this review may be used as a roadmap for future research in combination treatments of GB.