Advanced Therapeutics最新文献

Overcoming severe side effects from anticancer agents without decreasing their effects on tumor growth is a major challenge. A prodrug technology is reported using agents that are spatiotemporally activated primarily in tumors while the extratumoral toxicity to healthy cells is minimized. A ROS-activatable prodrug of a strong anticancer agent, doxazolidine (doxaz), is developed. Doxaz is a DNA alkylating agent with a half-life of 3 min and significantly higher cytotoxicity than the clinically used parental compound doxorubicin (dox). Importantly, doxaz is not affected by p-glycoprotein expression since it irreversibly alkylates DNA while dox inhibits the topoisomerase II DNA complex. As drug activators, reactive oxygen species (ROS) are already produced inside cancer cells in higher abundance than in normal cells but additionally generated by external stimuli such as radionuclides (via radiolysis of water) and/or ROS-inducing drugs. We synthesized the prodrug, Doxaz-BA, and evaluated its efficacy in vitro in cell cultures and then in vivo in xenograft mouse models. Doxaz-BA is effective in a broad range of cancer cells since most cancer cells produce higher levels of ROS. Combining with clinically relevant radiotracers such as ¹⁸F-FDG or other tumor-tropic agents / ROS inducing drugs results in a tumor-specific and enhanced localized therapy paradigm.

Since the 1940s, generalized cytotoxic therapy has been a valuable tool in cancer treatment. Over the years, there's been a significant increase in developing potential cytotoxic drugs. However, little progress has been made in enhancing patients' quality of life. The therapeutic index is limited due to the drug's poor solubility and lack of selectivity. Various carriers have been explored for drug delivery to enhance efficacy. Yet, there's a gap for a versatile delivery system that can adjust to specific drug and application requirements. Here, a multifaceted drug delivery platform based on a genetically engineered nature-inspired polymer, elastin-like polypeptide (ELP) is introduced. This technology enables the customization of the polymeric vehicle's physicochemical characteristics to suit the needs of a specific drug and application. The review highlights ELP's advantages in cancer targeting, such as site-specificity, controlled release, biocompatibility, and extended plasma circulation. For the first time, ELP-based drug delivery into passive and active targeting for better comprehension of its adaptability is classified. Moreover, numerous opportunities for loading different types of drugs onto the polymer are outlined. Finally, the polymer's efficacy in delivery across multiple cancer types, underscoring the wide spectrum of ELP-based cancer drug delivery is precisely described.

The cover image of article 2400114 by Marco Filice, Santiago Gómez-Ruiz, and co-workers illustrates the action and high potential of albumin-loaded silica-based porous nanomaterials functionalized with organotin(IV) cytotoxic agents. These systems adequately functionalized with both fluorescein derivatives and indocyanine green moieties can be applied as theranostic materials to target, track, internalize and decrease the viability of triple negative breast cancer cells.

In article 2400191, Zijian Zhao, Yanzhao Li, Yang Yu, and co-workers develop a highly accurate urine-based diagnostic tool for bladder cancer using an on-chip heating dPCR system. By integrating genetic and epigenetic biomarkers and optimizing the diagnostic model with machine learning, the tool achieved high sensitivity and specificity in detecting bladder cancer and shows potential for differentiating tumor stages.

Non-persistent nanoarchitectures showing both photoacoustic and photothermal features are introduced and preclinically validated. This approach fosters the establishment of alternative strategies for HPV-negative head/neck carcinoma management that support both real-time imaging and non-ionizing treatment. More details can be found in article 2400110 by Luca Menichetti, Valerio Voliani, and co-workers.

Nucleic acid therapeutics have demonstrated tremendous potential for treating diseases by targeting the genetic underpinnings at the transcriptomic level. However, their efficacy hinges on robust strategies to protect nucleic acids from degradation during circulation and to facilitate precise delivery to diseased tissues and cells. Here the critical roles of chemical modification and bioconjugation in advancing nucleic acid therapeutics for improved binding affinity, enhanced stability, and targeted delivery are reviewed. Commencing diverse applications, the significance of different chemical modifications is discussed based on recent literature and clinical products, on oligonucleotides. These modifications encompass backbone, ribose, base alterations and bioconjugation techniques such as N-acetylgalactosamine (GAlNac), aptamers, antibodies, and cell-penetrating peptides (CPPs). Supported by a clinical perspective, diverse applications and ongoing developments are highlighted. Furthermore, the current landscape of nucleic acid therapeutics and their potential in addressing genetic disorders with multiple cellular/organelle targeting is discussed. Here the promising prospect of combining chemical innovation and bioconjugation strategies is underscored to propel the development of more effective nucleic acid therapeutics.

In this pioneering study, an infrared light-activated highly efficient and uniform, small to large biomolecular delivery into various cell types is developed using a flower-shaped microstructure device (FMD). Featuring a unique structural design, this FMD consists of 8 µm in length, with edges of ≈3 and 20 µm gaps between FMD microstructure. When subjected to IR laser exposure at 1050 nm, the FMD triggers the generation of photothermal cavitation bubbles, exerting jet fluid flow on the cell's plasma membrane surface, and facilitating biomolecule delivery into cells. The platform achieves efficient intracellular delivery spanning various biomolecules — from low-molecular-weight propidium iodide dye to higher molecular weight siRNA, plasmid, and enzymes — across human cervical (SiHa), mouse fibroblast (L929), and neural crest-derived (N2a) cancer cells, ensuring consistently high efficiency without compromising cell viability. 95% delivery efficacy and 96% cell viability are achieved for smaller molecules like PI dye in L929 cells. For larger biomolecules such as enzymes, transfection efficiency reached 82%, and cell viability is nearly 90% in SiHa cells. This is confirmed via confocal microscopy and flow cytometry, the FMD-based delivery system holds broad potential for cellular diagnostics and therapeutics, promising significant advancements in cellular research and biomedical treatments.

Osteosarcoma (OS) is a rare primary malignant bone cancer affecting mainly young individuals. Treatment typically consists of chemotherapy and surgical tumor resection, which has undergone few improvements since the 1970s. This therapeutic approach encounters several limitations attributed to the tumor's inherent chemoresistance, marked heterogeneity and metastatic potential. Therefore, the development of in vitro platforms that closely mimic the OS pathophysiology is crucial to understand tumor progression and discover effective anticancer therapeutics. Contrary to 2D monolayer cultures and animal models, 3D in vitro platforms show promise in replicating the 3D tumor macrostructure, cell-cell and cell-extracellular matrix interactions. This review provides an overview of the biomanufacturing strategies employed in developing 3D in vitro OS models, highlighting their role in replicating different aspects of OS and improving OS anticancer research and drug screening. A variety of 3D in vitro models are explored, including both scaffold-free and scaffold-based models, encompassing cell spheroids, hydrogels, and innovative approaches like electrospun nanofibers, microfluidic devices and bioprinted constructs. By examining the distinctive features of each model type, this review offers insights into their potential transformative impact on the landscape of OS research and therapeutic innovation, addressing the challenges and future directions of 3D in vitro OS modeling.

This review offers a comprehensive exploration of optimized drug delivery systems tailored for controlled release and their crucial role in addressing cerebrovascular diseases. Through an in-depth analysis, various controlled release methods, including nanoparticles, liposomes, hydrogels, and other emerging technologies are examined. Highlighting the importance of precise drug targeting, it is delved into the underlying mechanisms of these delivery systems and their potential to improve therapeutic outcomes while minimizing adverse effects. Additionally, the specific applications of these optimized drug delivery systems in treating cerebrovascular disorders such as ischemic stroke, cerebral aneurysms, and intracranial hemorrhage are discussed. By shedding light on the advancements in drug delivery techniques and their implications in cerebrovascular medicine, this review offers valuable insights into the future of therapeutic interventions in neurology.