Chitosan–Polycaprolactone Core–Shell Microparticles for Sustained Delivery of Bevacizumab

• Published in: Molecular pharmaceutics Vol. 17; no. 7; pp. 2570 - 2584
• Main Authors: Jiang, Pengfei, Jacobs, Kane M, Ohr, Matthew P, Swindle-Reilly, Katelyn E
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 06.07.2020
• Subjects: Angiogenesis Inhibitors - administration & dosage; Angiogenesis Inhibitors - pharmacology; Animals; Antibodies, Monoclonal, Humanized - therapeutic use; Bevacizumab - administration & dosage; Bevacizumab - pharmacology; Cell Line; Cell Survival - drug effects; Chitosan - chemistry; Choroidal Neovascularization - drug therapy; Drug Delivery Systems - methods; Drug Liberation; Human Umbilical Vein Endothelial Cells; Humans; Intravitreal Injections; Macular Degeneration - drug therapy; Microplastics - chemical synthesis; Microplastics - chemistry; Microplastics - toxicity; Microscopy, Electron, Scanning; Microspheres; Particle Size; Polyesters - chemistry; Retina - drug effects; Swine; Vascular Endothelial Growth Factor A - antagonists & inhibitors; core−shell; wet age-related macular degeneration; angiogenesis; AMD; bevacizumab; anti-VEGF; microparticles; drug delivery; intravitreal injection; ocular
• ISSN: 1543-8384; 1543-8392
• DOI: 10.1021/acs.molpharmaceut.0c00260

The current therapy for treating neovascular age-related macular degeneration requires monthly intravitreal injection of angiogenesis inhibitors such as bevacizumab or ranibizumab via a 31-gauge needle to inhibit choroidal neovascularization. However, repeated intravitreal injections are associated with poor patient compliance and potential side effects. Microparticle-based injectable devices have shown great promise to address this issue by sustained delivery of protein therapeutics, but critical barriers remain, including limited loading capacity and steady long-term release without compromising the anti-angiogenic activity of drugs. Addressing these challenges, we developed a unique method for synthesizing biodegradable polymer-based core–shell microparticles with sizes around 10 μm, high physical integrity, and uniform size. Subsequent electrostatic and physical interactions to control protein diffusion were designed for the core–shell microparticles to effectively increase the capacity of drug loading to 25%, reduce burst release by almost 30%, and extend the period of drug release from 3 to 6 months. Remarkably, the microparticles enabled a longer-term drug administration and maintained high drug potency up to 6 months in vitro, representing significant advancement compared to conventional microparticle-based delivery platforms or currently commercialized devices. Additionally, the microparticles presented minimal toxicity to human retinal cells in vitro with over 90% cell viability, and they also exhibited good injection feasibility through 31-gauge needles in an ex vivo porcine eye model. These results warrant further studies to evaluate the clinical potential for treating posterior ophthalmic diseases as well as other conditions or injuries requiring long-term local drug administration.