Institute of Bioengineering and Nanotechnology , 31 Biopolis Way , Singapore 138669 , Singapore.
IBM Almaden Research Center , 650 Harry Road , San Jose , California 95120 , United States.
ACS Appl Mater Interfaces. 2018 Apr 25;10(16):13274-13282. doi: 10.1021/acsami.7b14319. Epub 2018 Apr 16.
In this study, bortezomib (BTZ, a cytotoxic water-insoluble anticancer drug) was encapsulated in micellar nanoparticles having a catechol-functionalized polycarbonate core through a pH-sensitive covalent bond between phenylboronic acid (PBA) in BTZ and catechol, and these drug-loaded micelles were incorporated into hydrogels to form micelle/hydrogel composites. A series of injectable, biodegradable hydrogels with readily tunable mechanical properties were formed and optimized for sustained delivery of the BTZ-loaded micelles through ionic coacervation between PBA-functionalized polycarbonate/poly(ethylene glycol) (PEG) "ABA" triblock copolymer and a cationic one having guanidinium- or thiouronium-functionalized polycarbonate as "A" block. An in vitro release study showed the pH dependence in BTZ release. At pH 7.4, the BTZ release from the micelle/hydrogel composite remained low at 7%, whereas in an acidic environment, ∼85% of BTZ was released gradually over 9 days. In vivo studies performed in a multiple myeloma MM.1S xenograft mouse model showed that the tumor progression of mice treated with BTZ-loaded micelle solution was similar to that of the control group, whereas those treated with the BTZ-loaded micelle/hydrogel composite resulted in significant delay in the tumor progression. The results demonstrate that this hydrogel has great potential for use in subcutaneous and sustained delivery of drug-loaded micelles with superior therapeutic efficacy.
在这项研究中，硼替佐米（BTZ，一种细胞毒性的水溶性抗癌药物）通过 BTZ 中的苯硼酸（PBA）与儿茶酚之间的 pH 敏感共价键被包裹在具有儿茶酚功能化聚碳酸酯核的胶束纳米粒子中，并且这些载药胶束被掺入水凝胶中以形成胶束/水凝胶复合材料。一系列可注射的、可生物降解的水凝胶具有易于调节的机械性能，通过 PBA 功能化聚碳酸酯/聚（乙二醇）（PEG）“ABA”三嵌段共聚物与具有胍基或硫代尿嘧啶功能化聚碳酸酯作为“A”嵌段的阳离子之间的离子凝聚来形成和优化，用于持续输送载 BTZ 的胶束。体外释放研究表明 BTZ 释放具有 pH 依赖性。在 pH 7.4 时，胶束/水凝胶复合材料中 BTZ 的释放率仍保持在 7%，而在酸性环境中，约 85%的 BTZ 在 9 天内逐渐释放。在多发性骨髓瘤 MM.1S 异种移植小鼠模型中的体内研究表明，用载 BTZ 胶束溶液治疗的小鼠的肿瘤进展与对照组相似，而用载 BTZ 胶束/水凝胶复合材料治疗的小鼠的肿瘤进展则明显延迟。结果表明，这种水凝胶具有用于皮下和持续输送载药胶束的巨大潜力，具有优异的治疗效果。
