Ekladious Iriny, Liu Rong, Zhang Heng, Foil Daniel H, Todd Daniel A, Graf Tyler N, Padera Robert F, Oberlies Nicholas H, Colson Yolonda L, Grinstaff Mark W
Departments of Biomedical Engineering and Chemistry , Boston University , Boston , MA 02215 , USA . Email:
Department of Surgery , Brigham and Women's Hospital , Boston , MA 02215 , USA . Email:
Chem Sci. 2017 Dec 1;8(12):8443-8450. doi: 10.1039/c7sc03501b. Epub 2017 Oct 20.
Current chemotherapeutic dosing strategies are limited by the toxicity of anticancer agents and therefore rely on multiple low-dose administrations. As an alternative, we describe a novel sustained-release, biodegradable polymeric nanocarrier as a single administration replacement of multi-dose paclitaxel (PTX) treatment regimens. The first synthesis of poly(1,2-glycerol carbonate)--succinic acid-paclitaxel (PGC-PTX) is described, and its use enables high, controlled PTX loadings of up to 74 wt%. Moreover, the polymer backbone is composed of biocompatible building blocks-glycerol and carbon dioxide. When formulated as nanoparticles (NPs), PGC-PTX NPs exhibit PTX concentrations >15 mg mL, sub-100 nm diameters, narrow dispersity, storage stability for up to 6 months, and sustained and controlled PTX release kinetics over an extended period of 70 days. A safely administered single dose of PGC-PTX NPs contains more PTX than the median lethal dose of standard PTX. In murine models of peritoneal carcinomatosis, in which the clinical implementation of multi-dose intraperitoneal (IP) treatment regimens is limited by catheter-related complications, PGC-PTX NPs exhibit improved safety at high doses, tumor localization, and efficacy even after a single IP injection, with comparable curative effect to PTX administered as a multi-dose IP treatment regimen.
当前的化疗给药策略受到抗癌药物毒性的限制，因此依赖于多次低剂量给药。作为一种替代方案，我们描述了一种新型的缓释、可生物降解的聚合物纳米载体，可单次给药替代多剂量紫杉醇（PTX）治疗方案。本文描述了聚（1,2-甘油碳酸酯）-琥珀酸-紫杉醇（PGC-PTX）的首次合成，其应用能够实现高达74 wt%的高可控PTX负载量。此外，聚合物主链由生物相容性构建块——甘油和二氧化碳组成。当制成纳米颗粒（NPs）时，PGC-PTX NPs的PTX浓度>15 mg/mL，直径小于100 nm，分散性窄，储存稳定性长达6个月，并在长达70天的时间内呈现持续且可控的PTX释放动力学。安全给药的单剂量PGC-PTX NPs所含的PTX比标准PTX的半数致死剂量还多。在腹膜癌小鼠模型中，多剂量腹腔内（IP）治疗方案的临床应用受到导管相关并发症的限制，PGC-PTX NPs即使在单次IP注射后，在高剂量下也表现出更高的安全性、肿瘤定位性和疗效，其治疗效果与多剂量IP治疗方案给药的PTX相当。
