Xia Yingchun, Wang Ningning, Qin Zhouliang, Wu Juan, Wang Fang, Zhang Li, Xia Xinnian, Li Jishan, Lu Yanbing
Institute of Polymer Science, College of Chemistry and Chemical Engineering, Hunan University, Changsha 410082, China.
J Mater Chem B. 2018 May 28;6(20):3348-3357. doi: 10.1039/c8tb00346g. Epub 2018 May 10.
We reported a facile and efficient strategy for the construction of polycarbonate-based core-crosslinked redox-responsive nanoparticles (CC-RRNs), which can efficiently regulate the drug loading content and redox-responsive drug release. A series of CC-RRNs for delivery of doxorubicin (DOX) were synthesized by the click reaction between alkyne-bearing amphiphilic block copolymer PEG-b-poly(MPC) (PMPC) and azide-terminated α-lipoic acid derivative (LA) and 6-bromohexanoic acid derivative (AHE) at different ratios, followed by introduction of crosslinked networks under a catalytic amount of dithiothreitol (DTT). Dynamic light scattering (DLS) experiments showed that the CC-RRNs presented more excellent stability over non-crosslinked unresponsive nanoparticles (NC-URNs) under physiological conditions. Interestingly, the DOX loading content of nanoparticles (NPs) increased as the proportion of LA moieties increased, and the maximum value was up to 20.0 ± 0.6%, close to the theoretical value of 23.1%. The in vitro redox-responsive release of DOX and MTT assays confirmed that the ratio of LA-to-AHE of PMPC-based polymers not only determined the ultimate drug release of DOX-loaded CC-RRNs in a reductive environment, but also dominated the cytotoxicity towards HepG2 cells. Confocal laser scanning microscopy (CLMS) and flow cytometry further proved the enhancement of cellular uptake and tumor accumulation. This facile strategy overcomes tedious fabrication procedures for drug nanocarriers, offers an opportunity for regulating the functionality of NPs, and thus paves the pathway for scale-up production of biodegradable drug carriers with biocompatibility, stability and targetability.
我们报道了一种简便高效的策略，用于构建基于聚碳酸酯的核心交联氧化还原响应性纳米颗粒（CC-RRNs），其能够有效调节药物负载量和氧化还原响应性药物释放。通过含炔基的两亲性嵌段共聚物聚乙二醇-b-聚（2-甲基-2-丙烯酰氧基丙磺酸）（PMPC）与叠氮基封端的α-硫辛酸衍生物（LA）和6-溴己酸衍生物（AHE）以不同比例进行点击反应，随后在催化量的二硫苏糖醇（DTT）作用下引入交联网络，合成了一系列用于递送阿霉素（DOX）的CC-RRNs。动态光散射（DLS）实验表明，在生理条件下，CC-RRNs比非交联无响应纳米颗粒（NC-URNs）具有更优异的稳定性。有趣的是，纳米颗粒（NPs）的DOX负载量随着LA部分比例的增加而增加，最大值高达20.0±0.6%，接近理论值23.1%。DOX的体外氧化还原响应性释放和MTT测定证实，基于PMPC的聚合物中LA与AHE的比例不仅决定了负载DOX的CC-RRNs在还原环境中的最终药物释放，还主导了对HepG2细胞的细胞毒性。共聚焦激光扫描显微镜（CLMS）和流式细胞术进一步证明了细胞摄取和肿瘤积累的增强。这种简便的策略克服了药物纳米载体繁琐的制备程序，为调节NPs的功能提供了机会，从而为大规模生产具有生物相容性、稳定性和靶向性的可生物降解药物载体铺平了道路。
