Biomedical Polymers Laboratory, and Jiangsu Key Laboratory of Advanced Functional Polymer Design and Application, College of Chemistry, Chemical Engineering and Materials Science, and State Key Laboratory of Radiation Medicine and Protection, Soochow University, Suzhou 215123, PR China.
Biomedical Polymers Laboratory, and Jiangsu Key Laboratory of Advanced Functional Polymer Design and Application, College of Chemistry, Chemical Engineering and Materials Science, and State Key Laboratory of Radiation Medicine and Protection, Soochow University, Suzhou 215123, PR China.
Acta Biomater. 2021 Apr 15;125:280-289. doi: 10.1016/j.actbio.2021.02.044. Epub 2021 Mar 4.
It is highly tempting to develop high-efficacy targeted nanotherapeutics based on FDA approved polymers like PLGA. Herein, we describe facile fabrication of robust, hyaluronic acid-surfaced and disulfide-crosslinked star-PLGA nanoparticles (HA-sPLGA XNPs) for targeted and reduction-triggered release of docetaxel (DTX), achieving markedly enhanced treatment of A549 lung tumor in vivo. HA-sPLGA XNPs carrying 5.2 wt.% DTX (DTX-HA-sPLGA XNPs) had a size of 105.5 ± 0.5 nm and great stability while almost completely released DTX under 10 mM glutathione. Confocal and flow cytometry experiments revealed fast cellular uptake of HA-sPLGA XNPs by CD44-overexpressing A549 cells. DTX-HA-sPLGA XNPs held much higher potency to A549 cells than DTX-loaded HA-surfaced and non-crosslinked star-PLGA nanoparticles (DTX-HA-sPLGA NPs), DTX-loaded HA-surfaced and non-crosslinked linear-PLGA nanoparticles (DTX-HA-lPLGA NPs), and free DTX (IC = 0.18 versus 0.38, 1.21 and 0.83 µg DTX equiv./mL). Intriguingly, DTX-HA-sPLGA XNPs revealed a prolonged elimination half-life of 4.18 h and notable accretion of 9.49%ID/g in A549 tumor after 8 h injection. Accordingly, DTX-HA-sPLGA XNPs demonstrated significantly better suppression of subcutaneous A549 lung tumor than DTX-HA-PLGA NPs, DTX-HA-lPLGA NPs, and free DTX controls. HA-sPLGA XNPs with low toxicity and multi-functionality appear to be a unique targeted vehicle for chemotherapy of CD44-overexpressing tumors. STATEMENT OF SIGNIFICANCE: PLGA nanoparticles with superior safety and biodegradability are among the most advanced vehicles for therapeutic delivery. The efficacy of nanomedicines based on PLGA is, however, suboptimal, due to poor tumor cell selectivity and uptake, drug leakage, and slow drug release at the pathological site. It is highly desired to develop functional PLGA nanoparticles to improve their tumor-targeting ability and therapeutic efficacy. The sophisticated fabrication and potential toxicity concerns of reported novel PLGA nanoformulations, nevertheless, preclude their clinical translation. Here, we developed hyaluronic acid-surfaced and disulfide-crosslinked star-PLGA nanoparticles (HA-sPLGA XNPs) that enabled stable encapsulation and targeted delivery of docetaxel (DTX) to CD44+ A549 lung cancer cells in vitro and in vivo, affording markedly improved tumor accumulation and repression and lower side effects compared with free DTX control. Importantly, HA-sPLGA XNPs are based on fully biocompatible materials and comparably simple to fabricate. The evident tumor targetability and safety makes HA-sPLGA XNPs a unique and potentially translatable platform for chemotherapy of CD44+ cancers.
基于 FDA 批准的聚合物（如 PLGA）开发高效靶向纳米疗法极具吸引力。在此，我们描述了一种简便的方法来制备坚固的、透明质酸表面和二硫键交联的星形 PLGA 纳米粒子（HA-sPLGA XNPs），用于靶向和还原触发的多西紫杉醇（DTX）释放，从而显著增强体内 A549 肺肿瘤的治疗效果。载有 5.2wt.% DTX 的 HA-sPLGA XNPs（DTX-HA-sPLGA XNPs）的粒径为 105.5±0.5nm，具有很好的稳定性，而在 10mM 谷胱甘肽下几乎完全释放 DTX。共聚焦和流式细胞术实验表明，HA-sPLGA XNPs 能够快速被 CD44 过表达的 A549 细胞摄取。与载有 DTX 的 HA 表面和非交联星形 PLGA 纳米粒子（DTX-HA-sPLGA NPs）、载有 DTX 的 HA 表面和非交联线性 PLGA 纳米粒子（DTX-HA-lPLGA NPs）和游离 DTX 相比，DTX-HA-sPLGA XNPs 对 A549 细胞具有更高的效力（IC=0.18 对 0.38、1.21 和 0.83μg DTX 当量/mL）。有趣的是，DTX-HA-sPLGA XNPs 在 8 小时注射后，在 A549 肿瘤中的消除半衰期延长至 4.18 小时，并且显著增加了 9.49%ID/g。因此，与 DTX-HA-PLGA NPs、DTX-HA-lPLGA NPs 和游离 DTX 对照组相比，DTX-HA-sPLGA XNPs 对皮下 A549 肺肿瘤的抑制作用明显更好。具有低毒性和多功能性的 HA-sPLGA XNPs 似乎是一种针对 CD44 过表达肿瘤的独特靶向给药载体。
具有优越的安全性和生物降解性的 PLGA 纳米粒子是最先进的治疗药物输送载体之一。然而，基于 PLGA 的纳米药物的疗效并不理想，因为其对肿瘤细胞的选择性和摄取、药物泄漏以及在病理部位的药物释放均较差。因此，人们希望开发功能性的 PLGA 纳米粒子以提高其肿瘤靶向能力和治疗效果。然而，报道的新型 PLGA 纳米制剂的复杂制备和潜在毒性问题，排除了它们的临床转化。在此，我们开发了透明质酸表面和二硫键交联的星形 PLGA 纳米粒子（HA-sPLGA XNPs），使其能够在体外和体内稳定地包封和靶向递送多西紫杉醇（DTX）至 CD44+A549 肺癌细胞，与游离 DTX 对照组相比，显著提高了肿瘤的积累和抑制作用，同时降低了副作用。重要的是，HA-sPLGA XNPs 基于完全生物相容性的材料，且制备相对简单。明显的肿瘤靶向性和安全性使 HA-sPLGA XNPs 成为 CD44+癌症化疗的独特且具有潜在转化能力的平台。
