Liang Desheng, Wang Ai-Ting, Yang Zhen-Zhen, Liu Yu-Jie, Qi Xian-Rong
State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, 38 Xueyuan Road, Beijing 100191, People's Republic of China.
Mol Pharm. 2015 Jun 1;12(6):2189-202. doi: 10.1021/acs.molpharmaceut.5b00129. Epub 2015 May 18.
Multidrug resistance (MDR) presents a clinical obstacle to cancer chemotherapy. The main purpose of this study was to evaluate the potential of a hyaluronic acid (HA) and α-tocopheryl succinate (α-TOS) based nanoparticle to enhance cancer cell recognition and overcome MDR, and to explore the underlying mechanisms. A multifunctional nanoparticle, HTTP-50 NP, consisted of HA-α-TOS (HT) conjugate and d-α-tocopheryl polyethylene glycol succinate (TPGS) with docetaxel loaded in its hydrophobic core. The promoted tumor cell recognition and accumulation, cytotoxicity, and mitochondria-specific apoptotic pathways for the HTTP-50 NP were confirmed in MCF-7/Adr cells (P-gp-overexpressing cancer model), indicating that the formulated DTX and the conjugated α-TOS in the HTTP-50 NP could synergistically circumvent the acquired and intrinsic MDR in MCF-7/Adr cells. In vivo investigation on the MCF-7/Adr xenografted nude mice models confirmed that HTTP-50 NP possessed much higher tumor tissue accumulation and exhibited pronouncedly enhanced antiresistance tumor efficacy with reduced systemic toxicity compared with HTTP-0 NP and Taxotere. The mechanisms of the multifunctional HTTP-50 NP to overcome MDR and enhance antiresistance efficacy may be contributed by CD44 receptor-targeted delivery and P-gp efflux inhibition, and meanwhile to maximize antitumor efficacy by synergism of DTX and mitocan of α-TOS killing tumor cells.
多药耐药（MDR）是癌症化疗的临床障碍。本研究的主要目的是评估基于透明质酸（HA）和琥珀酸α-生育酚（α-TOS）的纳米颗粒增强癌细胞识别和克服MDR的潜力，并探索其潜在机制。一种多功能纳米颗粒HTTP-50 NP，由HA-α-TOS（HT）缀合物和聚乙二醇琥珀酸d-α-生育酚（TPGS）组成，其疏水核心中负载了多西他赛。在MCF-7/Adr细胞（P-糖蛋白过表达癌症模型）中证实了HTTP-50 NP促进肿瘤细胞识别和积累、细胞毒性以及线粒体特异性凋亡途径，表明HTTP-50 NP中配制的多西他赛和缀合的α-TOS可以协同规避MCF-7/Adr细胞中获得性和固有性MDR。对MCF-7/Adr异种移植裸鼠模型的体内研究证实，与HTTP-0 NP和泰索帝相比，HTTP-50 NP具有更高的肿瘤组织积累，并表现出显著增强的抗耐药肿瘤疗效，同时全身毒性降低。多功能HTTP-50 NP克服MDR和增强抗耐药疗效的机制可能是由CD44受体靶向递送和P-糖蛋白外排抑制所致，同时通过多西他赛和α-TOS的丝裂霉素协同杀死肿瘤细胞来最大化抗肿瘤疗效。
