title: Enhance Cancer Cell Recognition and Overcome Drug Resistance Using Hyaluronic Acid and α-Tocopheryl Succinate Based Multifunctional Nanoparticles.
abstract: 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.
authors.affiliation: State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, 38 Xueyuan Road, Beijing 100191, People's Republic of China.
authors.forename: Desheng
authors.initials: D
authors.lastname: Liang
authors.affiliation: State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, 38 Xueyuan Road, Beijing 100191, People's Republic of China.
authors.forename: Ai-Ting
authors.initials: AT
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, 38 Xueyuan Road, Beijing 100191, People's Republic of China.
authors.forename: Zhen-Zhen
authors.initials: ZZ
authors.lastname: Yang
authors.affiliation: State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, 38 Xueyuan Road, Beijing 100191, People's Republic of China.
authors.forename: Yu-Jie
authors.initials: YJ
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, 38 Xueyuan Road, Beijing 100191, People's Republic of China.
authors.forename: Xian-Rong
authors.initials: XR
authors.lastname: Qi
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D000077143:Docetaxel; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D006820:Hyaluronic Acid / Q000737:chemistry*; D061986:MCF-7 Cells; D051379:Mice; D008819:Mice, Nude; D053758:Nanoparticles / Q000737:chemistry*; D043823:Taxoids / Q000737:chemistry / Q000494:pharmacology; D014961:X-Ray Diffraction; D024502:alpha-Tocopherol / Q000737:chemistry*
chemical_list: D043823:Taxoids; D000077143:Docetaxel; D006820:Hyaluronic Acid; D024502:alpha-Tocopherol
keywords: docetaxel; hyaluronic acid; multidrug resistance; nanoparticle; α-tocopheryl succinate