title: Multifunctional tumor-targeting nanocarriers based on hyaluronic acid-mediated and pH-sensitive properties for efficient delivery of docetaxel.
abstract: OBJECTIVE
  The objective of this work was to develop a multifunctional tumor-targeting nanocarrier based on the mechanism of CD44-mediated endocytosis and pH-induced drug release to improve the therapeutic efficacy of docetaxel (DTX).
  
  
  METHODS
  Hyaluronic acid-coated docetaxel-loaded cholesteryl hemisuccinate vesicles (HA-CHEMS vesicles) were prepared. The physiochemical properties and pH-dependent drug release of HA-CHEMS vesicles were evaluated. The HA-CHEMS vesicles were investigated for CD44-mediated internalization and in vitro cell viability using MCF-7,A549 and L929 cells.In addition,tissue distribution as well as antitumor efficacy was also evaluated in MCF-7 tumor-bearing mouse model.
  
  
  RESULTS
  The particle size and zeta potential of HA-CHEMS vesicles were 131.4 ± 6.2 nm and -13.3 ± 0.04 mV,respectively. The in vitro drug release results demonstrated a pH-responsive drug release under different pH conditions. In vitro cell viability tests suggested that the encapsulation of DTX in HA-CHEMS vesicles led to more than 51.6-fold and 46.3-fold improved growth inhibition in MCF-7 and A549 cell lines,respectively compared to Taxotere®. From the cell uptake studies,the coumarin 6-loaded HA-CHEMS vesicles enhanced intracellular fluorescent intensity in the CD44-overexpressing cell line (MCF-7). Biodistribution studies revealed selective accumulation of HA-CHEMS vesicles in the MCF-7 bearing BalB/c nude mice as a result of passive accumulation and active targeting (CD44-mediated endocytosis). Compared to Taxotere®,HA-CHEMS vesicles exhibited higher antitumor activity by reducing tumor volume (P < 0.05) and drug toxicity,demonstrating the success of the multifunctional targeting delivery.
  
  
  CONCLUSIONS
  This work corresponds to the preparation of a multifunctional tumor-targeted delivery system. Our investigation shows that hyaluronan-bearing docetaxel-loaded cholesteryl hemisuccinate vesicles (HA-CHEMS vesicles) is a highly promising therapeutic system,leading to tumor regression after intravenous administration without visible toxicity.
authors.affiliation: Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, PO Box No. 122, 103 Wenhua Rd., Shenyang, 110016, People's Republic of China.
authors.forename: Shuangshuang
authors.initials: S
authors.lastname: Song
authors.forename: Fen
authors.initials: F
authors.lastname: Chen
authors.forename: Huan
authors.initials: H
authors.lastname: Qi
authors.forename: Fei
authors.initials: F
authors.lastname: Li
authors.forename: Tiegang
authors.initials: T
authors.lastname: Xin
authors.forename: Jingwen
authors.initials: J
authors.lastname: Xu
authors.forename: Tiantian
authors.initials: T
authors.lastname: Ye
authors.forename: Naicheng
authors.initials: N
authors.lastname: Sheng
authors.forename: Xinggang
authors.initials: X
authors.lastname: Yang
authors.forename: Weisan
authors.initials: W
authors.lastname: Pan
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000737:chemistry; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D000077143:Docetaxel; D004337:Drug Carriers / Q000008:administration & dosage* / Q000737:chemistry; D016503:Drug Delivery Systems / Q000379:methods*; D006820:Hyaluronic Acid / Q000008:administration & dosage* / Q000737:chemistry; D006863:Hydrogen-Ion Concentration; D061986:MCF-7 Cells; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D053758:Nanoparticles / Q000008:administration & dosage* / Q000737:chemistry; D011897:Random Allocation; D043823:Taxoids / Q000008:administration & dosage* / Q000737:chemistry; D014018:Tissue Distribution / Q000187:drug effects / Q000502:physiology; D023041:Xenograft Model Antitumor Assays / Q000379:methods
chemical_list: D000970:Antineoplastic Agents; D004337:Drug Carriers; D043823:Taxoids; D000077143:Docetaxel; D006820:Hyaluronic Acid