title: Hyaluronic acid-quercetin conjugate micelles: synthesis, characterization, in vitro and in vivo evaluation.
abstract: A tumor cell-targeted prodrug was developed for quercetin, using hyaluronic acid as polymeric carrier. Hyaluronic acid-quercetin (HA-QT) bioconjugates were synthesized by linking the hydroxy of quercetin via a succinate ester to adipic dihydrazide-modified hyaluronic acid. The mirco-morphology demonstrated that the prepared prodrug could form self-assembled micelles possessing spherical shape, 172.1 nm average diameter and -20.30 mV surface potential. The HA-QT micelles exhibited significant sustained and pH-dependent drug release behaviors without dramatic initial burst. Compared to free quercetin solution, the HA-QT micelles were found a 4 times increase in cytotoxicity on MCF-7 cells (CD44-overexpressing cell lines), while weak enhancement in inhibitory activity was observed towards L929 cells (CD44 deficient cell lines). Promisingly, 20.1-fold increase in the half-life and 4.9-fold increase in the area-under-the-curve (AUC) of quercetin were achieved for the HA-QT micelles compared with the parent drug. In addition, the HA-QT micelles also showed excellent inhibition effect on tumor growth in H22 tumor-bearing mice. Hemolytic toxicity and vein irritation assay further suggested that the HA-QT micelles were a safe and potent drug delivery system for targeted antitumor therapy.
authors.affiliation: Department of Pharmaceutics, College of Pharmacy, Shandong University, Jinan 250012, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Pang
authors.affiliation: Department of Pharmacy, Taian Rongjun Hospital of Shandong Province, Taian 271000, China.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Lu
authors.affiliation: Department of Pharmaceutics, College of Pharmacy, Shandong University, Jinan 250012, China.
authors.forename: Hongliang
authors.initials: H
authors.lastname: Du
authors.affiliation: Department of Pharmaceutics, College of Pharmacy, Shandong University, Jinan 250012, China.
authors.forename: Xiaoye
authors.initials: X
authors.lastname: Yang
authors.affiliation: Department of Pharmaceutics, College of Pharmacy, Shandong University, Jinan 250012, China. Electronic address: professorgxzhai@126.com.
authors.forename: Guangxi
authors.initials: G
authors.lastname: Zhai
mesh_terms: D002460:Cell Line; D006801:Humans; D018960:Hyaluronan Receptors / Q000737:chemistry; D006820:Hyaluronic Acid / Q000737:chemistry*; D008823:Micelles; D011794:Quercetin / Q000737:chemistry*
chemical_list: D018960:Hyaluronan Receptors; D008823:Micelles; D006820:Hyaluronic Acid; D011794:Quercetin
keywords: CD44; Hyaluronic acid; Polymer-drug conjugates; Quercetin; Tumor targeting