title: Reversibly crosslinked hyaluronic acid nanoparticles for active targeting and intelligent delivery of doxorubicin to drug resistant CD44+ human breast tumor xenografts.
abstract: The existence of drug resistance poses a major obstacle for the treatment of various malignant human cancers. Here, we report on reduction-sensitive reversibly crosslinked hyaluronic acid (HA) nanoparticles based on HA-Lys-LA conjugates (Lys: l-lysine methyl ester, LA: lipoic acid) for active targeting delivery of doxorubicin (DOX) to CD44+ breast cancers in vitro and in vivo, effectively overcoming drug resistance (ADR). HA-Lys-LA with degrees of substitution of 5, 10 and 28% formed robust nano-sized nanoparticles (152-219nm) following auto-crosslinking. DOX-loaded crosslinked nanoparticles revealed inhibited DOX release under physiological conditions while fast drug release in the presence of 10mM glutathione (GSH). Notably, MTT assays showed that DOX-loaded crosslinked HA-Lys-LA10 nanoparticles possessed an apparent targetability and a superior antitumor activity toward CD44 receptor overexpressing DOX-resistant MCF-7 human breast cancer cells (MCF-7/ADR). The in vivo pharmacokinetics and biodistribution studies in MCF-7/ADR tumor xenografts in nude mice showed that DOX-loaded crosslinked HA-Lys-LA10 nanoparticles had a prolonged circulation time and a remarkably high accumulation in the tumor (12.71%ID/g). Notably, DOX-loaded crosslinked HA-Lys-LA10 nanoparticles exhibited effective inhibition of tumor growth while continuous tumor growth was observed for mice treated with free drug. The Kaplan-Meier survival curves showed that in contrast to control groups, all mice treated with DOX-loaded crosslinked HA-Lys-LA10 nanoparticles survived over an experimental period of 44days. Importantly, DOX-loaded crosslinked HA nanoparticles caused low side effects. The reversibly crosslinked hyaluronic acid nanoparticles with excellent biocompatibility, CD44-targetability, and effective reversal of drug resistance have a great potential in cancer therapy.
authors.affiliation: Biomedical Polymers Laboratory, and Jiangsu Key Laboratory of Advanced Functional Polymer Design and Application, College of Chemistry, Chemical Engineering and Materials Science, Soochow University, Suzhou 215123, PR China.
authors.forename: Yinan
authors.initials: Y
authors.lastname: Zhong
authors.affiliation: Biomedical Polymers Laboratory, and Jiangsu Key Laboratory of Advanced Functional Polymer Design and Application, College of Chemistry, Chemical Engineering and Materials Science, Soochow University, Suzhou 215123, PR China.
authors.forename: Jian
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Biomedical Polymers Laboratory, and Jiangsu Key Laboratory of Advanced Functional Polymer Design and Application, College of Chemistry, Chemical Engineering and Materials Science, Soochow University, Suzhou 215123, PR China. Electronic address: rcheng@suda.edu.cn.
authors.forename: Ru
authors.initials: R
authors.lastname: Cheng
authors.affiliation: Biomedical Polymers Laboratory, and Jiangsu Key Laboratory of Advanced Functional Polymer Design and Application, College of Chemistry, Chemical Engineering and Materials Science, Soochow University, Suzhou 215123, PR China.
authors.forename: Chao
authors.initials: C
authors.lastname: Deng
authors.affiliation: Biomedical Polymers Laboratory, and Jiangsu Key Laboratory of Advanced Functional Polymer Design and Application, College of Chemistry, Chemical Engineering and Materials Science, Soochow University, Suzhou 215123, PR China.
authors.forename: Fenghua
authors.initials: F
authors.lastname: Meng
authors.affiliation: Department of Pathology, School of Biology and Basic Medical Sciences, Soochow University, Suzhou 215123, PR China. Electronic address: xiefang@suda.edu.cn.
authors.forename: Fang
authors.initials: F
authors.lastname: Xie
authors.affiliation: Biomedical Polymers Laboratory, and Jiangsu Key Laboratory of Advanced Functional Polymer Design and Application, College of Chemistry, Chemical Engineering and Materials Science, Soochow University, Suzhou 215123, PR China. Electronic address: zyzhong@suda.edu.cn.
authors.forename: Zhiyuan
authors.initials: Z
authors.lastname: Zhong
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D002626:Chemistry, Pharmaceutical; D003432:Cross-Linking Reagents / Q000737:chemistry*; D004317:Doxorubicin / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D004337:Drug Carriers; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism*; D006820:Hyaluronic Acid / Q000031:analogs & derivatives / Q000737:chemistry*; D007275:Injections, Intravenous; D008239:Lysine / Q000031:analogs & derivatives / Q000737:chemistry; D061986:MCF-7 Cells; D008819:Mice, Nude; D058990:Molecular Targeted Therapy; D050997:Nanomedicine; D053758:Nanoparticles; D012995:Solubility; D013678:Technology, Pharmaceutical / Q000379:methods; D008063:Thioctic Acid / Q000737:chemistry; D014018:Tissue Distribution; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000903:Antibiotics, Antineoplastic; C497483:CD44 protein, human; D003432:Cross-Linking Reagents; D004337:Drug Carriers; D018960:Hyaluronan Receptors; C015331:L-lysine methyl ester; D008063:Thioctic Acid; D004317:Doxorubicin; D006820:Hyaluronic Acid; D008239:Lysine
keywords: CD44-targeting; Cancer therapy; Crosslinked nanoparticles; Drug resistance; Hyaluronic acid; Reduction-sensitive