title: Conjugating an anticancer drug onto thiolated hyaluronic acid by acid liable hydrazone linkage for its gelation and dual stimuli-response release.
abstract: A prodrug gelation strategy was developed for the sustained and dual stimuli-response release of doxorubicin hydrochloride (DOX·HCl), a commonly used anticancer drug. For this purpose, the chemical conjugation of DOX·HCl onto thiolated hyaluronic acid (HA) was carried out by an acid liable hydrazone linkage and verified by (1)H NMR analyses. When exposed to the air, such a polysaccharide conjugate showed unique self-gelation ability in aqueous solution. The gelation time and extent depended mainly on the content of thiol groups on thiolated HA. The resultant hydrogel exhibited a dominant elastic response and a thixotropic property. In particular, it could release sustainably conjugated DOX·HCl in dual pH- and reduction-responsive modes. The cumulative drug release was found to be significantly accelerated under the conditions mimicking the intracellular environments of cancer cells. The in vitro cytotoxicity assays for the human nasopharyngeal carcinoma CNE2 cells treated with various release media confirmed the effectiveness of this conjugate hydrogel for cancer cell inhibition.
authors.affiliation: PCFM Lab and GDHPPC Lab, Institute of Polymer Science, Department of Polymer and Materials Science, School of Chemistry and Chemical Engineering, Sun Yat-sen University, Guangzhou 510275, China; Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Science, Sun Yat-sen University, Guangzhou 510006, China.
authors.forename: Chaoping
authors.initials: C
authors.lastname: Fu
authors.affiliation: Department of Otorhinolaryngology Head and Neck Surgery, Zhujiang Hospital, Southern Medical University, Guangzhou 510282, China.
authors.forename: Hailiang
authors.initials: H
authors.lastname: Li
authors.affiliation: PCFM Lab and GDHPPC Lab, Institute of Polymer Science, Department of Polymer and Materials Science, School of Chemistry and Chemical Engineering, Sun Yat-sen University, Guangzhou 510275, China.
authors.forename: Nannan
authors.initials: N
authors.lastname: Li
authors.affiliation: Department of Otorhinolaryngology Head and Neck Surgery, Zhujiang Hospital, Southern Medical University, Guangzhou 510282, China.
authors.forename: Xiangwan
authors.initials: X
authors.lastname: Miao
authors.affiliation: Department of Otorhinolaryngology Head and Neck Surgery, Zhujiang Hospital, Southern Medical University, Guangzhou 510282, China.
authors.forename: Minqiang
authors.initials: M
authors.lastname: Xie
authors.affiliation: Department of Chemistry, Central Michigan University, Mount Pleasant, MI 48858, USA.
authors.forename: Wenjun
authors.initials: W
authors.lastname: Du
authors.affiliation: PCFM Lab and GDHPPC Lab, Institute of Polymer Science, Department of Polymer and Materials Science, School of Chemistry and Chemical Engineering, Sun Yat-sen University, Guangzhou 510275, China; Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Science, Sun Yat-sen University, Guangzhou 510006, China. Electronic address: ceszhlm@mail.sysu.edu.cn.
authors.forename: Li-Ming
authors.initials: LM
authors.lastname: Zhang
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000737:chemistry*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003692:Delayed-Action Preparations / Q000008:administration & dosage / Q000737:chemistry; D004317:Doxorubicin / Q000008:administration & dosage* / Q000737:chemistry*; D065546:Drug Liberation; D006801:Humans; D006820:Hyaluronic Acid / Q000737:chemistry*; D006835:Hydrazones / Q000737:chemistry; D020100:Hydrogels; D006863:Hydrogen-Ion Concentration; D013438:Sulfhydryl Compounds / Q000737:chemistry
chemical_list: D000970:Antineoplastic Agents; D003692:Delayed-Action Preparations; D006835:Hydrazones; D020100:Hydrogels; D013438:Sulfhydryl Compounds; D004317:Doxorubicin; D006820:Hyaluronic Acid
keywords: Cancer cell inhibition; Chemical conjugation; Doxorubicin hydrochloride; Gelation; Stimuli-responsive release; Thiolated hyaluronic acid