title: pH sensitive polymeric complex of cisplatin with hyaluronic acid exhibits tumor-targeted delivery and improved in vivo antitumor effect.
abstract: Cisplatin (CDDP) is widely used anticancer drug for various solid tumors including lung cancer. However, its indiscriminate distribution causes serious adverse effects and limits its therapeutic effect. In this study, by using hyaluronic acid (HA) we synthesized a complex of CDDP (HA-CDDP), by utilizing ionic interaction between Pt(2+) of CDDP with carboxyl group of HA. The mean HA-CDDP particle size was 208.5nm in PBS according to dynamic light scattering which was also confirmed by TEM, which could exert tumor-targeting property by enhanced permeability and retention (EPR) effect. The CDDP loading in this preparation was 13% (w/w), and release rate of free CDDP from the HA-CDDP complex at physiological pH (7.4) was ∼20%/day. However, in acidic pH the release was much faster, i.e., ∼95% of CDDP was released in 72h at pH 5.5. Moreover, HA-CDDP showed a 2.5-fold higher tumor accumulation than free CDDP whereas no increase of distribution was found in most normal tissues. In addition, because HA receptor CD44 is overexpressed in many tumor cells, we also observed CD44-based endocytosis of HA-CDDP in mouse lung carcinoma LCC cells. These findings together suggest that HA-CDDP may show tumor-selective cytotoxicity by taking advantage of EPR effect, weak acidic environment of tumor tissues (e.g., pH 6∼7), as well as CD44-based intracellular uptake. As expected, HA-CDDP exhibited much improved therapeutic effect than free CDDP in mouse LCC tumor model, whereas no apparent side effect was found. These findings may shed some light on the potential utility of HA for development of tumor-targeted polymeric CDDP drugs, which need further investigations.
authors.affiliation: Shanghai Chest Hospital, Shanghai Jiaotong University, Shanghai, PR China. Electronic address: elizabethfan@sina.com.
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Fan
authors.affiliation: Department of Pediatric Surgery, The First Hospital of Jilin University, Changchun, PR China.
authors.forename: Xuesong
authors.initials: X
authors.lastname: Zhao
authors.affiliation: Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiaotong University, Shanghai, PR China.
authors.forename: Xinkai
authors.initials: X
authors.lastname: Qu
authors.affiliation: Research Institute of Drug Delivery Sciences, Faculty of Pharmaceutical Sciences, Sojo University, Kumamoto, Japan. Electronic address: fanjgun@ph.sojo-u.ac.jp.
authors.forename: Jun
authors.initials: J
authors.lastname: Fang
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000378:metabolism; D018827:Carcinoma, Lewis Lung / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000008:administration & dosage* / Q000378:metabolism; D004337:Drug Carriers / Q000008:administration & dosage* / Q000378:metabolism; D016503:Drug Delivery Systems / Q000379:methods; D006820:Hyaluronic Acid / Q000008:administration & dosage* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D047368:Tumor Burden / Q000187:drug effects* / Q000502:physiology
chemical_list: D000970:Antineoplastic Agents; D004337:Drug Carriers; D006820:Hyaluronic Acid; D002945:Cisplatin
keywords: Antitumor therapy; Cisplatin; EPR effect; Hyaluronic acid; Tumor targeting