title: Sequential release of autophagy inhibitor and chemotherapeutic drug with polymeric delivery system for oral squamous cell carcinoma therapy.
abstract: Autophagy inhibition is emerging as a new paradigm for efficient cancer therapy by overcoming multidrug resistance (MDR). Here, we developed an effective chemotherapeutic system for oral squamous cell carcinoma (OSCC) based on polymeric nanomicelles for codelivery of the anticancer drug doxorubicin (DOX) and the autophagy inhibitor LY294002 (LY). The hydrophobic DOX was conjugated onto a hydrophilic and pH-responsive hyperbranched polyacylhydrazone (HPAH), forming the DOX-conjugated HPAH (HPAH-DOX). Due to its amphiphilicity, HPAH-DOX self-assembled into nanomicelles in an aqueous solution and the autophagy inhibitor LY could be loaded into the HPAH-DOX micelles. The release of DOX and LY from the LY-loaded HPAH-DOX micelles was pH-dependent, whereas LY was released significantly faster than DOX at a mildly acidic condition. The in vitro evaluation demonstrated that the LY-loaded HPAH-DOX micelles could rapidly enter cancer cells and then release LY and DOX in response to an intracellular acidic environment. Compared to the HPAH-DOX micelles and the physical mixture of HPAH-DOX and LY, the LY-loaded HPAH-DOX micelles induced a higher proliferation inhibition of tumor cells, illustrating a synergistic effect of LY and DOX. The preferentially released LY inhibited the autophagy of tumor cells and made them more sensitive to the subsequent liberation of DOX. The polymeric codelivery system for programmable release of the chemotherapy drug and the autophagy inhibitor provides a new platform for combination of traditional chemotherapy and autophagy inhibition.
authors.affiliation: Department of Oral and Maxillofacial Surgery, School of Dentistry, Harbin Medical University , 141 Yiman Street, Nangang District, Harbin 150001, People's Republic of China.
authors.forename: Wuliji
authors.initials: W
authors.lastname: Saiyin
authors.forename: Dali
authors.initials: D
authors.lastname: Wang
authors.forename: Lili
authors.initials: L
authors.lastname: Li
authors.forename: Lijuan
authors.initials: L
authors.lastname: Zhu
authors.forename: Bing
authors.initials: B
authors.lastname: Liu
authors.forename: Lijian
authors.initials: L
authors.lastname: Sheng
authors.forename: Yanwu
authors.initials: Y
authors.lastname: Li
authors.forename: Bangshang
authors.initials: B
authors.lastname: Zhu
authors.forename: Limin
authors.initials: L
authors.lastname: Mao
authors.forename: Guolin
authors.initials: G
authors.lastname: Li
authors.forename: Xinyuan
authors.initials: X
authors.lastname: Zhu
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000737:chemistry* / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D002294:Carcinoma, Squamous Cell / Q000378:metabolism; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000008:administration & dosage* / Q000737:chemistry* / Q000494:pharmacology; D004337:Drug Carriers / Q000737:chemistry; D006801:Humans; D008823:Micelles; D009062:Mouth Neoplasms / Q000378:metabolism; D011108:Polymers / Q000737:chemistry*
chemical_list: D000970:Antineoplastic Agents; D004337:Drug Carriers; D008823:Micelles; D011108:Polymers; D004317:Doxorubicin