title: PLK1shRNA and doxorubicin co-loaded thermosensitive PLGA-PEG-PLGA hydrogels for osteosarcoma treatment.
abstract: Combination cancer therapy has emerged as crucial approach for achieving superior anti-cancer efficacy. In this study, we developed a strategy by localized co-delivery of PLK1shRNA/polylysine-modified polyethylenimine (PEI-Lys) complexes and doxorubicin (DOX) using biodegradable, thermosensitive PLGA-PEG-PLGA hydrogels for treatment of osteosarcoma. When incubated with osteosarcoma Saos-2 and MG-63 cells, the hydrogel containing PLK1shRNA/PEI-Lys and DOX displayed significant synergistic effects in promoting the apoptosis of osteosarcoma cells in vitro. After subcutaneous injection of the hydrogel containing PLK1shRNA/PEI-Lys and DOX beside the tumors of nude mice bearing osteosarcoma Saos-2 xenografts, the hydrogels exhibited superior antitumor efficacy in vivo compared to the hydrogels loaded with PLK1shRNA/PEI-Lys or DOX alone. It is noteworthy that the combination treatment in vivo led to almost complete suppression of tumor growth up to 16 days, significantly enhanced PLK1 silencing, higher apoptosis of tumor masses, as well as increased cell cycle regulation. Additionally, ex vivo histological analysis of major organs of the mice indicated that the localized treatments showed no obvious damage to the organs, suggesting lower systemic toxicity of the treatments. Therefore, the strategy of localized, sustained co-delivery of PLK1shRNA and DOX by using the biodegradable, injectable hydrogel may have potential for efficient clinical treatment of osteosarcoma.
authors.affiliation: Department of Orthopaedics, The First Hospital of Jilin University, Jilin University, Changchun, Jilin 130021, China.
authors.forename: Hecheng
authors.initials: H
authors.lastname: Ma
authors.affiliation: Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, China. Electronic address: clhe@ciac.ac.cn.
authors.forename: Chaoliang
authors.initials: C
authors.lastname: He
authors.affiliation: Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, China.
authors.forename: Yilong
authors.initials: Y
authors.lastname: Cheng
authors.affiliation: Department of Orthopaedics, The First Hospital of Jilin University, Jilin University, Changchun, Jilin 130021, China.
authors.forename: Dongsong
authors.initials: D
authors.lastname: Li
authors.affiliation: Department of Orthopaedics, The First Hospital of Jilin University, Jilin University, Changchun, Jilin 130021, China.
authors.forename: Yubao
authors.initials: Y
authors.lastname: Gong
authors.affiliation: Department of Orthopaedics, The First Hospital of Jilin University, Jilin University, Changchun, Jilin 130021, China. Electronic address: jgliu.2005@aliyun.com.
authors.forename: Jianguo
authors.initials: J
authors.lastname: Liu
authors.affiliation: Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, China. Electronic address: thy@ciac.ac.cn.
authors.forename: Huayu
authors.initials: H
authors.lastname: Tian
authors.affiliation: Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, China.
authors.forename: Xuesi
authors.initials: X
authors.lastname: Chen
mesh_terms: D000818:Animals; D002453:Cell Cycle / Q000187:drug effects / Q000235:genetics; D018797:Cell Cycle Proteins / Q000378:metabolism*; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004317:Doxorubicin / Q000494:pharmacology / Q000627:therapeutic use*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D020100:Hydrogels / Q000737:chemistry*; D020287:In Situ Nick-End Labeling; D019344:Lactic Acid / Q000138:chemical synthesis / Q000737:chemistry*; D008239:Lysine / Q000737:chemistry; D008297:Male; D008819:Mice, Nude; D012516:Osteosarcoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D044367:Phase Transition / Q000187:drug effects; D011094:Polyethyleneimine / Q000737:chemistry; D011100:Polyglycolic Acid / Q000138:chemical synthesis / Q000737:chemistry*; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000378:metabolism*; D017208:Rats, Wistar; D012996:Solutions; D014018:Tissue Distribution / Q000187:drug effects; D014162:Transfection; D000097869:Polo-Like Kinase 1
chemical_list: D018797:Cell Cycle Proteins; D004317:Doxorubicin; D020100:Hydrogels; D019344:Lactic Acid; D008239:Lysine; D011094:Polyethyleneimine; D011100:Polyglycolic Acid; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D034741:RNA, Small Interfering; D012996:Solutions; D000097869:Polo-Like Kinase 1
keywords: Combination therapy; Injectable hydrogel; Localized delivery; Osteosarcoma; PLK1 silencing; Synergistic effect