title: Combined mTOR inhibitor rapamycin and doxorubicin-loaded cyclic octapeptide modified liposomes for targeting integrin α3 in triple-negative breast cancer.
abstract: A novel therapeutic strategy combining mTOR inhibitor rapamycin (RAPA) and doxorubicin (DOX)-loaded cyclic octapeptide liposomes for targeting integrin α3 was expected to combat the triple-negative breast cancer (TNBC). RAPA was loaded into PEG-PCL polymer micelles (M-RAPA) to realize solubilization. Flow cytometry analysis and laser confocal microscopy were used to evaluate the in vitro cellular uptake. The in vivo tumor targeting and bio-distribution were investigated by living fluorescence imaging. As the results, LXY modification significantly enhanced the cellular uptake of liposomal DOX in integrin α3 overexpressed TNBC cells (MDA-MB-231) in vitro and accordingly improved the tumor accumulation of liposomes in vivo. When used alone or in combination with LXY-LS-DOX, M-RAPA could greatly inhibit the expression of HIF-1α protein, which is always highly expressed in malignant cancers and involved in tumor angiogenesis, proliferation, therapeutic resistance and poor prognosis. Meanwhile, the improved efficacy of combined targeted therapy with LXY-LS-DOX and M-RAPA was demonstrated by the in vitro cytotoxicity against model TNBC cells and in vivo anti-tumor activity against mouse bearing TNBC model. These results suggested that the targeted combinational therapy based on LXY-LS-DOX and M-RAPA systems may provide a rational strategy to improve therapeutic outcomes of TNBC.
authors.affiliation: State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
authors.forename: Wenbing
authors.initials: W
authors.lastname: Dai
authors.affiliation: State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
authors.forename: Fang
authors.initials: F
authors.lastname: Yang
authors.affiliation: State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
authors.forename: Ling
authors.initials: L
authors.lastname: Ma
authors.affiliation: State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
authors.forename: Yuchen
authors.initials: Y
authors.lastname: Fan
authors.affiliation: State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
authors.forename: Bing
authors.initials: B
authors.lastname: He
authors.affiliation: Medical and Healthy Analytical Center, Peking University, Beijing 100191, China.
authors.forename: Qihua
authors.initials: Q
authors.lastname: He
authors.affiliation: State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
authors.forename: Xueqing
authors.initials: X
authors.lastname: Wang
authors.affiliation: Medical and Healthy Analytical Center, Peking University, Beijing 100191, China.
authors.forename: Hua
authors.initials: H
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China. Electronic address: zqdodo@bjmu.edu.cn.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Zhang
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000031:analogs & derivatives* / Q000494:pharmacology; D005260:Female; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D039422:Integrin alpha3 / Q000235:genetics / Q000378:metabolism*; D008081:Liposomes; D061986:MCF-7 Cells; D051379:Mice; D008807:Mice, Inbred BALB C; D008823:Micelles; D018613:Microscopy, Confocal; D046529:Microscopy, Electron, Transmission; D011092:Polyethylene Glycols / Q000494:pharmacology; D011108:Polymers / Q000737:chemistry; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D020123:Sirolimus / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D064726:Triple Negative Breast Neoplasms / Q000628:therapy*
chemical_list: D000903:Antibiotics, Antineoplastic; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D039422:Integrin alpha3; D008081:Liposomes; D008823:Micelles; D011108:Polymers; D047428:Protein Kinase Inhibitors; C506643:liposomal doxorubicin; D011092:Polyethylene Glycols; D004317:Doxorubicin; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus
keywords: Combined therapy; Liposomal doxorubicin; Rapamycin; Targeting delivery; Triple-negative breast cancer