title: A low-molecular-weight heparin-coated doxorubicin-liposome for the prevention of melanoma metastasis.
abstract: Tumor metastasis is the biggest challenge in cancer therapy. During the metastasis process, metastatic cells could acquire stealth ability toward immune system through the formation of a protection cloak by hijacking platelets (PTs). Heparins, a heterogeneous mixture of glycosaminoglycans, can inhibit metastatic cascades by blocking P-selectin-mediated intercellular adhesion between tumor cells and PTs. In this study, low-molecular-weight heparin-coated doxorubicin-loaded liposome (LMWH-DOX-Lip) was developed for metastasis preventative therapy. The formation of LMWH-DOX-Lip was based on electrostatic interactions between the negatively charged heparins and cationic lipids. LMWH-DOX-Lip prepared at the optimum prescription possessed high entrapment efficiency, ideal particle size and zeta potential. Morphology of LMWH-DOX-Lip was characterized by atomic force microscopy and transmission electron microscopy. The results of confocal microscopic observations and flow cytometry analysis indicated that LMWH-DOX-Lip mediated an efficient cellular uptake in B16F10 melanoma cell line. Besides, LMWH-DOX-Lip displayed an increased cytotoxic over their unmodified counterparts. Furthermore, the inhibition effect of LMWH-DOX-Lip on adhesion between tumor cells and PTs/P-selectin was observed. In vivo study performed on a pulmonary melanoma mouse model revealed a substantially tumor metastasis prevention by LMWH-DOX-Lip. All these results suggested that LMWH-DOX-Lip could significantly inhibit metastasis through preventing the tumor cell-platelet interactions and in the meantime suppressed tumor growth.
authors.affiliation: State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University , Nanjing , P.R. China and.
authors.forename: Yi
authors.initials: Y
authors.lastname: Chen
authors.forename: Jianqing
authors.initials: J
authors.lastname: Peng
authors.forename: Miaomiao
authors.initials: M
authors.lastname: Han
authors.forename: Mezghrani
authors.initials: M
authors.lastname: Omar
authors.forename: Danrong
authors.initials: D
authors.lastname: Hu
authors.forename: Xue
authors.initials: X
authors.lastname: Ke
authors.forename: Na
authors.initials: N
authors.lastname: Lu
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage / Q000494:pharmacology; D001792:Blood Platelets / Q000378:metabolism; D004317:Doxorubicin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D006495:Heparin, Low-Molecular-Weight / Q000737:chemistry* / Q000494:pharmacology; D008175:Lung Neoplasms / Q000517:prevention & control* / Q000556:secondary; D008297:Male; D008546:Melanoma, Experimental / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018625:Microscopy, Atomic Force; D046529:Microscopy, Electron, Transmission; D019007:P-Selectin / Q000378:metabolism; D010316:Particle Size; D011092:Polyethylene Glycols / Q000008:administration & dosage / Q000494:pharmacology; D055672:Static Electricity
chemical_list: D000903:Antibiotics, Antineoplastic; D006495:Heparin, Low-Molecular-Weight; D019007:P-Selectin; C506643:liposomal doxorubicin; D011092:Polyethylene Glycols; D004317:Doxorubicin
keywords: B16F10 melanoma; P-selectin; liposome; low-molecular-weight heparin; lung metastasis