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.

Dangerous liaisons: complement, coagulation, and kallikrein/kinin cross‐talk act as a linchpin in the events leading to thromboinflammation

“…This is due to formation of IgM (and IgG) antibodies to the PEGylated nanoparticles . Another strategy is to modify the surface of the liposomes with heparin of various molecular weights according to different protocols . Recently, we explored a novel strategy to produce a “stealth effect” by using a novel heparin complex that is of advantage when compared to unfractionated or low molecular weight heparin because it is built upon a multimeric heparin conjugate and therefore shows a markedly increased stability in human plasma …”

Targeting Selectins and Their Ligands in Cancer

“…A drug-free copolymer was also able to prevent lung metastases, suggesting decreased cancer cells extravasation due to inhibition of E-selectin/selectin ligands interactions. Similarly, low-molecular-weight, heparin-coated, doxorubicin-loaded liposomes were shown to inhibit melanoma metastases to the lungs by inhibiting tumor cells platelets formations ( 109 ).…”

Radionuclide therapy using 131I-labeled anti-epidermal growth factor receptor-targeted nanoparticles suppresses cancer cell growth caused by EGFR overexpression

“…The EGFR-BSA-PCL and BSA-PCL conjugates were synthesized by Liu Zhongyun, Ph.D., and Professor Chang Jin from TianJin University, Department of Polymer Materials Science and Engineering (Liu et al 2014). Nanoparticles were dissolved in 10 % Triton X-100 for measurement of BSA and cetuximab antibody content by high-performance liquid chromatography (HPLC) (Chen et al 2015). Measurement of the amount of antibody per nanoparticle was performed by the ratio of their surface areas; the BSA and EGFR protein qualification were performed by high-performance liquid chromatography (HPLC), and the detailed description is provided by in Kao et al (2013) and Cho et al (2010).…”