Radhika Narayanaswamy1, Vladimir P Torchilin2,3. 1. Center for Pharmaceutical Biotechnology and Nanomedicine, Northeastern University, 140 The Fenway Building 360 Huntington Avenue, Boston, Massachusetts, 02115, USA. 2. Center for Pharmaceutical Biotechnology and Nanomedicine, Northeastern University, 140 The Fenway Building 360 Huntington Avenue, Boston, Massachusetts, 02115, USA. v.torchilin@neu.edu. 3. Department of Oncology, Radiotherapy and Plastic Surgery, I.M. Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russia. v.torchilin@neu.edu.
Abstract
PURPOSE: To develop immunoliposomes modified with monoclonal cancer-specific antibody (mAb) 2C5 and co-loaded with a combination of two chemotherapeutics, in order to simultaneously target bulk cancer cells using paclitaxel and cancer stem cells (CSCs) using salinomycin to prevent cancer growth and metastases. METHODS: Breast cancer cells (MDA-MB-231 and/or SK-BR-3) were chosen as models for all in vitro testing. Liposomes composed of natural phospholipids co-loaded with salinomycin and paclitaxel were prepared and physically characterized. Immunoliposomes modified with mAb 2C5 coupled to polymeric conjugate were prepared and characterized for specific targeting. Wound healing assay was performed using the combination of free drugs in vitro. In vitro studies on cellular interaction and uptake were followed by holographic imaging to study cell-killing, cell-division and proliferation inhibiting effects of the formulation. Ex-vivo study on hemolysis was investigated to check possible toxicity of the formulation. RESULTS: Physical characterization of the liposomes showed stable nanoparticles of consistent and desirable size range (170-220 nm), zeta potential (-13 mV to - 20 mV), polydispersity indices (<0.2) and drug encapsulation efficiencies (~150 μg per ml for salinomycin, ~210 μg/ml for paclitaxel and 1:1 for combination drug loaded liposomes). Combination therapy strongly affected cancer cell proliferation as shown by significant diminishing of artificial gap closure at the wound site on MDA-MB-231 cells in culture using wound healing assay. Quantitation of changes in wound widths showed ~219 μm for drug combination, ~104 μm for only paclitaxel, and ~ 7 μm for only salinomycin treatments. Statistically significant increase in cellular interaction and specific uptake of the targeted drug co-loaded liposomal nanopreparation (p value ≤ 0.05) by MDA-MB-231 and SK-BR-3 cells confirmed the effectiveness of the approach. Holographic imaging using MDA-MB-231 cells produced visible increase in cell-killing, proliferation and division in vitro. Ex-vivo experimentation showed reduced hemolysis correlating with low toxicity in athymic nude mice model. CONCLUSION: The results demonstrated the enhanced therapeutic efficacy of a combination of salinomycin and paclitaxel delivered by mAb 2C5-modified liposomal preparation in cancer therapy.
PURPOSE: To develop immunoliposomes modified with monoclonal cancer-specific antibody (mAb) 2C5 and co-loaded with a combination of two chemotherapeutics, in order to simultaneously target bulk cancer cells using paclitaxel and cancer stem cells (CSCs) using salinomycin to prevent cancer growth and metastases. METHODS:Breast cancer cells (MDA-MB-231 and/or SK-BR-3) were chosen as models for all in vitro testing. Liposomes composed of natural phospholipids co-loaded with salinomycin and paclitaxel were prepared and physically characterized. Immunoliposomes modified with mAb 2C5 coupled to polymeric conjugate were prepared and characterized for specific targeting. Wound healing assay was performed using the combination of free drugs in vitro. In vitro studies on cellular interaction and uptake were followed by holographic imaging to study cell-killing, cell-division and proliferation inhibiting effects of the formulation. Ex-vivo study on hemolysis was investigated to check possible toxicity of the formulation. RESULTS: Physical characterization of the liposomes showed stable nanoparticles of consistent and desirable size range (170-220 nm), zeta potential (-13 mV to - 20 mV), polydispersity indices (<0.2) and drug encapsulation efficiencies (~150 μg per ml for salinomycin, ~210 μg/ml for paclitaxel and 1:1 for combination drug loaded liposomes). Combination therapy strongly affected cancer cell proliferation as shown by significant diminishing of artificial gap closure at the wound site on MDA-MB-231 cells in culture using wound healing assay. Quantitation of changes in wound widths showed ~219 μm for drug combination, ~104 μm for only paclitaxel, and ~ 7 μm for only salinomycin treatments. Statistically significant increase in cellular interaction and specific uptake of the targeted drug co-loaded liposomal nanopreparation (p value ≤ 0.05) by MDA-MB-231 and SK-BR-3 cells confirmed the effectiveness of the approach. Holographic imaging using MDA-MB-231 cells produced visible increase in cell-killing, proliferation and division in vitro. Ex-vivo experimentation showed reduced hemolysis correlating with low toxicity in athymic nude mice model. CONCLUSION: The results demonstrated the enhanced therapeutic efficacy of a combination of salinomycin and paclitaxel delivered by mAb 2C5-modified liposomal preparation in cancer therapy.
Entities:
Keywords:
cancer stem cells; cancer therapy; combination therapy; liposomes; monoclonal antibody 2C5; paclitaxel; salinomycin; targeted drug delivery
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