Codelivery of Docetaxel and Ceramide Enhanced Synergistic Cancer Therapy by Lipid-based Nanosuspension
Combination therapy as novel therapeutic strategies has attracted great attention in the field of anti-cancer therapy.The principal purpose of this study was to investigate the efficient system to co-delivery of Ceramide (CE) in combination with Docetaxel (DTX) (CE+DTX).Lipid-based nanosuspension (LNS) loaded with CE and DTX (CE+DTX-LNS) was prepared by high pressure homogenization method.MTT assay and combination index (CI) assay were carried out to verify the synergistic effect in vitro.The cell apoptosis induction,Caspase-3 activity,cell cycle arrest and cytoskeleton destruction study were systematically conducted to explain the synergy mechanism.The in vivo antitumor efficacy was evaluated in murine malignant melanoma cell (B16) tumor-bearing mice.The MTT and CI results showed that simultaneous administration of CE and DTX with a molar ratio of 0.5:1 could generate the optimal synergistic effect on B16 (CI=0.31) and human breast carcinoma cell (MCF-7,CI=0.48).CE+DTX was able to induce a significant higher apoptosis in comparison with double-dose of DTX (P<0.05),and the synergistic enhancement of apoptosis was probably mediated by the significant increased levels of Caspase-3 activated by CE+DTX.CE could act synergistically with DTX and consequently contribute to the significant higher arrest in G2/M phase (P<0.01).Moreover,CE could target the microfilament actin,leading to the polymerization and destruction of actin cytoskeleton,while DTX could target and disrupt the microtubules cytoskeleton.LNS could successfully deliver CE and DTX and CE+DTX-LNS could produce a significant higher anti-tumor efficacy than either agent alone (P<0.01),which suggest promising application prospects of CE+DTX-LNS as novel delivery system to achieve combination therapy.
Ceramide Docetaxel combination therapy synergy mechanisms lipid-based nanosuspension
Lixia Feng Na Zhang
School of Pharmaceutical Science,Shandong University
国内会议
南宁
英文
1-21
2013-11-01（万方平台首次上网日期，不代表论文的发表时间）