Targeted delivery of RGD-modified liposomes encapsulating both combretastatin A-4 and doxorubicin for tumor therapy: in vitro and in vivo studies.
Arg-Gly-Asp (RGD) modified doxorubicin-loaded liposomes could improve anticancer effect, and vascular disrupting agents (VDAs) could induce a rapid and selective shutdown of the blood vessels of tumors. We propose that RGD-modified liposomes for co-encapsulation and sequential release of vascular disrupting agent combretastatin A-4 (CA-4) and cytotoxic agent doxorubicin (Dox) could enhance tumor inhibition responses. In this study, we encapsulated Dox and CA-4 in RGD-modified liposomes. The release rate of Dox was proved to be much slower than that of CA-4 in vitro. Flow cytometry and laser confocal scanning microscopy clearly showed that RGD-modification promoted intracellular uptake of liposomal drugs by B16/B16F10 melanoma tumor cells and human umbilical vein endothelial cells (HUVECs). Cytotoxicity assay showed that the IC(50) of RGD-modified liposomes was lower than that of the corresponding unmodified liposomes. Therapeutic benefits were examined on B16F10 melanoma tumors subcutaneously growing in C57BL/6 mice. In vivo study demonstrated that RGD-modified liposomes exhibited the most pronounced tumor regression effect when both CA-4 and Dox were co-encapsulated. These results suggest that the targeted drug delivery system for co-encapsulation of vascular disrupting agents and anticancer agents may be a promising strategy for cancer treatment.
Zhang
Yi-Fei
YF
State Key Laboratory of Natural and Biomimetic Drugs, Peking University Health Science Center, Beijing, China.
Wang
Jian-Cheng
JC
Bian
Dong-Yan
DY
Zhang
Xuan
X
Zhang
Qiang
Q
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D018929:Cell Culture Techniques; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004317:Doxorubicin / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D004337:Drug Carriers / Q000737:chemistry*; D004338:Drug Combinations; D004339:Drug Compounding; D016503:Drug Delivery Systems; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D005434:Flow Cytometry; D006801:Humans; D008081:Liposomes; D008297:Male; D008546:Melanoma, Experimental / Q000188:drug therapy* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009842:Oligopeptides / Q000737:chemistry*; D013267:Stilbenes / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D004337:Drug Carriers; D004338:Drug Combinations; D008081:Liposomes; D009842:Oligopeptides; D013267:Stilbenes; C047981:arginyl-glycyl-aspartic acid; D004317:Doxorubicin; C058728:fosbretabulin