Materializing sequential killing of tumor vasculature and tumor cells via targeted polymeric micelle system.
The purpose of this study was to develop a targeted combinatorial polymeric micelle system that can sequentially kill tumor vasculature and tumor cells and increase the anticancer efficacy. Toward this goal, αvβ3 integrin-targeting peptide (RGD) functionalized polymeric micelles (RFPMs) based on the use of poly(ethylene glycol)-b-poly(d,l-lactide) (PEG-PLA) was developed. Doxorubicin was conjugated to the biodegradable PEG-PLA micelle core, and combretastatin A4 was physically encapsulated into micelles (RFPMs-DOX-CA4). The RFPMs-DOX-CA4 has a particle size of 29.2 ± 2.5nm with spherical shape and high encapsulation efficiency for both drugs (> 95%). The micelles exhibited sequential release kinetics for both drugs. Treatment with RFPMs-DOX-CA4 resulted in the sequential killing of endothelial cells and tumor cells in vitro. RFPMs displayed prolonged circulation time and more drug accumulation in solid tumor than unfunctionalized polymeric micelles (UFPMs). In B16-F10 tumor-bearing mice, RFPMs-DOX-CA4 showed stronger tumor growth inhibition and significantly higher survival rate compared with the other treatment groups. Treatment with RFPMs-DOX-CA4 caused a dramatic destruction of tumor vasculature and reduction of tumor cell proliferation in vivo. These results suggested that the integrated strategy can be exploited as a potential treatment modality for cancer.
State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, 100083, P R China.
Yiguang
Y
Wang
Tingyuan
T
Yang
Xun
X
Wang
Wenbing
W
Dai
Jiancheng
J
Wang
Xuan
X
Zhang
Zaiquan
Z
Li
Qiang
Q
Zhang
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004317:Doxorubicin / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D006801:Humans; D008545:Melanoma / Q000098:blood supply* / Q000188:drug therapy*; D051379:Mice; D008823:Micelles; D011092:Polyethylene Glycols / Q000737:chemistry; D013267:Stilbenes / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use
D000903:Antibiotics, Antineoplastic; D000970:Antineoplastic Agents; D000972:Antineoplastic Agents, Phytogenic; D008823:Micelles; D013267:Stilbenes; C542623:monomethoxypolyethyleneglycol-polylactide block copolymer; D011092:Polyethylene Glycols; D004317:Doxorubicin; C058728:fosbretabulin