Targeted polymeric micelle system for delivery of combretastatin A4 to tumor vasculature in vitro.
OBJECTIVE
To develop an efficient tumor vasculature-targeted polymeric micelle delivery system for combretastatin A4 (CA4), a novel antivascular agent.


METHODS
CA4-loaded micelles were prepared from poly (ethylene glycol)-b-poly (d, l-lactide) copolymers. RGD peptides that target integrins alphavbeta3 and alphavbeta5, markers of angiogenic endothelial cells, were coupled to the surface of micelles. The micelles were characterized in terms of particle size, morphology, drug loading, and drug release. Cellular uptake of micelles was evaluated by fluorometric determination and confocal microscopy. Anti-proliferation of targeted micelles was also evaluated by SRB method.


RESULTS
The mean diameters of CA4-loaded targeted micelles were 25.9 +/- 1.3 nm and spherical in shape. Approximately 4 mg/mL of micellar CA4 loading was obtained with an entrapment efficiency of 97.2 +/- 1.4%. In vitro release studies revealed that targeted micelles release CA4 in a sustained-release manner within 48 h. In vitro cellular uptake studies demonstrated that targeted micelles significantly facilitated the intracellular delivery of the encapsulated agents via integrin-mediated endocytosis. Anti-proliferation studies showed that targeted micelles containing CA4 present superior efficacy over nontargeted micelles.


CONCLUSIONS
These results suggested that RGD conjugated PEG-PLA micelles loading CA4 have potential as a new formulation for targeting angiogenic tumor vasculature.
Wang
Yiguang
Y
State Key Laboratory of Natural and Biomimetic Drugs School of Pharmaceutical Sciences, Peking University, 38 Xueyuan Road, Beijing 100083, China.
Yang
Tingyuan
T
Wang
Xun
X
Wang
Jiancheng
J
Zhang
Xuan
X
Zhang
Qiang
Q
D020533:Angiogenesis Inhibitors / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D018929:Cell Culture Techniques; D049109:Cell Proliferation / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D004305:Dose-Response Relationship, Drug; D004337:Drug Carriers / Q000737:chemistry*; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D016023:Integrins / Q000096:biosynthesis; D008823:Micelles; D018613:Microscopy, Confocal; D009842:Oligopeptides / Q000737:chemistry; D011091:Polyesters / Q000737:chemistry*; D011092:Polyethylene Glycols / Q000737:chemistry*; D012995:Solubility; D013267:Stilbenes / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology
D020533:Angiogenesis Inhibitors; D000972:Antineoplastic Agents, Phytogenic; D004337:Drug Carriers; D016023:Integrins; D008823:Micelles; D009842:Oligopeptides; D011091:Polyesters; D013267:Stilbenes; C492425:methoxy poly(ethylene glycol)-poly(lactide); D011092:Polyethylene Glycols; C047981:arginyl-glycyl-aspartic acid; C058728:fosbretabulin