α(V)β(3) integrin-targeted PLGA-PEG nanoparticles for enhanced anti-tumor efficacy of a Pt(IV) prodrug

Targeted delivery of therapeutics to tumor neovasculature is potentially a powerful approach for selective cancer treatment. Integrins are heterodimeric transmembrane proteins involved in cell adhesion and cell signaling, and their expression is commonly upregulated in cancers and inflammatory disea...

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Bibliographic Details
Published in:ACS nano 2012-05, Vol.6 (5), p.4530
Main Authors: Graf, Nora, Bielenberg, Diane R, Kolishetti, Nagesh, Muus, Christoph, Banyard, Jacqueline, Farokhzad, Omid C, Lippard, Stephen J
Format: Article
Language:English
Subjects:
Antineoplastic Agents - therapeutic use
Cell Line, Tumor
Female
Humans
Integrin alphaVbeta3 - metabolism
Lactic Acid - chemistry
Male
Microscopy, Electron, Scanning
Nanoparticles
Organoplatinum Compounds - therapeutic use
Polyethylene Glycols - metabolism
Polyglycolic Acid - chemistry
Prodrugs - therapeutic use
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Summary:Targeted delivery of therapeutics to tumor neovasculature is potentially a powerful approach for selective cancer treatment. Integrins are heterodimeric transmembrane proteins involved in cell adhesion and cell signaling, and their expression is commonly upregulated in cancers and inflammatory diseases. The α(v)β(3) integrin is differentially upregulated on angiogenic endothelial cells as well as on many cancer cells. Here we demonstrate the differential targeting of cisplatin prodrug-encapsulated poly(d,l-lactic-co-glycolic acid)-block-polyethylene glycol (PLGA-PEG) nanoparticles (NPs) to the α(v)β(3) integrin on cancer cells using the cyclic pentapeptide c(RGDfK). Cisplatin is one of the most widely used anticancer drugs, and approaches that can improve its therapeutic index are of broad importance. The RGD-targeted Pt(IV)-encapsulated NPs displayed enhanced cytotoxicity as compared to cisplatin administered in its conventional dosage form in model prostate and breast cancer epithelial cells in vitro. Cytotoxicities were also elevated in comparison to those of previously reported systems, a small molecule Pt(IV)-RGD conjugate and a Pt(IV) nanoscale coordination polymer carrying RGD moieties. This result encouraged us also to evaluate the anticancer effect of the new construct in an animal model. The RGD-targeted PLGA-PEG NPs were more efficacious and better tolerated by comparison to cisplatin in an orthotopic human breast cancer xenograft model in vivo.
ISSN:1936-086X
DOI:10.1021/nn301148e