Journal
ACS NANO
Volume 6, Issue 5, Pages 4530-4539Publisher
AMER CHEMICAL SOC
DOI: 10.1021/nn301148e
Keywords
RGD peptide; integrin targeting; Pt(IV) complex; polymeric nanoparticle; breast cancer xenograft
Categories
Funding
- National Cancer Institute [CA034992, CA119349]
- National Institute of Biomedical Imaging and Bioengineering [EB003647]
- Koch-Prostate Cancer Foundation
- German Academic Exchange Service
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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 alpha(v)beta(3) integrin is differentially unregulated 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 alpha(v)beta(3) integrin on cancer cells using the cydic pentapeptide c(RGDfK). Cisplatin is one of the most widely used anticancer chugs, 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.
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