Journal
DRUG DELIVERY AND TRANSLATIONAL RESEARCH
Volume 5, Issue 1, Pages 15-26Publisher
SPRINGER HEIDELBERG
DOI: 10.1007/s13346-014-0210-2
Keywords
RGD conjugated solid lipid nanoparticle; alpha(v)beta(3) integrin receptor; Cell adhesion; Cell invasion; Metastasis; Triple negative breast cancer cell
Funding
- Canadian Breast Cancer Foundation-Ontario Region
- National Science and Engineering Research Council of Canada
- University of Toronto
- University of Toronto Nanotechnology Network Award
- Anna and Alex Beverly Fellowship
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alpha(v)beta(3) integrin receptors expressed on cancer cell surfaces play a crucial role in promoting tumor angiogenesis and cancer cell metastasis. Thus, cyclic arginyl-glycylaspartic acid (cRGD) peptides have been explored as a alpha(v)beta(3) integrin receptor-specific targeting moiety for the targeted delivery of nanoparticle-loaded therapeutics. However, our previous study showed that cyclic RGD could act as a double-edged sword that, on one hand, extended the retention of cRGD-modified solid lipid nanoparticles (RGD-SLNs) at alpha(v)beta(3) integrin receptor overexpressing breast carcinoma, and yet on the other hand, decreased the amount of tumor accumulation of RGD-SLNs attributable to the greater uptake by the mononuclear phagocyte system (MPS). Therefore, we aimed to optimize the RGD-decorated nanoparticle systems for (1) inhibiting alpha(v)beta(3) integrin receptor overexpressing tumor cell metastasis and (2) increasing nanoparticle accumulation to tumor site. SLNs with cRGD content ranging from 0 to 10 % mol of total polyethyleneglycol (PEG) chains were synthesized. The binding of RGD-SLNs with alpha(v)beta(3) integrin receptors increased with increasing cRGD concentration on the nanoparticles. RGD-SLNs were demonstrated to inhibit MDA-MB-231 cell adhesion to fibronectin and invasion through Matrigel. In vivo whole-body fluorescence imaging revealed that 1 % cRGD on the SLNs' surface had maximum tumor accumulation with extended tumor retention among all formulations tested in an orthotopic MDA-MB-231/EGFP breast tumor model. This work has laid a foundation for further development of anticancer drug-loaded optimized cRGD nanoparticle formulations for the treatment of breast cancer metastasis.
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