Spatiotemporal Targeting of a Dual-Ligand Nanoparticle to Cancer Metastasis

• Published in: ACS nano 2015-08, Vol.9 (8), p.8012-8021
• Main Authors: Doolittle, Elizabeth, Peiris, Pubudu M, Doron, Gilad, Goldberg, Amy, Tucci, Samantha, Rao, Swetha, Shah, Shruti, Sylvestre, Meilyn, Govender, Priya, Turan, Oguz, Lee, Zhenghong, Schiemann, William P, Karathanasis, Efstathios
• Format: Article
• Language: English
• Subjects: 1,2-Dipalmitoylphosphatidylcholine - chemistry; Animals; Breast; Cancer; Cell Line, Tumor; Cholesterol - chemistry; Diagnostic Imaging - methods; Drug Compounding; Drug Delivery Systems - methods; Female; Gene Expression; Humans; Integrin alphaVbeta3 - genetics; Integrin alphaVbeta3 - metabolism; Lung Neoplasms - diagnosis; Lung Neoplasms - genetics; Lung Neoplasms - secondary; Mice; Mice, Inbred BALB C; Nanoparticles; Nanoparticles - chemistry; Nanoparticles - ultrastructure; Nanostructure; Neoplasm Transplantation; P-Selectin - genetics; P-Selectin - metabolism; Peptides; Protein Binding; Receptors; Recombinant Proteins - genetics; Recombinant Proteins - metabolism; Strategy; Triple Negative Breast Neoplasms - diagnosis; Triple Negative Breast Neoplasms - genetics; Triple Negative Breast Neoplasms - pathology; Tumors
• ISSN: 1936-0851; 1936-086X
• DOI: 10.1021/acsnano.5b01552

Various targeting strategies and ligands have been employed to direct nanoparticles to tumors that upregulate specific cell-surface molecules. However, tumors display a dynamic, heterogeneous microenvironment, which undergoes spatiotemporal changes including the expression of targetable cell-surface biomarkers. Here, we investigated a dual-ligand nanoparticle to effectively target two receptors overexpressed in aggressive tumors. By using two different chemical specificities, the dual-ligand strategy considered the spatiotemporal alterations in the expression patterns of the receptors in cancer sites. As a case study, we used two mouse models of metastasis of triple-negative breast cancer using the MDA-MB-231 and 4T1 cells. The dual-ligand system utilized two peptides targeting P-selectin and αvβ3 integrin, which are functionally linked to different stages of the development of metastatic disease at a distal site. Using in vivo multimodal imaging and post mortem histological analyses, this study shows that the dual-ligand nanoparticle effectively targeted metastatic disease that was otherwise missed by single-ligand strategies. The dual-ligand nanoparticle was capable of capturing different metastatic sites within the same animal that overexpressed either receptor or both of them. Furthermore, the highly efficient targeting resulted in 22% of the injected dual-ligand nanoparticles being deposited in early-stage metastases within 2 h after injection.