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Renally Excreted Multimodal Silica Nanoparticles as Melanoma-Selective Therapeutic Platforms for Nanomedicine
Abstract Text:
Objectives Molecular imaging research in the Department of Radiology, MSKCC focuses on developing novel imaging approaches for improving cancer diagnosis/treatment using the latest advances in imaging probe and device technologies. One recent innovation is FDA IND-approved cancer-targeting, multimodal C dots. These silica nanoparticles are nontoxic, successfully integrating multiple functionalities for cancer diagnostics, and can be adapted for radiotherapy of melanoma. Methods A particle platform, 124I-cRGDY-PEG-dots, was synthesized for targeting ???3-integrin-expressing melanoma models using optical/PET imaging strategies. cRGDY(cyclic arginine–glycine–aspartic acid–tyrosine) binds with high affinity to ?v?3 integrin receptors overexpressed on melanoma cells, and is involved in metastasis and angiogenesis. The silica matrix is coated with PEG molecules to neutralize surface charge, eliminating immune system recognition and reducing uptake by the reticuloendothelial system. PEG molecules serve as a scaffold for attaching small numbers of cRGDY peptides and 124I radiolabels. The relatively long-lived radiolabel 124I (physical half-life:4.2 d) results in sufficient signal for extended radiodetection and maximum tumor-to-background contrast. Results Using multimodal imaging, subcutaneous hindleg melanoma xenografts were clearly visualized following intravenous injection at times spanning a 96-hr interval; results were confirmed by ex-vivo gamma counting. Region-of-interest measurements over the tumor site showed maximum accumulation of 124I-cRGDY-PEG-dots at 4-hrs and maximum tissue contrast at 24 hrs, which was statistically increased over particle controls. Implications Renally-excreted, multimodal C dots represent a first-of-its-kind, inorganic probe demonstrating tumor-selective targeting without associated toxicity. Next Steps These results have led to FDA IND approval for use in a first-in-human clinical trial of metastatic melanoma patients.
Abstract Text:
Objectives Molecular imaging research in the Department of Radiology, MSKCC focuses on developing novel imaging approaches for improving cancer diagnosis/treatment using the latest advances in imaging probe and device technologies. One recent innovation is FDA IND-approved cancer-targeting, multimodal C dots. These silica nanoparticles are nontoxic, successfully integrating multiple functionalities for cancer diagnostics, and can be adapted for radiotherapy of melanoma. Methods A particle platform, 124I-cRGDY-PEG-dots, was synthesized for targeting ???3-integrin-expressing melanoma models using optical/PET imaging strategies. cRGDY(cyclic arginine–glycine–aspartic acid–tyrosine) binds with high affinity to ?v?3 integrin receptors overexpressed on melanoma cells, and is involved in metastasis and angiogenesis. The silica matrix is coated with PEG molecules to neutralize surface charge, eliminating immune system recognition and reducing uptake by the reticuloendothelial system. PEG molecules serve as a scaffold for attaching small numbers of cRGDY peptides and 124I radiolabels. The relatively long-lived radiolabel 124I (physical half-life:4.2 d) results in sufficient signal for extended radiodetection and maximum tumor-to-background contrast. Results Using multimodal imaging, subcutaneous hindleg melanoma xenografts were clearly visualized following intravenous injection at times spanning a 96-hr interval; results were confirmed by ex-vivo gamma counting. Region-of-interest measurements over the tumor site showed maximum accumulation of 124I-cRGDY-PEG-dots at 4-hrs and maximum tissue contrast at 24 hrs, which was statistically increased over particle controls. Implications Renally-excreted, multimodal C dots represent a first-of-its-kind, inorganic probe demonstrating tumor-selective targeting without associated toxicity. Next Steps These results have led to FDA IND approval for use in a first-in-human clinical trial of metastatic melanoma patients.
