Molecular Engineering of Ultrasmall Silica Nanoparticle-Drug Conjugates as Lung Cancer Therapeutics.

Autor:	Madajewski B; Department of Radiology, Sloan Kettering Institute for Cancer Research, New York, New York.; MSK-Cornell Center for Translation of Cancer Nanomedicines, Memorial Sloan Kettering Cancer Center, New York, New York., Chen F; Department of Radiology, Sloan Kettering Institute for Cancer Research, New York, New York.; MSK-Cornell Center for Translation of Cancer Nanomedicines, Memorial Sloan Kettering Cancer Center, New York, New York., Yoo B; MSK-Cornell Center for Translation of Cancer Nanomedicines, Memorial Sloan Kettering Cancer Center, New York, New York.; Department of Chemistry, Hunter College, New York, New York., Turker MZ; MSK-Cornell Center for Translation of Cancer Nanomedicines, Memorial Sloan Kettering Cancer Center, New York, New York.; Department of Materials Science and Engineering, Cornell University, Ithaca, New York., Ma K; Department of Materials Science and Engineering, Cornell University, Ithaca, New York., Zhang L; Department of Radiology, Sloan Kettering Institute for Cancer Research, New York, New York.; MSK-Cornell Center for Translation of Cancer Nanomedicines, Memorial Sloan Kettering Cancer Center, New York, New York., Chen PM; Department of Radiology, Sloan Kettering Institute for Cancer Research, New York, New York.; MSK-Cornell Center for Translation of Cancer Nanomedicines, Memorial Sloan Kettering Cancer Center, New York, New York., Juthani R; Department of Neurosurgery, Memorial Sloan Kettering Cancer Center, New York, New York., Aragon-Sanabria V; Department of Radiology, Sloan Kettering Institute for Cancer Research, New York, New York.; MSK-Cornell Center for Translation of Cancer Nanomedicines, Memorial Sloan Kettering Cancer Center, New York, New York., Gonen M; Department of Epidemiology and Biostatistics, Sloan Kettering Institute for Cancer Research, New York, New York., Rudin CM; MSK-Cornell Center for Translation of Cancer Nanomedicines, Memorial Sloan Kettering Cancer Center, New York, New York.; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York., Wiesner U; MSK-Cornell Center for Translation of Cancer Nanomedicines, Memorial Sloan Kettering Cancer Center, New York, New York. bradburm@mskcc.org brennanc2@mskcc.org ubw1@cornell.edu.; Department of Materials Science and Engineering, Cornell University, Ithaca, New York., Bradbury MS; Department of Radiology, Sloan Kettering Institute for Cancer Research, New York, New York. bradburm@mskcc.org brennanc2@mskcc.org ubw1@cornell.edu.; MSK-Cornell Center for Translation of Cancer Nanomedicines, Memorial Sloan Kettering Cancer Center, New York, New York.; Molecular Pharmacology Program, Sloan Kettering Institute for Cancer Research, New York, New York., Brennan C; MSK-Cornell Center for Translation of Cancer Nanomedicines, Memorial Sloan Kettering Cancer Center, New York, New York. bradburm@mskcc.org brennanc2@mskcc.org ubw1@cornell.edu.; Department of Neurosurgery, Memorial Sloan Kettering Cancer Center, New York, New York.
Jazyk:	angličtina
Zdroj:	Clinical cancer research : an official journal of the American Association for Cancer Research [Clin Cancer Res] 2020 Oct 15; Vol. 26 (20), pp. 5424-5437. Date of Electronic Publication: 2020 Jul 28.
DOI:	10.1158/1078-0432.CCR-20-0851
Abstrakt:	Purpose: Small-molecule inhibitors have had a major impact on cancer care. While treatments have demonstrated clinically promising results, they suffer from dose-limiting toxicities and the emergence of refractory disease. Considerable efforts made to address these issues have more recently focused on strategies implementing particle-based probes that improve drug delivery and accumulation at target sites, while reducing off-target effects. Experimental Design: Ultrasmall (<8 nm) core-shell silica nanoparticles, C' dots, were molecularly engineered to function as multivalent drug delivery vehicles for significantly improving key in vivo biological and therapeutic properties of a prototype epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, gefitinib. Novel surface chemical components were used to conjugate gefitinib-dipeptide drug-linkers and deferoxamine (DFO) chelators for therapeutic delivery and PET imaging labels, respectively. Results: Gefitinib-bound C' dots (DFO-Gef-C' dots), synthesized using the gefitinib analogue, APdMG, at a range of drug-to-particle ratios (DPR; DPR = 11-56), demonstrated high stability for DPR values≤ 40, bulk renal clearance, and enhanced in vitro cytotoxicity relative to gefitinib (LD 50 = 6.21 nmol/L vs. 3 μmol/L, respectively). In human non-small cell lung cancer mice, efficacious Gef-C' dot doses were at least 200-fold lower than that needed for gefitinib (360 nmoles vs. 78 μmoles, respectively), noting fairly equivalent tumor growth inhibition and prolonged survival. Gef-C' dot-treated tumors also exhibited low phosphorylated EFGR levels, with no appreciable wild-type EGFR target inhibition, unlike free drug. Conclusions: Results underscore the clinical potential of DFO-Gef-C' dots to effectively manage disease and minimize off-target effects at a fraction of the native drug dose. (©2020 American Association for Cancer Research.)
Databáze:	MEDLINE
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