Molecular engineering of ultrasmall silica nanoparticle-drug conjugates as lung cancer therapeutics Journal Article
| Authors: | Madajewski, B.; Chen, F.; Yoo, B.; Turker, M. Z.; Ma, K.; Zhang, L.; Chen, P. M.; Juthani, R.; Aragon-Sanabria, V.; Gonen, M.; Rudin, C. M.; Wiesner, U.; Bradbury, M. S.; Brennan, C. |
| Article Title: | Molecular engineering of ultrasmall silica nanoparticle-drug conjugates as lung cancer therapeutics |
| Abstract: | 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 gefitinibdipeptide 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 drugto-particle ratios (DPR; DPR = 11-56), demonstrated high stability for DPR values <= 40, bulk renal clearance, and enhanced in vitro cytotoxicity relative to gefitinib (LD50 = 6.21 nmol/L vs. 3 mmol/ 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 mmoles, respectively), noting fairly equivalent tumor growth inhibition and prolonged survival. Gef-C' dot-treated tumors also exhibited low phosphorylated EFGR levels, with no appreciable wildtype EGFR target inhibition, unlike free drug. Conclusions: Results underscore the clinical potential of DFOGef-C' dots to effectively manage disease and minimize off-target effects at a fraction of the native drug dose. |
| Keywords: | proteins; melanoma; inhibitor; gefitinib; in-vitro; tyrosine kinase; design; growth-factor receptor; delivery; egfrviii |
| Journal Title: | Clinical Cancer Research |
| Volume: | 26 |
| Issue: | 20 |
| ISSN: | 1078-0432 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2020-10-15 |
| Start Page: | 5424 |
| End Page: | 5437 |
| Language: | English |
| ACCESSION: | WOS:000582352800018 |
| DOI: | 10.1158/1078-0432.Ccr-20-0851 |
| PROVIDER: | wos |
| PMCID: | PMC7686858 |
| PUBMED: | 32723835 |
| Notes: | Article -- Source: Wos |
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