Ultrasmall dual-modality silica nanoparticle drug conjugates: Design, synthesis, and characterization Journal Article
| Authors: | Yoo, B.; Ma, K.; Zhang, L.; Burns, A.; Sequeira, S.; Mellinghoff, I.; Brennan, C.; Wiesner, U.; Bradbury, M. S. |
| Article Title: | Ultrasmall dual-modality silica nanoparticle drug conjugates: Design, synthesis, and characterization |
| Abstract: | The physicochemical design and synthesis of effective cancer-directed and particle-based nanotherapeutic imaging agents remains a challenging task. Of critical importance is the ability to demonstrate maximum delivery, retention, and treatment efficacy for platforms designed to deposit their cargo at sites of disease without attendant dose-limiting toxicity. In this work, we describe dual-modality nanoparticle drug conjugates (NDCs) which utilize protease sensitive linkers to attached drug compounds and imaging labels to a clinically translated class of ultrasmall silica nanoparticle (C′ dots). We describe the synthesis and characterization of these linker-drug constructs. Linkers incorporating dipeptide enzyme substrates are attached to analogs of a prototypical epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), through a cleavable amide bond or para-aminobenzyloxycarbonyl (PABC) group. These constructs are conjugated onto C′ dots leading to the desired NDCs. These NDCs exhibit fast and predictable release kinetics in the presence of model proteases, and are stable in various biological media. Finally, in vitro assays show NDCs to be highly active in reducing phosphorylated EGFR levels in H1650 cells, a human tumor-derived cell line. The data suggests that NDCs exhibit desirable properties that warrant further development toward oncological therapy. © 2015 Elsevier Ltd. All rights reserved. |
| Keywords: | controlled study; unclassified drug; enzyme inhibition; drug structure; in vitro study; drug design; structure activity relation; drug distribution; drug retention; isotope labeling; gefitinib; nanoparticle; macrogol; drug conjugation; concentration response; particle size; drug delivery; kinase inhibitor; nanopharmaceutics; drug coating; drug conjugate; controlled drug release; nanoanalysis; nanofabrication; cancer; article; lung cancer cell line; silica nanoparticle; 9 fluorenylmethoxycarbonyl n amido polyethylene(glycol) aminopropyl o des morpholino gefitinib; amino polyethylene(glycol) aminopropyl o des morpholino gefitinib; aminopropyl o des morpholino gefitinib; morpholino oligonucleotide; n (tert butyloxycarbonyl) aminopropyl o des morpholino gefitinib; o des morpholino gefitinib |
| Journal Title: | Bioorganic & Medicinal Chemistry |
| Volume: | 23 |
| Issue: | 22 |
| ISSN: | 0968-0896 |
| Publisher: | Pergamon-Elsevier Science Ltd |
| Date Published: | 2015-11-15 |
| Start Page: | 7119 |
| End Page: | 7130 |
| Language: | English |
| DOI: | 10.1016/j.bmc.2015.09.050 |
| PROVIDER: | scopus |
| PUBMED: | 26462054 |
| PMCID: | PMC4842310 |
| DOI/URL: | |
| Notes: | Export Date: 2 December 2015 -- Source: Scopus |
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