Journal
BIOORGANIC & MEDICINAL CHEMISTRY
Volume 23, Issue 22, Pages 7119-7130Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2015.09.050
Keywords
Nanoparticle; Drug delivery; Drug conjugate; Kinase inhibitor; Cancer
Funding
- Experimental Therapeutics Center of Memorial Sloan-Kettering Cancer Center
- Commonwealth Foundation for Cancer Research
- NIH/NCI Center of Cancer Nanotechnology Excellence Grant [1 U54 CA199081-01]
- Dana Foundation Award
- Brain and Immuno-Imaging program
- NIH Center [P30 CA008748]
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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. (C) 2015 Elsevier Ltd. All rights reserved.
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