23 February 2018 Nanoparticle bioconjugate for controlled cellular delivery of doxorubicin
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Abstract
Nanoparticle (NP)-mediated drug delivery offers the potential to overcome limitations of systemic delivery, including the ability to specifically target cargo and control release of NP-associated drug cargo. Doxorubicin (DOX) is a widely used FDA-approved cancer therapeutic; however, multiple side effects limit its utility. Thus, there is wide interest in modulating toxicity after cell delivery. Our goal here was to realize a NP-based DOX-delivery system that can modulate drug toxicity by controlling the release kinetics of DOX from the surface of a hard NP carrier. To achieve this, we employed a quantum dot (QD) as a central scaffold which DOX was appended via three different peptidyl linkages (ester, disulfide, hydrazone) that are cleavable in response to various intracellular conditions. Attachment of a cell penetrating peptide (CPP) containing a positively charged polyarginine sequence facilitates endocytosis of the ensemble. Polyhistidine-driven metal affinity coordination was used to self-assemble both peptides to the QD surface, allowing for fine control over both the ratio of peptides attached to the QD as well as DOX dose delivered to cells. Microplate-based Förster resonance energy transfer assays confirmed the successful ratiometric assembly of the conjugates and functionality of the linkages. Cell delivery experiments and cytotoxicity assays were performed to compare the various cleavable linkages to a control peptide where DOX is attached through an amide bond. The role played by various attachment chemistries used in QD-peptide-drug assemblies and their implications for the rationale in design of NPbased constructs for drug delivery is described here.
Conference Presentation
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Ajmeeta Sangtani, Eleonora Petryayeva, Miao Wu, Kimihiro Susumu, Eunkeu Oh, Alan L. Huston, Guillermo Lasarte-Aragones, Igor L. Medintz, W. Russ Algar, James B. Delehanty, "Nanoparticle bioconjugate for controlled cellular delivery of doxorubicin", Proc. SPIE 10507, Colloidal Nanoparticles for Biomedical Applications XIII, 105070M (23 February 2018); doi: 10.1117/12.2290031; https://doi.org/10.1117/12.2290031
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