Nanoparticle (NP)-mediated drug delivery offers many potential benefits over the traditional systemic delivery of therapeutic drug compounds including the ability to specifically target and control the release of the NP-associated drug cargo. Doxorubicin (DOX) is a widely used FDA-approved cancer therapeutic that has been shown to be effective for the treatment of a variety of cancers. However, one of the many side effects of systemic administration of DOX is cardiac toxicity, which limits the utility of this otherwise very potent anti-cancer drug. Thus, there is wide interest in understanding to what extent DOX toxicity can be modulated once delivered to cells. Here, we utilize a quantum dot (QD) as a central scaffold to conjugate DOX via three different peptidyl linkages (ester, disulfide, hydrazone) that are responsive to enzymatic cleavage, reducing conditions and low pH, respectively. The QD-[peptide-DOX] complex is endocytosed into cells by appending a cell penetrating peptide (CPP) containing a highly positive polyarginine sequence which facilitates uptake of the complex. Polyhistidine-driven metal affinity coordination will be used to self-assemble both peptides to the QD surface. This allows fine control over the ratio of peptides attached to the QD in the ensemble. Importantly, this allows for the fine control over the dosage of DOX delivered to cells by simply varying the number of copies of peptide-DOX assembled onto the QD surface. Gel electrophoresis, dynamic light scattering studies and microplate-based Förster resonance energy transfer assays confirmed the successful ratiometric assembly of the conjugates. Cell delivery experiments were performed to track the residence of the QD-[peptide-DOX]-CPP complexes in the endocytic pathway and distinct differences amongst the various peptide-DOX conjugates are noted. Cytotoxicity assays confirm the augmented cell killing of the QD-[peptide-DOX]-CPP conjugate when the DOX is attached via an ester linkage compared to a control peptide where the DOX is attached through an amide bond. Attachment of the DOX through hydrazone and disulfide linkages show intermediary cytotoxicity. Here, we discuss the results in the context of the role played by various attachment chemistries used in QD-peptide-drug assemblies and their implications for the rationale in design of nanoparticle-based constructs for drug delivery.

Spatiotemporal modulation of doxorubicin toxicity via delivery as a nanoparticle-bioconjugate complex

254th National Meeting (2017)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.