Nanoparticle mediated drug delivery (NMDD) is a rapidly developing field aimed at improving the efficacy of therapeutics that currently rely on systemic delivery, which often produces numerous secondary side effects. NMDD aims to overcome these shortfalls by potentially increasing circulation time, adding specified targeting or incorporating visualization capabilities within one particle complex. One critical area of NMDD research focuses on the release of the drug cargo from the nanoparticle (NP) through one of three general methods: 1) passive release 2) active release facilitated via an environmental change (pH, REDOX) or 3) active release triggered by an external source (UV, magnetism). This research focuses on designing a new method of active cargo actuation triggered via the extracellular addition of a secondary molecule. Our complex utilizes quantum dots (QDs) as the central NP scaffold, with maltose binding protein (MBP) appended onto the QD surface and loaded with either a drug or dye molecule conjugated to the maltose analog beta-cyclodextrin (βCD). In choosing the QD as the central scaffold, Förster resonance energy transfer (FRET) can be used to visualize cargo release, as the 520 nm QD acts as an ideal FRET donor for both the dye, TideFluor3 (TF3), and drug, doxorubicin (DOX), chosen as cargo. Actuation of the cargo from the NP is facilitated through the addition of maltose, which competitively displaces the βCD from the MBP binding pocket. As the cargo is released, the QD photoluminescent intensity changes and the associated FRET change can be quantified. Microplate analysis of these constructs showed a dynamic response to increasing concentrations of maltose that was directly monitored as a change in FRET. The efficacy of these constructs in vitro was determined by microinjecting them into the cytosol of COS-1 cells and monitoring their stability and maltose-associated cargo release over time using FRET-based confocal microscopy. Our results show the potential efficacy of these self-assembled QD-MBP-βCD to facilitate intracellular cargo actuation through the extracellular addition of a well-tolerated nutrient. We anticipate that this method of extracellularly triggered cargo release will be useful for future development of in vivo on-demand drug delivery.

Design of quantum dot-protein bioconjugates for extracellular control of intracellular drug release

256th National Meeting (2018)

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