Many nanomaterials based cancer therapeutics under development and those currently utilized in clinical settings, rely on the enhanced permeability and retention (EPR) effect to passively accumulate in tumors. However, the EPR effect has limited utility in disseminated disease, such as leukemia, in which active cell targeting is required. To address this need, we developed highly stable, monosized therapeutic nanoparticles based on the protocell platform. The protocell consists of a mesoporous silica nanoparticle (MSN) encapsulated within a supported lipid bilayer and forms a modular platform composed of interchangeable biocompatible components. Utilizing the protocell platform, we developed a highly specific delivery vehicle targeted to CD19 expression on B-cell leukemia using both antibodies and scFvs as targeting agents.  During the development phase, ideal conditions for protocell creation were identified and drug loading of two therapeutic agents, gemcitabine and cytarabine, was quantified. The biological interaction of the targeted protocells was characterized utilizing a naturally CD19 negative T-cell leukemia cell line and a matched T-cell leukemia cell line engineered to express CD19. Using this cell line pair, we examined protocell binding, internalization and cargo delivery characteristics <i>in vitro. </i>As leukemia is a disseminated disease in the bloodstream, we examined both binding and cargo delivery to leukemia cells utilizing the vascularized chick chorioallantoic membrane (CAM) model and intra vital imaging. Using the CAM system, we demonstrated targeting binding and small molecule delivery to CD19 expressing cells while sparing CD19 negative cells within the vasculature.  We then extended the binding and delivery studies within the CAM to a naturally CD19 expressing B-cell leukemia cell line.  Following demonstration of cargo delivery, we demonstrated specific therapeutic delivery of both cytarabine and gemcitabine to CD19 positive engineered T-cells and naturally CD19 expressing B-cells while sparing the CD19 negative T-cells.  Finally, we demonstrated specific binding and cargo delivery within the vascularized CAM system to patient derived leukemia samples which express CD19, but not patient samples in which CD19 expression has been lost.<br/>

Active targeting and small molecule delivery to individual leukemia cells utilizing mesoporous silica nanoparticle-supported bilayers (protocells)

254th National Meeting (2017)

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