1 research outputs found
Mesoporous Silica Nanoparticle-Supported Lipid Bilayers (Protocells) for Active Targeting and Delivery to Individual Leukemia Cells
Many
nanocarrier cancer therapeutics currently under development,
as well as those used in the clinical setting, rely upon the enhanced
permeability and retention (EPR) effect to passively accumulate in
the tumor microenvironment and kill cancer cells. In leukemia, where
leukemogenic stem cells and their progeny circulate within the peripheral
blood or bone marrow, the EPR effect may not be operative. Thus, for
leukemia therapeutics, it is essential to target and bind individual
circulating cells. Here, we investigate mesoporous silica nanoparticle
(MSN)-supported lipid bilayers (protocells), an emerging class of
nanocarriers, and establish the synthesis conditions and lipid bilayer
composition needed to achieve highly monodisperse protocells that remain stable in complex media as assessed <i>in vitro</i> by dynamic light scattering and cryo-electron microscopy and <i>ex ovo</i> by direct imaging within a chick chorioallantoic membrane (CAM) model. We show that for vesicle fusion conditions where the lipid surface area exceeds the external surface area of the MSN and the ionic strength exceeds 20 mM, we form monosized protocells (polydispersity index <0.1) on MSN cores with varying size, shape, and pore size, whose conformal zwitterionic supported lipid bilayer confers excellent stability as judged by circulation in the CAM and minimal opsonization <i>in vivo</i> in a mouse model. Having established protocell formulations that are stable colloids, we further modified them with anti-EGFR antibodies as targeting agents and reverified their monodispersity and stability. Then, using intravital imaging in the CAM, we directly observed in real time the progression of selective targeting of individual leukemia cells (using the established REH leukemia cell line transduced with EGFR) and delivery of a model cargo. Overall, we have established the effectiveness of the protocell platform for individual cell targeting and delivery needed for leukemia and other disseminated disease