Multiscale Simulation of Biodegradable Diblock Copolymers for Drug Delivery

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DESCRIPTION (provided by applicant): Project Summary. In this proposal, a scheme is outlined to develop multi-scale modelling efforts of two biologically relevant, degradable diblock copolymers. These diblock copolyers self-assemble into vesicles and worm-like micelles in the aqueous phase with several unique characteristics-high stability and morphological tunability, as well efficient encapsulation of hydrophobic drugs. Particularly interesting is their ability to convect in the blood circulation for a very long time and thereby navigate through tissues and deliver high loads of drug. Upon the degradation of the hydrophobic portion of the diblock copolymer, there is a transition from the worm-like micelle to the spherical micelle state, releasing the encapsulated hydrophobic drug. Multi-scale modelling efforts are proposed that incorporate the hydrolysis effects on the stability of the worm-like micelle morphology: starting from atomistic molecular dynamics, moving to new coarse-grained models that capture experimental properties of the interfacial surface and solubilities, and finally progressing to mesoscopic simulations of entire worm-like micelles. In addition, atomistic and coarse-grained models of paclitaxel, a clinically relevant anti-cancer drug, are proposed. The partitioning of the drug in lipid and diblock copolymer membranes will be studied, and then incorporated into mesoscopic models of the worm- like micelle. A central goal of this proposal is to simulate the degradative break-up of micelles, with coordinated release of hydrophobic drugs embedded in the core for delivery to cellular targets. Relevance. State of the art simulation and modeling techniques will be used to pursue the nature of Taxol sequestration in micelles composed of biodegradable diblock copolymers. Insight gained should inform the design of novel anticancer drug delivery systems.