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(5be) Functional Gene and Drug Delivery Systems Based on Molecular Self-Assembly

Wood, K. C., Massachusetts Institute of Technology
Langer, R., Massachusetts Institute of Technology
Hammond, P. T., Massachusetts Institute of Technology

Macromolecular self-assembly has been utilized in recent years as a tool for fabricating materials systems with precisely controlled nanoscale architectures for a wide range of applications. Along the way, a toolkit of techniques has been developed which allows for the synthesis and assembly of hierarchical, self-assembled polymeric systems with complex structures and multiple functionalities. In our work, we utilize elements from this diverse toolkit to build gene and drug delivery systems in both solution and bulk states. Specifically, we are interested in building systems with highly controlled, ordered architectures that present appropriate functionalities when and where they are needed. Under this broad heading, my work involves two specific thrusts. In one area, we are building targeted gene delivery systems from a family of linear-dendritic hybrid polymers that can self-assemble with DNA to yield stable nanostructures with a series of concentric, functional ?shells? that can be independently modified. These systems can transfect cells at levels equal to that of branched poly (ethylenimine) (PEI, the best commercially available polymer for in vitro transfections) in the absence of serum proteins and better than 3-fold more efficiently in the presence of serum proteins. Moreover, these systems exhibit selective targeting to cells bearing the targeted receptor of interest and exhibit no measurable toxicity at concentrations 100-fold higher than those at which PEI is toxic. In a second area, we are using the layer-by-layer (LbL) directed self-assembly technique to construct conformal thin films capable of releasing complex, multi-drug schedules. We have examined the degradation and drug release properties of films containing a series of model therapeutics alternately deposited with a degradable, cationic poly (beta amino ester). Films exhibit linear degradation profiles and can be engineered to release multiple drugs in series or in parallel. Additionally, we have used these degradable systems to probe fundamental questions central to the architecture of all LbL films.