Multistage Nanoparticle Delivery System for Deep Penetration into Solid Tumor and Electrically Controlled Catalytic Nanowire Growth

Assembly of functional nanocomponents offers promising applications in drug delivery to solid tumors and bottom-up synthesis and integration of nanodevices. This thesis presents a novel multistage nanoparticle delivery system consisting of an assembly of nanoparticles that can change its size to facilitate transport into solid tumors. Current FDA-approved nanotherapeutics, which function based on the enhanced permeation and retention (EPR) effect, suffer from poor penetration into the extravascular regions of the tumor due to the dense collagen matrix, resulting in heterogeneous therapeutic effects and likely contributing to tumor regression and development of resistance. We propose a multistage nanoparticle system that "shrinks" when it extravasates into the tumor and is exposed to the tumor microenvironment, allowing enhanced penetration into the tumor parenchyma. This "shrinkage" is preferentially triggered in the tumor through cleavage by MMPs, proteases highly expressed in the tumor microenvironment. A multistage nanoparticle system allows us to engineer the size and surface properties of each stage independently for preferential transvascular transport into tumors and high diffusion in the tumor's interstitial space. To our knowledge, this work is the first demonstration of a size-changing nanoparticle delivery system in vivo. Multistage nanoparticle delivery systems provide a promising approach to improving the delivery of anticancer agents into solid tumors and as a result the enhancement of the drug's therapeutic efficacy. Another area that necessitates the controlled assembly of nanocomponents is in the integration of nanodevices and nanocircuitry. We have developed a method of combining the synthesis and assembly of semiconducting nanowires in a single step using electrically controlled catalytic nanowire growth. Our results demonstrate electric field-modulated nanowire growth that can be used as a simple and inexpensive method for fabricating and integrating nanoscale devices. Thesis Supervisor: Moungi G. Bawendi, Ph.D. Title: Lester Wolfe Professor in Chemistry