Cancer Drug Delivery: The Role of Extracellular Matrix Structure

Recent studies have shown that the inefficiency of nanotherapeutics in tumors can be attributed, in part, to transport hindrance posed by the vasculature, and components of the tumor interstitium. Although several agents have been used to improve the distribution and efficacy of nanotherapeutics in tumors, many of these agents have shown negative effects on tumor growth and progression. Furthermore, the exact role of the structure and organization of interstitial components like collagen on drug distribution and efficacy is not clearly known.;The goal of this thesis is to determine the effect of collagen I structure on interstitial transport and develop a clinically translatable and safe method of increasing diffusion in the tumor interstitium by modifying the structure and organization of collagen fibers. To accomplish this goal, we tested three major hypotheses. We first tested whether the transport of nanoparticles in collagen hydrogels and tumors is affected by the structure and organization of collagen fibers. Then we determined whether nanoparticle transport in tumors could be improved by modifying the interstitial collagen matrix organization and structure. Finally, we tested whether the efficacy of nanotherapeutic agents can be improved in tumors by modifying the interstitial matrix structure with a collagen modifying pharmaceutical agent.;Our findings show that modifying the structure of in vitro and in vivo collagen I networks improves nanoparticle transport and distribution. We also show that the antitumor efficacy of oncolytic HSV and liposomal doxorubicin with a clinically approved agent that modifies collagen matrices in tumors.