TY - JOUR TI - Engineering tumor-targeted poly(amidoamine) (PAMAM) dendrimers for improved penetration and cellular delivery of short-interfering RNA (siRNA) through solid tumors DO - https://doi.org/doi:10.7282/T36M35XG PY - 2011 AB - Cancer remains the second leading cause of death in the United States, despite significant advances in anticancer research. The standard-of-care for the treatment of cancer includes surgery in conjunction with traditional chemotherapy drugs or radiation therapy. However, the inherent cytotoxicity of conventional chemotherapeutics often causes adverse side effects in patients. Nanoscale materials have found utility for drug delivery to tumors as they accumulate in the tumor vasculature , reducing the necessary drug dose to patients. They have also proven useful to deliver unconventional drugs, including short-interfering RNA (siRNA), which is being explored to silence oncogenes. However, the current lack of safe, efficient siRNA delivery systems limits its widespread clinical use. The objective of this dissertation was to study the ability of poly(amidoamine) (PAMAM) dendrimers to facilitate the delivery of siRNA to malignant glioma on the cellular and tumor tissue levels. The intracellular delivery aspects of PAMAM-mediated siRNA delivery to malignant glioma cells were explored by employing partial surface amine acetylation of PAMAM dendrimers to reduce their net positive charge This work demonstrated the importance of endosomal buffering and the advantages of charge reduction on siRNA delivery. The ability of PAMAM dendrimers to mediate tumor-targeted siRNA delivery to tumor tissue was also studied. Dendrimers were modified to display various numbers of RGD peptides, and the number of peptides present influenced the distribution of siRNA cargo throughout a three-dimensional tumor model of malignant glioma. A biophysical analysis was performed to elucidate the transport mechanisms governing the tumoral penetration of these bioconjugates, and cellular binding affinity was found to influence significantly the transport of the bioconjugate materials through solid tumors. The results from this dissertation provide insights into the mechanisms governing siRNA delivery to cancer on both the cellular and tumor tissue levels. Design guidelines for tumor-targeted nanoscale siRNA delivery vectors were derived, and a methodology was developed to understand the mechanisms governing the penetration and transport of siRNA drugs throughout solid tumors. This work will help other researchers to design more effective drug delivery systems for anticancer applications, and it may impact the effect of siRNA and nanoscale materials on human disease. KW - Chemical and Biochemical Engineering KW - Drug delivery systems KW - Dendrimers in medicine KW - Gliomas--Treatment KW - RNA LA - eng ER -