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Engineering tumor-targeted poly(amidoamine) (PAMAM) dendrimers for improved penetration and cellular delivery of short-interfering RNA (siRNA) through solid tumors
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Waite, Carolyn Leigh. Engineering tumor-targeted poly(amidoamine) (PAMAM) dendrimers for improved penetration and cellular delivery of short-interfering RNA (siRNA) through solid tumors. Retrieved from https://doi.org/doi:10.7282/T36M35XG

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TitleEngineering tumor-targeted poly(amidoamine) (PAMAM) dendrimers for improved penetration and cellular delivery of short-interfering RNA (siRNA) through solid tumors
NameWaite, Carolyn Leigh (author); Roth, Charles M (chair); Uhrich, Kathryn E (internal member); Moghe, Prabhas V (internal member); Shreiber, David I (internal member); Minko, Tamara (outside member); Rutgers University; Graduate School - New Brunswick
Date Created2011
Other Date2011-10 (degree)
SubjectChemical and Biochemical Engineering, Drug delivery systems, Dendrimers in medicine, Gliomas--Treatment, RNA
Extentxiv, 140 p. : ill.
DescriptionCancer 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.
NotePh.D.
NoteIncludes bibliographical references
NoteIncludes vita
Noteby Carolyn Leigh Waite
Genretheses, ETD doctoral
Persistent URLhttps://doi.org/doi:10.7282/T36M35XG
Languageeng
CollectionGraduate School - New Brunswick Electronic Theses and Dissertations
Organization NameRutgers, The State University of New Jersey
RightsThe author owns the copyright to this work.
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