PROGRAM | Materials Science and Engineering

By: Vinu Krishnan Chair: Ayyappan K. Rajasekaran Co-Chair: Xinqiao Jia

ABSTRACT

Chemotherapy for pediatric cancers employs combinations of highly toxic drugs. This has achieved 5-year survival rates exceeding 90% in children treated for leukemia – the most prominent form of pediatric cancer. However, delayed onset of harmful side effects in more than 60% of survivors result in death or low quality of life post therapy. This is primarily due to the non-specific effect of drugs on healthy dividing cells in a growing child. Nanomedicine has advanced tremendously to improve adult cancer therapy, but as yet has had minimal impact in pediatric oncology. There is a pressing need for innovative therapeutic strategies that can reduce life-threatening side effects caused by conventional chemotherapy in the clinic. Targeting chemotherapeutic agents specifically to leukemia cells may alleviate treatment-related toxicity in children. The research objective of this dissertation is to bioengineer and advance preclinically a novel nanotherapeutic approach that can specifically target and deliver drugs into leukemic cells.

Dexamethasone (Dex) is one of the most commonly used chemotherapeutic drugs in treating pediatric leukemia. For the first part in this study, we encapsulated Dex in polymeric NPs and validated its anti-leukemic potential in vitro and in vivo. NPs with an average diameter of 110 nm were assembled from an amphiphilic block copolymer of poly(ethylene glycol) (PEG) and poly(ε-caprolactone) (PCL) bearing pendant cyclic ketals (ECT2). The blank NPs were nontoxic to cultured cells in vitro and to mice in vivo. Encapsulation of Dex into the NPs (Dex-NP) did not compromise the bioactivity of the drug. Dex-NPs induced glucocorticoid phosphorylation and showed cytotoxicity similar to free drug when treated with leukemic cells. Studies using NPs labeled with fluorescent dyes revealed leukemic cell surface binding and internalization. In vivo biodistribution studies showed NP accumulation in the liver and spleen with subsequent clearance of particles with time. In a preclinical model of leukemia, Dex-NPs significantly improved the quality of life and survival of mice compared to the group treated with free Dex.

In the second section, we demonstrate, that doxorubicin (DOX, an anthracycline commonly used in pediatric leukemia therapy) when encapsulated within 80 nm sized NPs and modified with targeting ligands against CD19 (a B-lymbhoblast antigen, CD19-DOX-NPs) can be delivered in a CD19-specific manner to leukemic cells. The CD19-DOX-NPs were internalized via receptor-mediated endocytosis and imparted cytotoxicity in a CD19-dependent manner in CD19 positive (CD19+) leukemic cells.  Leukemic mice treated with CD19-DOX-NPs survived significantly longer and manifested a higher degree of agility indicating reduced apparent systemic toxicity during treatment compared to mice treated with free DOX. To our knowledge, this study for the first time shows the efficacy of polymeric NPs to target and deliver chemotherapeutic drugs in pediatric oncology and suggests that targeted nanotherapy can potentially improve the therapeutic efficacy of conventional chemotherapy and reduce treatment-related side effects in children.

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