Date of Award

January 2015

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Industrial and Physical Pharmacy

First Advisor

Yoon Yeo

Committee Member 1

Kinam Park

Committee Member 2

Elizabeth M Topp

Committee Member 3

David H Thompson

Committee Member 4

Mohamed Seleem

Abstract

A main challenge in chemotherapy is to deliver an anti-cancer drug selectively to tumor and avoid off-target exposure to other body tissues and organs. Nanoparticles (NPs) have been considered a promising approach for tumor drug delivery, with popularity attributable to the famous “Enhanced Permeability and Retention effect”, where small particles enter tumor tissues through leaky vasculature and be retained there. Currently, the phagocytic clearance of NPs is avoided by coating NP surface with Polyethylene glycol (PEG). Although successful in prolonging NPs circulation, PEG prevents proper interaction of NPs with the target cells, known as “PEG dilemma”. Low molecular weight chitosan (LMWC) can function as a hydrophilic pH-sensitive alternative stealth coating for NPs. The LMWC-coated NPs were previously made with a conjugate of poly(lactide-co-glycolic) acid (PLGA) and LMWC (PLGA-LMWC) and showed pH-sensitive surface charge. However, this preparation method has disadvantages such as production complexity and difficulty in drug encapsulation. We used an alternative surface modification method based on dopamine polymerization, which formed a layer of polydopamine (pD) on NP surface allowing for conjugation of LMWC to the preformed NP cores. When compared to PLGA-LMWC NPs, PLGA-pD-LMWC NPs had superior control over drug release. Additionally, obtained PLGA-pD-LMWC NPs had similar cellular interactions to that of PLGA-LMWC NPs, achieving cellular uptake in cancer cells under mildly acidic conditions, which was not achieved with PEG coated NPs. However, when tested in vivo, there was no significant difference between LMWC and PEG-coated NPs in terms of tumor growth suppression and tumor accumulation. While the exact reason behind the poor in vitro-in vivo correlation remain be confirmed, it is hypothesized to be premature drug release or protein corona formation.

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