Drug delivery to solid tumors via polymeric nanoparticles
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. Additionally, the use of tannic acid (TA) as an alternative functionalizing coating material for polymeric NPs was investigated. In a preliminary study, TA helped functionalize PLGA NPs with small ligands (FA) or macromolecules (albumin). Considering the strong interactions of TA with different macromolecules (e.g. proteins and nucleic acids), TA is hypothesized to be an ideal coating material to functionalize NPs for drug delivery applications. However, the stability of the coating in physiological conditions is yet to be investigated.
Degree
Ph.D.
Advisors
Yeo, Purdue University.
Subject Area
Pharmacy sciences
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