Graduation Date

Spring 5-7-2016

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Programs

Pharmaceutical Sciences

First Advisor

Alexander V. Kabanov

Abstract

“There is plenty of room at the bottom”. In this visionary lecture in 1959 Prof. Richard Feynman spoke of the interesting ramifications of working with matter at the atomic scale. Since then, scientists have worked relentlessly towards realizing his vision. The influence of nanobiotechnology on material science and polymer chemistry has given rise to a new field called ‘theranostics’, combining drug delivery and diagnostics within the same nanostructures, thereby enabling simultaneous diagnosis, targeted drug delivery and continued therapy monitoring. Iron oxide nanoparticles (MNPs) are one such class of MRI contrast agents that can be converted into theranostic nanomedicines for cancer therapy. However, development of a stable theranostic contrast system comprising of MNPs is complex and requires a careful balance between the therapeutic diagnostic components.

We explored the potential of biodegradable hydrophilic block ionomers such as anionic poly (glutamic acid-b-ethylene glycol) and cationic poly (l-lysine-b-ethylene glycol) in formulating stable magnetic nanoclusters (MNCs). These MNCs were extensively characterized for their composition, colloidal stability and factors influencing their MRI capability. Extensive in vitro studies revealed that the anionic cisplatin-loaded MNCs showed minimal non-specific uptake, a highly preferred feature for targeted cancer therapy. Luteinizing hormone releasing hormone receptor (LHRHr) targeting significantly enhanced the uptake of these formulations in LHRHr-positive ovarian cancer cells. LHRHr targeting also helped improve the theranostic efficacy in cisplatin resistant ovarian cancer cells. One the other hand, cationic MNCs were used to demonstrate the potential of MNCs to function as stimuli-responsive theranostic systems capable of releasing the payload in the acidic milieu breast and ovarian cancer cells. These cationic MNCs also exhibited significantly enhanced T2-weighted MRI contrasts at much lower concentrations than the anionic counterparts.

Finally, we successfully evaluated the feasibility of kinetically controlled flash nanoprecipitation technique using multi-inlet vortex mixer (MIVM) to formulate well-defined MNCs from non-ionic amphiphilic Pluronic tri-block copolymers. In comparison to self-assembly techniques, flash nanoprecipitation resulted in significant reduction in polydispersity. It was observed that the hydrophobic block-length of the copolymer dictates the extent of encapsulation hydrophobic therapeutic agents along with the MNPs. exhibited the potential to function as both T1 and T2 contrast agents.

In summary, looking at the bigger picture, the work presented here emphasizes on the importance of product development in establishing a critical balance between the therapeutic and imaging functionalities when designing an efficient targeted theranostic nanosystems.

Comments

Manuscript based on Chapter 3 was in preparation at the time of submission of the dissertation to the library

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