Date of Award

Spring 5-17-2010

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Graduate Group

Chemical and Biomolecular Engineering

First Advisor

Dr. Daniel A. Hammer

Abstract

ABSTRACT

POLYMERSOMES: MULTI-FUNCTIONAL TOOLS FOR IN VIVO CANCER THERANOSTIC APPLICATIONS

Dalia Hope Levine

Dr. Daniel A. Hammer

Nanoparticles are currently being developed as delivery vehicles for therapeutic and contrast imaging agents. Polymersomes (mesoscopic polymer vesicles) possess a number of attractive biomaterial properties, including greater biocompatibility, prolonged circulation times, and increased mechanical stability, that make them ideal for these applications. The polymersome architecture, with its large hydrophilic reservoir and thick hydrophobic lamellar membrane, provides significant storage capacity for water soluble and insoluble substances.

The primary thesis aims are to develop multi-functional polymersomes for combination therapeutic applications, as well as simultaneous therapeutic and diagnostic applications. These multi-functional vesicles are capable of simultaneously loading both therapeutic agents, such as doxorubicin and combretastatin, and optical imaging agents, such as porphyrin-based near infrared (NIR) fluorophores, into their hydrophobic and hydrophilic regions.

Doxorubicin, an anti-neoplastic agent, was encapsulated into PEO-b-PCL polymersomes and its release was characterized in situ. In vitro and in vivo studies confirmed the therapeutic potential of doxorubicin loaded polymersomes. Furthermore, the in vitro therapeutic efficacy of polymersomes loaded with combretastatin, an anti-vascular agent, was established with and without co-doxorubicin loading. The co-encapsulation of DOX and combretastatin into polymeric vesicles, generates a multi-functional drug loaded polymersome with the potential to eliminate tumorigenic cells an endothelial cells, respectively.

The use of near infrared (NIR) emissive porphyrin polymersomes, loaded with porphyrin, for biodistribution studies, to non-invasively track the location of the polymersomes in tumor bearing mice was demonstrated using a noninvasive small animal optical imaging instrument which detects NIR fluorescence signal. Passive accumulation of drug loaded NIR-emissive polymersomes in tumor tissues of mice, as well as other organs, was observed. The study findings suggest the potential utility of NIR-emissive porphyrin polymersome in clinical diagnostic applications. Furthermore, preliminary results utilizing drug loaded porphyrin polymersomes to retard tumor growth and monitor vesicle location suggest these vesicles may have great future clinical utility.

The ability to load components into the polymersome membrane and core shows enormous promise for future dual modality polymersomes with potential to be nanostructured biomaterials for future theranostic applications which provide both therapy and diagnosis.

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