Date of Award

2017

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Graduate Group

Chemical and Biomolecular Engineering

First Advisor

Dennis E. Discher

Abstract

Current chemotherapy causes a host of side effects and better delivery of drugs to tumors is required to reduce this. Nanocarriers have been proven to not only deliver better to tumors but also solubilize more drugs in the core, with flexible ‘filomicelles’ being particularly effective. They are still open to improvements and one obvious way is to increase drug loading and hence drug dosage delivered to tumors. In the first part, the core of filomicelles was modified by the integration of aromatic groups into the hydrophobic block of a degradable di-block copolymer with the aim of improving delivery of aromatic drugs. Formed by self-assembly of amphiphilic di-block copolymer PEG-PBCL, flexible worm-like micelles with an aromatic core loaded more Paclitaxel than analogous aliphatic systems. The death of cancer cells and ploidy in surviving cells were higher followed by tumor shrinkage in vivo.

When cancer cells are treated with single drugs alone during chemotherapy, development of drug resistance has been commonly noted, eventually leading to relapse. Retinoic acid (RA) induces differentiation and proliferation arrest in many cell types. With carcinoma lines, we find dual drug treatment with RA and Paclitaxel increases ploidy and cell death beyond those achieved by either drug single-handedly, with effects being durable. A month after treatment, relapse rates are low for RA-TAX treated cells (15%), compared to almost all (92%) for cells treated with Paclitaxel alone. Reduction in levels of key cell cycle factor Cyclin-D1 and proliferation marker Ki-67 help clarify the basis for this synergy. These effects are greatly enhanced by loading the drugs into filomicelles. Co-loading the drugs into filomicelles lead to a more potent system compared to separate loading, with no loss in the integration efficiency of drugs. Notably, relapse rates were ~2% three months after treatment, highlighting the improvement offered by filomicelles. The combination retains its potency across multiple cell lines despite their varying responsiveness to RA alone. Drug loaded filomicelles are able to shrink subcutaneous lung and liver tumors in vivo. Tumor shrinkage was also observed with orthotopic liver tumors, leading to a survival benefit. These results highlight the irreversible synergy of killing cancerous cells while driving differentiation.

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