Date of Award

8-1-2016

Degree Type

Dissertation

Degree Name

Doctor of Philosophy

Field of Study

Cancer Biology

Department

Graduate School of Biomedical Sciences

First Advisor

Andras G. Lacko

Second Advisor

Alakananda Basu

Third Advisor

Porunelloor A. Mathew

Abstract

The overall goal of this research was to determine the effectiveness of reconstituted high-density lipoprotein (rHDL) nanoparticles as a drug delivery system against metastatic triple negative breast cancer (TNBC). TNBC patients have a less favorable prognosis than those with hormone positive breast cancers. TNBC does not respond to current endocrine treatment. Consequently, the five- year survival rate for patients with metastatic TNBC is < 30%. The studies performed here were intended to fill a void in the treatment of metastatic TNBC with the use of targeted reconstituted high-density lipoprotein (rHDL) nanoparticles, an innovative approach. The rHDL nanoparticles are small, biocompatible, non-immunogenic complexes, targeted to the high-density lipoprotein receptor (scavenger receptor class B type 1 [SR-B1]). While most malignant cells and tumors overexpress the SR-B1 receptor, its expression levels are nearly undetectable in most normal tissues. These findings present the opportunity to exploit a key vulnerability of cancerous tumors as a “Trojan horse” therapeutic strategy and thus markedly limit the toxic impact of chemotherapy. Accordingly, we loaded rHDL nanoparticles with the anti-cancer drugs: valrubicin and lapatinib and tested their effectiveness against TNBC cells and cardiomyocytes. The outcome of these studies show that: (1) The rHDL encapsulated drugs performed significantly better than their free (un-encapsulated) counterparts, (2) The enhancement of the therapeutic effect of the drugs delivered via the rHDL nanoparticles was likely due to the overexpression of the SR-B1 receptor by the TNBC cells. This was confirmed by the enhanced uptake of valrubicin when delivered as a component of the rHDL complex. 3. We have also found that the combination of lapatinib and valrubicin may be ultimately more effective than the respective single drugs for the therapy of TNBC.

Comments

Available worldwide August 2017.

Share

COinS