Date of Graduation
5-2014
Document Type
Dissertation (PhD)
Program Affiliation
Biomedical Sciences
Degree Name
Doctor of Philosophy (PhD)
Advisor/Committee Chair
Dr. David Gorenstein
Committee Member
Dr. Mauro Ferrari
Committee Member
Dr. Biana Godin
Committee Member
Dr. Menashe Bar-Eli
Committee Member
Dr. Funda Meric-Bernstam
Abstract
Nanoparticle based therapeutics have been successfully used in the treatment of breast cancer. Development of nanovectors targeted to cancer cells or elements in the tumor microenvironment has been pursued to improve their site specific accumulation while reducing the non-specific delivery to normal tissues. However, addition of targeting ligands to the surface of nanovectors while maintaining their payload carrying potential is generally challenging. Therefore, there is a critical need to develop surface decoration strategies that allow for effective combination of targeting and payload delivery to the tumor.
In this study, we propose a novel strategy for covering the surface of mesoporous silicon particles (S1MP) with targeting entities (bacteriophage) and gold nanoparticles (AuNP) while maintaining their payload carrying potential. Retention of payload carrying potential after the formation of BASP was demonstrated by loading different types of nanoparticles and macromolecules into the porous structure of S1MP. Additionally, the BASP displayed enhanced near infrared (NIR) absorbance that could be used for thermal ablation of the tumor as well as for in vivo monitoring using NIR surface enhanced Raman spectroscopy (NIR-SERS). In vitro targeting studies under static and shear flow conditions, as experienced in healthy microvasculature (100s-1), did not display significant targeting efficiency of the CRKL targeted BASP. However, in shear rates relevant to the tumor microvasculature (10s-1), CRKL targeted BASP demonstrated 2-fold higher adhesion than S1MP to endothelial cells. These results were further exaggerated in in vivo conditions evidenced by intravital microscopy studies that showed up to 4 fold increase in the number of CRKL targeted BASP accumulating in the tumor vasculature compared to both S1MP and fd-tet non-targeted BASP. In vivo experiments also showed that BASP maintain their integrity following intravenous administration in mice and a 3-fold higher tumor accumulation than S1MP. Furthermore, treatment of breast tumor bearing mice with Abraxane loaded CRKL targeted BASP showed significantly reduced tumor growth in comparison to Abraxane or Abraxane loaded S1MP controls. Overall, this study demonstrates a simple and efficient strategy to target S1MP to breast cancer while maintaining their ability to carry large amounts of therapeutic payload.
Keywords
Nanomedicine, Porous Silicon, Breast Cancer, Targeted Drug Delivery