CELL-CELL INTERACTIONS IN THE TUMOR MICROENVIRONMENT: OVERCOMING THE ENDOTHELIAL BARRIER FOR TARGETED DRUG DELIVERY STRATEGIES

Restricted (Penn State Only)
Author:
Aragon Sanabria, Virginia
Graduate Program:
Biomedical Engineering
Degree:
Doctor of Philosophy
Document Type:
Dissertation
Date of Defense:
June 04, 2018
Committee Members:
  • Cheng Dong, Dissertation Advisor
  • Cheng Dong, Committee Chair
  • Esther Winter Gomez, Committee Member
  • William O Hancock, Committee Member
  • Andrea M. Mastro, Outside Member
Keywords:
  • Endothelial cells
  • Gap formation
  • Tumor Microenvironment
  • Nanoparticles
  • Immune-mediated therapy
  • Metastasis
  • Cell-cell interactions
Abstract:
Cancer is caused by the aberrant growth of abnormal cells in a localized part of the body. It is a genetic disease caused by changes in the DNA material that controls how cells function, especially the genes that regulate cell growth. As the disease progresses, cancer cells accumulate multiple different mutations that result in large cell population heterogeneities among patients but also within single tumors. This is one of the main obstacles to develop a cure for cancer; in the end, each cancer is unique. According to the World Health Organization WHO, cancer is still one of the leading causes of mortality worldwide, nearly 1 in 6 deaths. In the US, the overall cancer death rate fell by 13% between 2004 and 2013. However, new cases are projected to increase by 50% worldwide in the year 2030 relative to the cases in 2012, and cancer related deaths are also projected to increase by 60% during the same period of time. These statistics reflect the disparity between high and low-income countries in terms of access to treatments and technology. In the case of glioblastoma, current treatments are not curative because these tumors are invasive and grow aggressively in the central nervous system. No significant advancements in the treatment of GBM have occurred in the past decade and current therapy is incapacitating and limited by non-specific toxicity. Despite hundreds of clinical trials, only a handful of agents have been approved for use in the clinic in the last century. As a result, current therapy for brain tumors represents the most expensive medical therapy provided in the U.S. One of the main obstacles in finding a successful therapeutic approach to treat GBM is the heterogeneity of the tumors and the protective nature of the blood brain barrier (BBB). The BBB acts as a protective barrier that isolates the central nervous system and prevents most therapeutic molecules from reaching the brain. Successful approaches for the treatment of GBM must include a strategy to overcome these challenges. Penetration across the endothelial barrier is a key step for drug delivery, specially at early stages of the disease when the endothelium is not yet compromised. The first part of this project focuses on characterizing the mechanisms that contribute to the disruption of the endothelial barrier. In the second part, I explore the possibility of using primary human T-lymphocytes as vehicles to deliver therapeutic drugs across the BBB and into the brain. Efficient drug delivery strategies into solid tumors that target primarily malignant cells and avoid damaging healthy tissue are limited by the pharmacokinetics, solubility and specificity of the chemotherapeutic drugs. To develop a targeted drug delivery system for cancer treatment, this approach relies on the ability of immune cells to infiltrate solid tumors and carry nanoparticles along with them. The present work explores the use of “click” chemistry, as a way to maintain nanoparticles at the cell surface. This strategy might be advantageous for a systematic administration approach because it might minimize the effect on the immune cells while delivering the cargo and increase the killing effect once they reach the tumor. Normal physiological cell function is essential for this approach to work. Thus, this work focuses on testing these physiological functions to ensure the targeted drug delivery platform is successful.