Ph.D Thesis


Ph.D StudentAbumanhal Masarweh Hanan
SubjectTargeting the Tumor Microenvironment with Nanotechnology
DepartmentDepartment of Nanoscience and Nanotechnology
Supervisor ASSOCIATE PROF. Avi Schroeder
Full Thesis textFull thesis text - English Version


Abstract

Cancer is the leading cause of morbidity and mortality in developed countries. A tumor tissue is composed of cancer cells and of non-cancerous components, termed the tumor microenvironment. There is a direct link between the tumor microenvironment and the ability of cancer cells to invade adjacent tissues and metastasize. Furthermore, environmental changes within the tumor tissue can lead to drug resistance and consequently to treatment failure. Therefore, a multi-targeting drug strategy, which targets the cancer cells as well as key components of the tumor microenvironment, hold promise to significantly improve the clinical outcomes.

This PhD thesis addressed two main metabolic issues related to the tumor microenvironment and can affect disease control. Acidic pH in the tumor tissue is associated with cancer metabolism and creates a physiological barrier that prevents from drugs to penetrate cells. Specifically, ionizable weak-base drugs, such as doxorubicin, freely permeate membranes in their uncharged form, however, in the acidic tumor microenvironment these drugs become charged and their cellular permeability is retarded. In this PhD thesis, 100-nm liposomes loaded with sodium bicarbonate were designed and evaluated as adjuvants to elevate the tumor pH. Combined treatment of triple-negative breast cancer cells (4T1) with doxorubicin and bicarbonate enhanced drug uptake and increased its anti-cancer activity. In vivo, mice bearing 4T1 breast tumors were administered either liposomal or free bicarbonate intravenously. 3.7±0.3% of the injected liposomal dose was detected in the tumor after twenty-four hours, compared to 0.17%±0.04% in the group injected free bicarbonate, a 21-fold increase. Analyzing nanoparticle biodistribution within the tumor tissue revealed that 93% of the liposomes accumulated in the extracellular matrix, while 7% were detected intracellularly. Mice administered bicarbonate-loaded liposomes reached an intra-tumor pH value of 7.38±0.04. Treating tumors with liposomal bicarbonate combined with a sub-therapeutic dose of doxorubicin achieved an improved therapeutic outcome, compared to mice treated with doxorubicin alone. Interestingly, an increase in immune cells’ population in tumors treated with liposomal bicarbonate was observed.

In the second part of my research, the ability of the drug delivery itself, liposomal nanoparticles, to modify the tumor microenvironment was evaluated. Cancer cells activate de novo lipid synthesis in order to supply their proliferation needs. However, their rapid proliferation requires also exogenous lipid sources. Therefore, cancer cells source lipids from their microenvironment to supply their metabolic needs and increase proliferation. In this study we examined if cancer cells will prefer to internalize liposome that have specific lipid composition since it fits their metabolic needs and use these lipids later as an exogenous lipid source. Interestingly, it was found that liposomes composed of phospholipids having short carbon-long-tails, such as DMPC, decreased cell viability, due to a destabilizing effect these lipids had on cancer cell membrane. Contrarily, liposomes composed of phospholipids having longer carbon tails, such as DPPC and HSPC, enhanced cancer cell proliferation.

This PhD work demonstrates that targeting metabolic adjuvants with nanoparticles to the tumor microenvironment can enhance anticancer drug activity and improve treatment. It also demonstrates that tuning the lipid composition of liposomes can be leveraged to modulate their cellular uptake and effect on cancer cells metabolism.