A New System for Breast Cancer Drug Delivery
Creators: name: University Of California Office Of The President
Publisher: name: University of California Office of the President
publisherIdentifier: https://ror.org/00dmfq477
publisherIdentifierScheme: ROR
Year: 2024

description: Drug delivery, specificity, and stability are critical issues in the application of new therapies to treat breast cancer. Our interest is in the development and application of lipid encapsulated (liposome-mediated) delivery of anti-cancer drugs. Liposome approaches have the advantage of improved circulation times in the blood, protection of the drug within the lipid particle, and avoiding general tissue penetration due to size considerations. Recent advances in liposome technology have led to the development of small liposomes coated with polyethylene glycol (PEG). These have a relatively long half-life in the circulation and a limited tissue distribution. Importantly, these PEG-coated liposomes are able to localize in tumors as a result of increased local retention and release. This is because in the tumors, the blood vessels are disorganized or 'leaky'. Nevertheless, there still remains a critical issue of targeting drug-containing iposomes directly to the cancer cells in a tumor mass. Such tumor targeting would increase drug accumulation specifically at or in the breast cancer cells, which would eliminate or reduce non-specific toxicities typically associated with chemotherapy. The focus of this project is to explore this aspect of the technology, so that an anti-tumor drug can not only be delivered to the cell, but also released inside the cell itself. 
 
 
 
 
 
 
 
 Our drug delivery project has two elements. First, the chemotherapeutic drug (doxorubicin) is enclosed in a liposome formulation that includes antibody fragments at the surface directed at the Her-2 growth factor receptor. Her-2 is found on about 30% of the more aggressive breast cancers, and the use of an antibody makes it an 'immunoliposome'. We believe this approach will effectively target the drug directly to the most cancerous cells in the tumor. However, the drug must still enter the cell to work. Fortunately, antibody-containing particles are efficiently internalized into cells and contained within internal structures called endosomes. Thus, the next critical issue in this project is to construct and test liposomes that become unstable in endosomes and release their drug upon exposure to the local acidic environment. This would result in an increased killing effect inside the cell, and an enhanced therapeutic effect. Our specific methodology will be to use acid-sensitive protecting groups and cross-linking reagents, which should allow us to prepare liposomes that are both stable at neutral pH (plasma conditions) and become destabilized in endosomes. We will ultimately test our approach in Her-2 tumor bearing mice after the issues of liposome formulation are resolved using cells in culture. 
 
 
 
 
 
 
 
 Researchers have been able to kill breast cancer cells in the laboratory with drugs for many decades, and novel therapies are continuously being developed. Our goal is to overcome the gap between our laboratory success and our clinical ability to deliver drugs directly to the cancer to make a meaningful difference to the patients' quality of life and survival.