Enhanced HER-2 Directed Liposomal Therapeutics
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: Women suffer needlessly during treatments for breast cancer mainly because many drugs affect tissues other than the tumor due to their inability to be targeted specifically to the tumor. These problems are especially critical for chemotherapy. Our laboratory focuses on the development and engineering of lipid-based delivery systems, such as liposomes, for anti-cancer drugs and for gene therapy. In this strategy the drug or gene is contained within microscopic lipid droplets. We can increase the circulation time by reducing the tendency of the liposome to be taken up by the liver, and we can target the Iiposomes to breast cancer by attaching 'homing molecules' at the surface of the Iiposome. Even without these improvements there is a significant passive targeting of liposomes to breast cancers, because of the 'leaky' blood vessels supporting the tumor. 
 
 
 
 
 
 
 
 About 30% of breast cancer, especially the most aggressive type, have elevated amounts of a growth factor surface protein, called Her-2. Taking advantage of this, we have greatly increased liposome specificity by attaching human Her-2 single-chain antibodies to the surface of doxorubicin-containing liposomes. The results in animal tumor models experiments are encouraging. There is a 40-55% increase in efficacy compared to non-targeted liposomes or free doxorubicin. The National Cancer Institute is conducting preclinical toxicology experiments in monkeys and phase 1 clinical trials of this general liposome strategy. 
 
 
 
 
 
 
 
 There is still room for improvement. We propose to further optimize both drug release rates and tumor accumulation efficiencies for these drug-containing and antibody-targeted liposomes for an even greater therapeutic index. These enhanced properties will allow more drug to reach the cancer, while avoiding toxicity specific to long-circulating liposomes, such as Hand and Foot Syndrome. The main features of our approach include: (1) modifying the lipid composition of the liposome, (2) altering the method of drug entrapement inside liposomes, and (3) incorporating an acid-sensitive formulation. The purpose of making the liposome formulation acid-sensitive is to allow release of drug from the endosomal compartment within breast cancer cells following its internalization via the Her-2 antibody-receptor interaction. This will increase the amount of the active drug that is actually available to kill cancer cells, which should reduce the amount of total drug that needs to be administered. In the proposed studies we will measure how rapidly liposomal anti-cancer drugs arrive at the tumor as well as sites of potential toxicity. In addition, we will measure how fast the drug leaks from the liposomal carrier. Our aim is to search for the best strategy to deliver drugs to the breast cancer cell in a highly active form. For these experiments we use human breast cancers grown in mice.
 
 
 
 
 
 
 
 Cancer researchers have been able to use toxic drugs to kill breast cancer cells in the laboratory for many decades, and novel therapies are continuously being developed. The use of liposomal drug carriers offers a potential solution to many vexing clinical issues that greatly diminishes the current effectiveness of chemotherapeutic drugs. Our goal is to increase survival and reduce the suffering of breast cancer patients by selectively and efficiently delivering the drug to the cancer and away from healthy tissues.