Periodic Reporting for period 1 - CfC (Carrier for Cure: tailored combination drug delivery solutions for oncology)
Période du rapport: 2017-11-01 au 2019-04-30
CONTEXT AND OBJECTIVES
Chemotherapy, often given in conjunction with other therapies, is infamous for its off target side effects. Recent studies have shown that drugs combinations can act synergistically at certain ratios and are more effective and less toxic than single drug therapies. Despite promising in vitro results, combination drug therapy for oncology has not been successfully translated to the clinic due to lack of efficient delivery systems that can maintain the desired synergistic drug concentrations in the body as each drug has a different pharmacokinetics and toxicity profile. The objective of this project was to develop a platform for simultaneous delivery of multiple drugs to specific cells in vivo using the negatively supercharged AaLS-13 protein cage that we previously developed to encapsulate diverse macromolecular cargo. In the funding period, we established methods for encapsulating small molecules and imaging agents in the AaLS-13 capsids; utilized antibodies, antibody mimics and pH-dependent membrane insertion peptides appended to the exterior surface of the particles to target these constructs to specific tumor cell lines; and examined cellular uptake, biodistribution and immunogenicity of the engineered particles. Because a clear therapeutic benefit was not found for the encapsulated versus non-encapsulated drugs using the original AaLS-13 constructs, we modified the capsid structure to reduce the number of self-assembling components, covalently appending affibodies to its exterior surface and receptor sites for drug-binding proteins to its interior. We also explored the feasibility of using such systems for nucleic acid delivery. The resulting constructs are currently being tested for their efficacy as drug delivery vehicles. Glycosylation of the capsid surface was also investigated as a means to reduce immunogenicity.
Chemotherapy, often given in conjunction with other therapies, is infamous for its off target side effects. Recent studies have shown that drugs combinations can act synergistically at certain ratios and are more effective and less toxic than single drug therapies. Despite promising in vitro results, combination drug therapy for oncology has not been successfully translated to the clinic due to lack of efficient delivery systems that can maintain the desired synergistic drug concentrations in the body as each drug has a different pharmacokinetics and toxicity profile. The objective of this project was to develop a platform for simultaneous delivery of multiple drugs to specific cells in vivo using the negatively supercharged AaLS-13 protein cage that we previously developed to encapsulate diverse macromolecular cargo. In the funding period, we established methods for encapsulating small molecules and imaging agents in the AaLS-13 capsids; utilized antibodies, antibody mimics and pH-dependent membrane insertion peptides appended to the exterior surface of the particles to target these constructs to specific tumor cell lines; and examined cellular uptake, biodistribution and immunogenicity of the engineered particles. Because a clear therapeutic benefit was not found for the encapsulated versus non-encapsulated drugs using the original AaLS-13 constructs, we modified the capsid structure to reduce the number of self-assembling components, covalently appending affibodies to its exterior surface and receptor sites for drug-binding proteins to its interior. We also explored the feasibility of using such systems for nucleic acid delivery. The resulting constructs are currently being tested for their efficacy as drug delivery vehicles. Glycosylation of the capsid surface was also investigated as a means to reduce immunogenicity.