Targeted delivery of anti-anthrax therapeutics

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DESCRIPTION (provided by applicant): The overall goal of this project is the development of drug delivery vehicle that selectively targets cells affected by the anthrax toxin. The anticipated advantage of this system will be a decrease in side effects associated with systemic delivery of any anti-anthrax drug. The applicant's approach utilizes the mechanism of translocation of anthrax toxin across the cellular membrane. A tripartite anthrax toxin contains a moiety, known as protective antigen (PA). The PA binds to cellular receptors and mediates an independent translocation of two other anthrax proteins, cytotoxic lethal factor (LF) and edema factor (EF). Thus, in the course of anthrax infection, LF and EF affect only cells that bind PA. It was established recently that a non-toxic N-terminal fragment (1-254) of LF (LFn) can bind to PA and be translocated into the cell. Furthermore, several groups demonstrated that this fragment could be used for intracellular delivery of fused proteins and peptides via cell-bound PA. The investigators hypothesize that the LFn-based drug delivery vehicle would direct drugs to anthrax-affected cells. Effective late-stage anti-anthrax drug or combination of drugs might inhibit LF directly, and/or counteract downstream effects of this protein. Thus, the ideal LFn-based vehicle should be adaptable to different payloads. SibTech, Inc. has developed a modular technology that satisfies this requirement. The main advantage of this technology is a separation of targeting and carrying functions of drug delivery vehicles into separate modules that can be assembled together via non-covalent interactions. The LFn will be expressed with a "docking" tag for binding a specific adapter protein via non-covalent interactions. The adapter protein will be linked to liposome serving as a flexible high-capacity drug carrier and a carrier-liposome module will be docked to a tag in LFn. The proposed LFn-based vehicle can be used with any emerging anti-anthrax drug as long as it can be loaded into liposomes. Accomplishing the specific aims will establish feasibility of constructing flexible LFn-based vehicles for targeted delivery of anti-anthrax drugs. In Phase II of this project, the applicants will test LFn-based vehicles in the animal anthrax models. The applicants will also work on development of commercially viable adapter-carrier conjugates for anti-anthrax drugs and drug candidates.