This is an amended application 1 R41 AI052921-01. The overall goal of this project is to develop new targeted formulations of antibiotics for prevention and treatment of diseases caused by Category A pathogens, in particular Bacillus anthracis (anthrax), Yersinia pestis (plague), and Francisella tularensis (tularemia). These preparations will specifically accumulate inside and or in the near vicinity of cells harboring such pathogens after exposure to weaponized (aerosolized) biological agents. Availability of such preparations will provide new strategies of disease prevention for those at risk of exposure, and novel effective treatments for those already infected. The proposed new formulations will be based on lymph node-specific nanocarriers developed at Massachusetts General Hospital. These carriers are capable of transporting various drug substances to lymph node phagocytes (primary pathogen-harboring cells) after systemic administration. It is expected that delivery of antibiotics by such carriers will result in much higher drug levels in the infected lymph node tissue than conventional preparations of the same antibiotics. Thus, the primary site of germination and development of weaponized biological agents will be sufficiently saturated with drugs to prevent or stop disease development at the very early stage (before the onset of symptoms). The objective of this project is to test feasibility of previously established nanocarrier technology for loading lymph node phagocytes with two model antibiotics (one of Fluoroquinolone and one of Tetracycline families), and to develop two respective prototype preparations for further characterization and optimization. The specific aims are: (1) develop two prototype lymph node specific preparations (of Ciprofloxacin and Tetracycline); (2) investigate, in a rodent model, the degree of drug accumulation inside and in the near vicinity of target cells, and (3) evaluate efficacy in infected cells. If successful, this project will result in the development of a new class of preparations and a new strategy for prophylactic and early post-exposure treatment of bacterial diseases of Category A.
Thesaurus Terms: Yersinia pestis disease, anthrax, antibacterial agent, antibiotic, drug delivery system, drug design /synthesis /production, phagocyte, pharmacokinetics, tularemia bioterrorism /chemical warfare, quinoline, tetracycline fluorescence microscopy, fluorescence spectrometry, laboratory rat
