title: Targeting Brucella melitensis with polymeric nanoparticles containing streptomycin and doxycycline.
abstract: Treatment and eradication of intracellular pathogens such as Brucella is difficult because infections are localized within phagocytic cells and most antibiotics, although highly active in vitro, do not actively pass through cellular membranes. Thus, an optimum strategy to treat these infections should address targeting of active drugs to the intracellular compartment where the bacteria replicate, and should prolong the release of the antibiotics so that the number of doses and associated toxicity can be reduced. We incorporated streptomycin and doxycycline into macromolecular nanoplexes with anionic homo- and block copolymers via cooperative electrostatic interactions among the cationic drugs and anionic polymers. The approach enabled simultaneous binding of both antibiotics into the nanoplexes, and their use resulted in an improvement in performance as compared with the free drugs. Administration of two doses of the nanoplexes significantly reduced the Brucella melitensis load in the spleens and livers of infected BALB/c mice. The nanoplexes were more effective than free drugs in the spleens (0.72-log and 0.51-log reductions, respectively) and in the livers (0.79-log and 0.42-log reductions, respectively) of the infected mice. Further research regarding the design of optimum nanoplex structures will be directed towards alterations in both the core and the shell properties to investigate the effects of the rates and pathways of entry into immune cells where the brucellae replicate.
authors.affiliation: Institute for Critical Technology and Applied Science, Virginia Polytechnic Institute and State University, Blacksburg, VA 24061, USA.
authors.forename: Mohamed N
authors.initials: MN
authors.lastname: Seleem
authors.forename: Neeta
authors.initials: N
authors.lastname: Jain
authors.forename: Nikorn
authors.initials: N
authors.lastname: Pothayee
authors.forename: Ashish
authors.initials: A
authors.lastname: Ranjan
authors.forename: J S
authors.initials: JS
authors.lastname: Riffle
authors.forename: Nammalwar
authors.initials: N
authors.lastname: Sriranganathan
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology / Q000627:therapeutic use*; D017347:Brucella melitensis / Q000187:drug effects*; D002006:Brucellosis / Q000188:drug therapy*; D015169:Colony Count, Microbial; D004318:Doxycycline / Q000494:pharmacology / Q000627:therapeutic use*; D004337:Drug Carriers / Q000737:chemistry / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D008099:Liver / Q000382:microbiology; D051379:Mice; D008807:Mice, Inbred BALB C; D053758:Nanoparticles / Q000737:chemistry / Q000627:therapeutic use*; D013154:Spleen / Q000382:microbiology; D013307:Streptomycin / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D000900:Anti-Bacterial Agents; D004337:Drug Carriers; D004318:Doxycycline; D013307:Streptomycin