title: Overexpressed Macrophage Mannose Receptor Targeted Nanocapsules- Mediated Cargo Delivery Approach for Eradication of Resident Parasite: In Vitro and In Vivo Studies.
abstract: OBJECTIVE
  Since, Leishmania protozoans are obligate intracellular parasites of macrophages, an immunopotentiating macrophage-specific Amphotericin B (AB) delivery system would be ideally appropriate to increase its superiority for leishmaniasis treatment and to eliminate undesirable toxicity. Herein, we report AB entrapped mannose grafted chitosan nanocapsules (MnosCNc-AB) that results in effective treatment of visceral leishmaniasis, while also enhancing L. donovani specific T-cell immune responses in infected host.
  
  
  METHODS
  MnosCNc-AB were prepared via synthesized mannosylated chitosan deposition on interface of oil/water nanoemulsion intermediate and were characterized. J774A.1 macrophage uptake potential, antileishmanial activity and immunomodulatory profile were evaluated in hamster. Tissue localization, biodistribution and toxicity profile were also investigated.
  
  
  RESULTS
  MnosCNc-AB had nanometric size (197.8 ± 8.84 nm), unimodal distribution (0.115 ± 0.04), positive zeta potential (+31.7 ± 1.03 mV) and 97.5 ± 1.13% cargo encapsulation efficiency. Superior macrophage internalization of mannosylated chitosan nanocapsules compared to unmodified chitosan nanocapsules was observed by fluorescence-based assessment, further confirmed by rapid blood clearance and, greater localization and higher accumulation in macrophage rich liver and spleen. While, MnosCNc-AB mediated cargo distribution to kidney decreased. Augmented in vitro antileishmanial activity and in vivo pro-inflammatory mediator's expression were observed with MnosCNc-AB, led to significant reduction (∼90%) in splenic parasite burden.
  
  
  CONCLUSIONS
  Results demonstrated that mannose ligand grafted chitosan nanocapsules could improve selective delivery of AB into macrophages via interactions with overexpressed mannose receptors thus reduce undesirable toxicity. Study provides evidence for MnosCNc-AB potential to leishmaniasis therapeutics and presents valuable therapeutic strategies for combating chronic macrophage-resident microbial infections.
authors.affiliation: Pharmaceutics Division, Council of Scientific and Industrial Research-Central Drug Research Institute, B 10/1, Sector 10, Jankipuram Extension, Sitapur Road, Lucknow, UP, 226 031, India.
authors.forename: Shalini
authors.initials: S
authors.lastname: Asthana
authors.forename: Pramod K
authors.initials: PK
authors.lastname: Gupta
authors.forename: Anil K
authors.initials: AK
authors.lastname: Jaiswal
authors.forename: Anuradha
authors.initials: A
authors.lastname: Dube
authors.forename: Manish K
authors.initials: MK
authors.lastname: Chourasia
mesh_terms: D000666:Amphotericin B / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D000981:Antiprotozoal Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D001822:Body Burden; D002626:Chemistry, Pharmaceutical; D006224:Cricetinae; D004339:Drug Compounding; D016503:Drug Delivery Systems; D037181:Lectins, C-Type / Q000187:drug effects*; D007893:Leishmania donovani / Q000187:drug effects; D007898:Leishmaniasis, Visceral / Q000188:drug therapy / Q000523:psychology; D008264:Macrophages / Q000378:metabolism* / Q000469:parasitology*; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins / Q000187:drug effects*; D008647:Mesocricetus; D051379:Mice; D053769:Nanocapsules; D010316:Particle Size; D051381:Rats; D017208:Rats, Wistar; D011956:Receptors, Cell Surface / Q000187:drug effects*; D013154:Spleen / Q000469:parasitology; D013601:T-Lymphocytes / Q000187:drug effects / Q000469:parasitology; D014018:Tissue Distribution
chemical_list: D000981:Antiprotozoal Agents; D037181:Lectins, C-Type; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins; D053769:Nanocapsules; D011956:Receptors, Cell Surface; D000666:Amphotericin B