title: Antigen presenting cells targeting and stimulation potential of lipoteichoic acid functionalized lipo-polymerosome: a chemo-immunotherapeutic approach against intracellular infectious disease.
abstract: Antigen presenting cells (APC) are well-recognized therapeutic targets for intracellular infectious diseases, including visceral leishmaniasis. These targets have raised concerns regarding their potential for drug delivery due to overexpression of a variety of receptors for pathogen associated molecular pathways after infection. Since, lipoteichoic acid (LTA), a surface glycolipid of Gram-positive bacteria responsible for recognition of bacteria by APC receptors that also regulate their activation for pro-inflammatory cytokine secretion, provides additive and significant protection against parasite. Here, we report the nanoarchitechture of APC focused LTA functionalized amphotericin B encapsulated lipo-polymerosome (LTA-AmB-L-Psome) delivery system mediated by self-assembly of synthesized glycol chitosan-stearic acid copolymer (GC-SA) and cholesterol lipid, which can activate and target the chemotherapeutic agents to Leishmania parasite resident APC. Greater J774A and RAW264.7 macrophage internalization of FITC tagged LTA-AmB-L-Psome compared to core AmB-L-Psome was observed by FACSCalibur cytometer assessment. This was further confirmed by higher accumulation in macrophage rich liver, lung and spleen during biodistribution study. The LTA-AmB-L-Psome overcame encapsulated drug toxicity and significantly increased parasite growth inhibition beyond commercial AmB treatment in both in vitro (macrophage-amastigote system; IC50, 0.082 ± 0.009 μg/mL) and in vivo (Leishmania donovani infected hamsters; 89.25 ± 6.44% parasite inhibition) models. Moreover, LTA-AmB-L-Psome stimulated the production of protective cytokines like interferon-γ (IFN-γ), interleukin-12 (IL-12), tumor necrosis factor-α (TNF-α), and inducible nitric oxide synthase and nitric oxide with down-regulation of disease susceptible cytokines, like transforming growth factor-β (TGF-β), IL-10, and IL-4. These data demonstrate the potential use of LTA-functionalized lipo-polymerosome as a biocompatible lucrative nanotherapeutic platform for overcoming toxicity and improving drug efficacy along with induction of robust APC immune responses for effective therapeutics of intracellular diseases.
authors: †Pharmaceutics Division and ‡Parasitology Division, Council of Scientific and Industrial Research-Central Drug Research Institute, B 10/1, Sector 10, Jankipuram Extension, Sitapur Road, Lucknow, India 226031.
authors: Pramod K
authors: PK
authors: Gupta
authors: †Pharmaceutics Division and ‡Parasitology Division, Council of Scientific and Industrial Research-Central Drug Research Institute, B 10/1, Sector 10, Jankipuram Extension, Sitapur Road, Lucknow, India 226031.
authors: Anil K
authors: AK
authors: Jaiswal
authors: †Pharmaceutics Division and ‡Parasitology Division, Council of Scientific and Industrial Research-Central Drug Research Institute, B 10/1, Sector 10, Jankipuram Extension, Sitapur Road, Lucknow, India 226031.
authors: Shalini
authors: S
authors: Asthana
authors: †Pharmaceutics Division and ‡Parasitology Division, Council of Scientific and Industrial Research-Central Drug Research Institute, B 10/1, Sector 10, Jankipuram Extension, Sitapur Road, Lucknow, India 226031.
authors: Anuradha
authors: A
authors: Dube
authors: †Pharmaceutics Division and ‡Parasitology Division, Council of Scientific and Industrial Research-Central Drug Research Institute, B 10/1, Sector 10, Jankipuram Extension, Sitapur Road, Lucknow, India 226031.
authors: Prabhat R
authors: PR
authors: Mishra
mesh_terms: D000666:Amphotericin B / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D000938:Antigen-Presenting Cells / Q000187:drug effects* / Q000378:metabolism; D000977:Antiparasitic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology; D002460:Cell Line; D002784:Cholesterol / Q000737:chemistry; D006224:Cricetinae; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D007893:Leishmania donovani / Q000187:drug effects*; D008070:Lipopolysaccharides / Q000493:pharmacokinetics / Q000494:pharmacology*; D008081:Liposomes / Q000737:chemistry / Q000493:pharmacokinetics*; D008297:Male; D008647:Mesocricetus; D051379:Mice; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000235:genetics / Q000378:metabolism; D013682:Teichoic Acids / Q000493:pharmacokinetics / Q000494:pharmacology*; D014018:Tissue Distribution
chemical_list: D000977:Antiparasitic Agents; D016207:Cytokines; D008070:Lipopolysaccharides; D008081:Liposomes; D013682:Teichoic Acids; D009569:Nitric Oxide; C009900:lipoteichoic acid; D000666:Amphotericin B; D002784:Cholesterol; D019001:Nitric Oxide Synthase