title: Th-1 biased immunomodulation and synergistic antileishmanial activity of stable cationic lipid-polymer hybrid nanoparticle: biodistribution and toxicity assessment of encapsulated amphotericin B.
abstract: To address issues related to Amphotericin B (AmpB) clinical applications, we developed macrophage targeted cationic stearylamine lipid-polymer hybrid nanoparticles (LPNPs) with complementary characteristics of both polymeric nanoparticles and liposomes, for enhancement of therapeutic efficacy and diminishing toxic effect of encapsulated AmpB. The LPNPs (size 198.3 ± 3.52 nm, PDI 0.135 ± 0.03, zeta potential +31.6 ± 1.91 mV) provide core-shell type structure which has the ability to encapsulate amphiphilic AmpB in higher amount (Encapsulation efficiency 96.1 ± 2.01%), sustain drug release and stabilize formulation tremendously. Attenuated erythrocytes and J774A.1 toxicity of LPNPs demonstrated safe applicability for parenteral administration. Elevated macrophage uptake of LPNPs, rapid plasma clearance and higher drug allocation in macrophage abundant liver and spleen illustrated admirable antileishmanial efficacy of AmpB-LPNPs in vitro (IC50, 0.16 ± 0.04 μg AmpB/ml) and in vivo (89.41 ± 3.58% parasite inhibition) against visceral leishmaniasis models. Augmentation in antileishmanial activity due to Th-1 biased immune-alteration mediated by drug-free LPNPs which elevated microbicidal mediators of macrophages. Moreover, minimal distribution to kidney tissues and low level of nephrotoxicity markers (creatinine and BUN) demonstrated the safety profile of AmpB-LPNPs. Conclusively, reliable safety and macrophage directed therapeutic performance of AmpB-LPNPs suggest it as promising alternative to commercial AmpB-formulations for the eradication of intra-macrophage diseases.
authors.affiliation: Pharmaceutics Division, Council of Scientific and Industrial Research-Central Drug Research Institute, Lucknow, India. Electronic address: asthanashalini470@gmail.com.
authors.forename: Shalini
authors.initials: S
authors.lastname: Asthana
authors.affiliation: Parasitology Division, Council of Scientific and Industrial Research-Central Drug Research Institute, Lucknow, India. Electronic address: aniljaiswal4@gmail.com.
authors.forename: Anil K
authors.initials: AK
authors.lastname: Jaiswal
authors.affiliation: Pharmaceutics Division, Council of Scientific and Industrial Research-Central Drug Research Institute, Lucknow, India. Electronic address: pramodcdri10@gmail.com.
authors.forename: Pramod K
authors.initials: PK
authors.lastname: Gupta
authors.affiliation: Parasitology Division, Council of Scientific and Industrial Research-Central Drug Research Institute, Lucknow, India. Electronic address: anuradha_dube@hotmail.com.
authors.forename: Anuradha
authors.initials: A
authors.lastname: Dube
authors.affiliation: Pharmaceutics Division, Council of Scientific and Industrial Research-Central Drug Research Institute, Lucknow, India. Electronic address: manish_chourasia@cdri.res.in.
authors.forename: Manish K
authors.initials: MK
authors.lastname: Chourasia
mesh_terms: D000666:Amphotericin B / Q000276:immunology* / Q000494:pharmacology; D000818:Animals; D000981:Antiprotozoal Agents / Q000276:immunology* / Q000494:pharmacology; D002412:Cations / Q000276:immunology / Q000494:pharmacology; D002626:Chemistry, Pharmaceutical / Q000379:methods; D056747:Immunomodulation / Q000276:immunology*; D007668:Kidney / Q000276:immunology / Q000469:parasitology; D007893:Leishmania donovani / Q000187:drug effects; D007898:Leishmaniasis, Visceral / Q000188:drug therapy / Q000276:immunology; D008055:Lipids / Q000276:immunology* / Q000494:pharmacology; D008099:Liver / Q000276:immunology / Q000469:parasitology; D008264:Macrophages / Q000187:drug effects / Q000276:immunology / Q000469:parasitology; D008297:Male; D053758:Nanoparticles / Q000008:administration & dosage*; D011108:Polymers / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D013154:Spleen / Q000276:immunology / Q000469:parasitology; D018417:Th1 Cells / Q000276:immunology*; D014018:Tissue Distribution
chemical_list: D000981:Antiprotozoal Agents; D002412:Cations; D008055:Lipids; D011108:Polymers; D000666:Amphotericin B
keywords: Amphotericin-B; Creatinine; Cytokines; Hybrid nanoparticle; Leishmaniasis; Macrophage