Covalent functionalized self-assembled lipo-polymerosome bearing amphotericin B for better management of leishmaniasis and its toxicity evaluation.
Amphotericin B remains the preferred choice for leishmanial infection, but it has limited clinical applications due to substantial dose limiting toxicities. In the present work, AmB has been formulated in lipo-polymerosome (L-Psome) by spontaneous self-assembly of synthesized glycol chitosan-stearic acid copolymer. The optimized L-Psome formulation with vesicle size of 243.5 ± 17.9 nm, PDI of 0.168 ± 0.08 and zeta potential of (+) 27.15 ± 0.46 mV with 25.59 ± 0.87% AmB loading was obtained. The field emission scanning electron microscopy (FESEM) and high resolution transmission electron microscopy (HRTEM) images suggest nearly spherical morphology of L-Psome. An in vitro study showed comparatively sustained AmB release (66.082 ± 1.73% within 24 h) and high plasma stability compared to commercial Ambisome and Fungizone, where glycol chitosan content was found to be efficient in preventing L-Psome destabilization in the presence of plasma protein. In vitro and in vivo toxicity studies revealed less toxicity of AmB-L-Psome compared to commercialized Fungizone and Ambisome favored by monomeric form of AmB within L-Psome, observed by UV-visible spectroscopy. Experimental results of in vitro (macrophage amastigote system) and in vivo (Leishmania donovani infected hamsters) illustrated the efficacy of AmB-L-Psome to augment effective antileishmanial properties supported by upregulation of Th-1 cytokines (TNF-α, IL-12 and IFN-γ) and inducible nitric oxide synthase, and downregulation of Th-2 cytokines (TGF-β, IL-10 and IL-4), measured by quantitative mRNA analysis by real time PCR (RT-PCR). Conclusively, developed L-Psome system could be a viable alternative to the current less stable, toxic commercial formulations and developed as a highly efficacious drug delivery system.
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.
Pramod K
PK
Gupta
Anil K
AK
Jaiswal
Vivek
V
Kumar
Ashwni
A
Verma
Pankaj
P
Dwivedi
Anuradha
A
Dube
Prabhat R
PR
Mishra
D000666:Amphotericin B / Q000008:administration & dosage* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D000981:Antiprotozoal Agents / Q000008:administration & dosage* / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D002686:Chitin / Q000031:analogs & derivatives / Q000737:chemistry; D006224:Cricetinae; D016503:Drug Delivery Systems; D007124:Immunoenzyme Techniques; D056747:Immunomodulation; D007893:Leishmania donovani / Q000187:drug effects*; D007896:Leishmaniasis / Q000188:drug therapy* / Q000276:immunology / Q000469:parasitology; D008264:Macrophages / Q000187:drug effects; D008297:Male; D008647:Mesocricetus; D051379:Mice; D053769:Nanocapsules / Q000008:administration & dosage*; D011108:Polymers / Q000737:chemistry; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013229:Stearic Acids / Q000737:chemistry
D000981:Antiprotozoal Agents; D053769:Nanocapsules; D011108:Polymers; D012333:RNA, Messenger; D013229:Stearic Acids; C068538:liposomal amphotericin B; D002686:Chitin; D000666:Amphotericin B; C031610:glycolchitin
cholesterol; glycol chitosan; lipo-polymerosome; molecular organization; stearic acid