Exploitation of lectinized lipo-polymerosome encapsulated Amphotericin B to target macrophages for effective chemotherapy of visceral leishmaniasis.
We have designed lectin functionalized Lipo-polymerosome bearing Amphotericin B (Lec-AmB-L-Psome) for specific internalization via lectin receptors overexpressed on infected macrophages of mononuclear phagocytic system (MPS) for the effective management of intramacrophage diseases such as visceral leishmaniasis. The lipo-polymerosome composed of glycol chitosan-stearic acid copolymer (GC-SA25%) and model lipid cholesterol was surface-functionalized with lectin by the EDC/NHS carbodiimide coupling method. Our designed Lec-AmB-L-Psome showed >2-fold enhanced uptake and significantly higher internalization in macrophages as compared to AmB-L-Psome. Importantly, pharmacokinetic and organ distribution studies illustrate significantly higher accumulation of Lec-AmB-L-Psome in MPS especially in liver, spleen, and lung as compared to AmB-L-Psome, Ambisome, and Fungizone. The IC50 value demonstrated that Lec-AmB-L-Psome has 1.63, 2.23, and 3.43 times higher activity than AmB-L-Psome (p < 0.01), Ambisome (p < 0.05), and Fungizone (p < 0.05), respectively. Additionally, the Lec-AmB-L-Psome showed significantly higher splenic parasite inhibition (78.66 ± 3.08%) compared to Fungizone and Ambisome that caused only 56.54 ± 3.91% (p < 0.05) and 66.46 ± 2.08% (p < 0.05) parasite inhibition, respectively, in Leishmania-infected hamsters. The toxicity profile revealed that Lec-AmB-L-Psome is a safe delivery system with diminished nephrotoxicity which is a limiting factor of Fungizone application. Taken together, these studies suggest that this surface functionalized self-assembled Lec-AmB-L-Psome can introduce a new platform to specifically target macrophages for effective management of intramacrophage diseases.
Pharmaceutics 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
Shalini
S
Asthana
Anil K
AK
Jaiswal
Vivek
V
Kumar
Ashwni K
AK
Verma
Prashant
P
Shukla
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 / Q000737:chemistry / Q000494:pharmacology*; D002478:Cells, Cultured; D006224:Cricetinae; D037102:Lectins / Q000737:chemistry; D007893:Leishmania donovani / Q000187:drug effects*; D007898:Leishmaniasis, Visceral / Q000188:drug therapy* / Q000469:parasitology; D008081:Liposomes / Q000737:chemistry; D008264:Macrophages / Q000187:drug effects* / Q000469:parasitology; D008297:Male; D051379:Mice; D015394:Molecular Structure; D021261:Parasitic Sensitivity Tests; D011108:Polymers / Q000737:chemistry; D051381:Rats; D017208:Rats, Wistar; D014018:Tissue Distribution
D000981:Antiprotozoal Agents; D037102:Lectins; D008081:Liposomes; D011108:Polymers; D000666:Amphotericin B