Exploitation of Lectinized Lipo-Polymerosome Encapsulated Amphotericin B to Target Macrophages for Effective Chemotherapy of Visceral Leishmaniasis

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• 作者：Pramod K. Gupta ; Shalini Asthana ; Anil K. Jaiswal ; Vivek Kumar ; Ashwni K. Verma ; Prashant Shukla ; Pankaj Dwivedi ; Anuradha Dube ; Prabhat R. Mishra
• 刊名：Bioconjugate Chemistry
• 出版年：2014
• 出版时间：June 18, 2014
• 年：2014
• 卷：25
• 期：6
• 页码：1091-1102
• 全文大小：631K
• 年卷期：v.25,no.6(June 18, 2014)
• ISSN：1520-4812

文摘

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-SA_25%) 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 卤 3.08%) compared to Fungizone and Ambisome that caused only 56.54 卤 3.91% (p < 0.05) and 66.46 卤 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.