Novel derivatives of arabinogalactan, pullulan & lactobionic acid for targeting asialoglycoprotein receptor: Biomolecular interaction, synthesis & evaluation
2022
Warrier, Deepa U. | Dhanabalan, Anantha K. | Krishnasamy, Gunasekaran | Kolge, Henry | Ghormade, Vandana | Gupta, Chandan R. | Ambre, Premlata K. | Shinde, Ujwala A.
Targeted-drug administration to liver reduces side effects by minimising drug distribution to non-target organs and increases therapeutic efficacy by boosting drug concentration in target cells. In this study, arabinogalactan-(AG), pullulan-(PL) and lactobionic acid-(LA) were selected as natural ligands to target asialoglycoprotein receptor-(ASGPR-1) present on hepatocytes. In silico docking studies were performed and binding affinities of novel ligands viz. palmitoylated AG-(PAG), lauroylated AG-(LAG), palmitoylated PL-(PPL), lauroylated PL-(LPL) and lactobionic acid–adipic acid dihydrazide conjugate-(LAD) were compared with AG, PL and LA. These novel ligands were successfully synthesized and characterized. The ligands were incorporated into drug loaded nanostructured lipid carriers-(NLCs) for surface functionalization. HepG2 cellular internalization of hepatocyte-targeted NLCs was studied using fluorescence microscopy and LAD-decorated-drug loaded NLCs giving maximum cellular uptake were studied using confocal microscopy. Toxicity potential of LAD-decorated NLCs was assessed in vivo. Molecular docking results suggested that among the ligands, order of binding affinity was found to be LAD>PAG > PPL > LPL > LAG. Acute toxicity studies revealed hemocompatibility and absence of organ toxicity for ligand LAD. Additionally, the results establish proof-of-concept of enhanced targeting efficacy of novel ASGPR targeting ligands. These ligands can be used for surface modification of nanocarriers for future targeted delivery in treating various liver disorders.
اظهر المزيد [+] اقل [-]الكلمات المفتاحية الخاصة بالمكنز الزراعي (أجروفوك)
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