Mannose‐Decorated Composite Peptide Hydrogel with Thixotropic and Syneresis Properties and its Application in Treatment of Leishmaniasis

Abstract

Leishmaniasis, caused by the intramacrophage protozoan parasite Leishmania donovani, is a life-threatening yet neglected vector-borne disease. Few medications for the treatment of this disease are available. However, targeted delivery of drugs to macrophages remains a significant concern. Macrophages are equipped with many receptors, and therefore putting suitable ligands in the macrophage targeting drug delivery vehicle gained a lot of attention. One such receptor is the mannose receptor, abundantly expressed by macrophages. To treat this deadly disease, in this study, a mannose containing composite hydrogel is prepared by combining a self-aggregating short peptide (Nap-FFGE-NH 2 , Pep-A) and a mannose containing non-aggregating peptide (Nap-FF-mannosyl, Pep-B). The self-aggregation of the composite hydrogel is evaluated using various spectroscopic and microscopic techniques. Intermolecular hydrogen bonding and π-π stacking lead to an antiparallel β-sheet like arrangement of the peptides. Notably, the composite hydrogel showed shear-thinning and syneresis properties. Moreover, the composite hydrogel was found to be stable in cell-culture media, biodegradable and non-toxic to the macrophages. Both control and infected macrophages showed effective cell growth and proliferation when subjected to the composite 2D and 3D hydrogel matrix. When treated with Amphotericin B loaded composite hydrogel, the drug was effectively delivered to kill the parasite in the infected macrophages. Almost 3.5 fold decrease in the parasite burden was recorded when infected cells were treated with drug-loaded composite hydrogel. The injectability, biodegradability, non-cytotoxicity, and efficient drug delivery properties of the mannosefunctionalized hydrogel make it a suitable candidate for the treatment of Leishmaniasis.

Mannose Ligands for Mannose Receptor Targeting

“…Over the last couple of decades, peptide-based hydrogels have gained increasing attention for biomedical applications and diagnostic research considering their particular properties, such as their biocompatibility, biodegradability, tuneability,hydrophilic-lipophilic balance of the structure, tissue-like elasticity, and non-cytotoxicity [98]. Considering these properties, recently, Dowari and coworkers prepared a mannose-containing composite hydrogel by combining a self-aggregating short peptide (Nap-FFGE-NH 2 ) and a mannosecontaining non-aggregating peptide (Nap-FF-mannosyl) [99]. Nap-FF is a small peptide hydrogelator that can form versatile biofunctional nanofibrous structures [100].…”

Biomimetic Systems Involving Macrophages and Their Potential for Targeted Drug Delivery

“…Heli et al [274] investigated the effect of ligand modification of PM-loaded chitosan NPs on their anti-leishmanial activity and found the mannosylated formulation to be a suitable targeted drug delivery system for uptake into Leishmania-infected macrophages without any cytotoxic activity. Similarly, Das et al [275] prepared a mannose containing composite hydrogel loaded with AmB and showed it to be a suitable candidate for the treatment of leishmaniasis due to its injectability, biodegradability, non-cytotoxicity and efficient drug delivery properties.…”

Cationic and amphiphilic peptide-based hydrogels with dual activities as anticancer and antibacterial agents

“…19 These peptide gelators form hydrogels with micro-and nanofibril network structures under appropriate conditions through the selfassembly of individual molecules by using various noncovalent interactions including hydrogen bonding, p-p interactions, van der Waals interactions, hydrophobic interactions and others. [20][21][22][23][24] These hydrogels have a wide range of applications in the biomedical field, such as sustained release of drugs and important biomolecules, [25][26][27][28] drug delivery, 25,29 cell culture, 27 tissue engineering, 1,29 wound healing, 19,32 and antimicrobial, [30][31][32][33][34][35][36][37][38][39][40] antiparasitic 37,42 and anticancer agents. [41][42][43][44][45][46][47][48] The self-assembled nanostructures show a remarkably increased bioactivity compared to the unassociated peptide molecules.…”

“…Nowadays, antibacterial resistance is a primary concern due to inappropriate and irrational use of antibiotics. 38,39 The development of new antibiotics is quite expensive and time-consuming. To overcome these issues, antimicrobial peptides (AMPs) are chosen as promising agents for combating bacterial resistance.…”