Derivatives of D(-) glutamine-based MMP-2 inhibitors as an effective remedy for the management of chronic myeloid leukemia-Part-I: Synthesis, biological screening and in silico binding interaction analysis.

Chronic myeloid leukemia (CML) is a global issue and the available drugs such as tyrosine kinase inhibitors (TKIs) comprise various toxic effects as well as resistance and cross-resistance. Therefore, novel molecules targeting specific enzymes may unravel a new direction in antileukemic drug discovery. In this context, targeting gelatinases (MMP-2 and MMP-9) can be an alternative option for the development of novel molecules effective against CML. In this article, some D(-)glutamine derivatives were synthesized and evaluated through cell-based antileukemic assays and tested against gelatinases. The lead compounds, i.e., benzyl analogs exerted the most promising antileukemic potential showing nontoxicity in normal cell line including efficacious gelatinase inhibition. Both these lead molecules yielded effective apoptosis and displayed marked reductions in MMP-2 expression in the K562 cell line. Not only that, but both of them also revealed effective antiangiogenic efficacy. Importantly, the most potent MMP-2 inhibitor, i.e., benzyl derivative of p-tosyl D(-)glutamine disclosed stable binding interaction at the MMP-2 active site correlating with the highly effective MMP-2 inhibitory activity. Therefore, such D(-)glutamine derivatives might be explored further as promising MMP-2 inhibitors with efficacious antileukemic profiles for the treatment of CML in the future.

Shellac and locust bean gum coacervated curcumin, epigallocatechin gallate nanoparticle ameliorates diabetic nephropathy in a streptozotocin-induced mouse model.

Curcumin and epigallocatechin gallate have the disadvantage of low aqueous solubility and first-pass metabolism, resulting in limited bioavailability. This work aimed to enhance oral bioavailability by forming gastric pH-stable shellac nanoparticles containing curcumin and epigallocatechin gallate using locust bean gum by anti-solvent precipitation (CESL-NP). The nanoparticles were characterized by their particle size, morphology, zeta potential, gastric pH stability, release profile, drug loading, and entrapment efficiency. The findings showed that a network of hydrolyzed shellac, locust bean gum, curcumin, and epigallocatechin gallate successfully entrapped individual particles inside a complex system. The morphological investigation of the CESL-NP formulation using FESEM, TEM, and AFM revealed the presence of spherical particles. FTIR, DSC, and XRD analysis revealed that curcumin and epigallocatechin gallate were amorphous due to their bond interactions with the matrix. Streptozotocin-treated mice, upon treatment with CESL-NP, showed kidney and pancreatic improvements with normalized kidney hypertrophy index and histopathology, maintained biochemical parameters, increased beta cell count, and a 38.68-fold higher blood glucose level inhibition were observed when compared to free-(CUR + EGCG). This research affirms that the shellac-locust bean gum complex shows potential for the sustained oral delivery of curcumin and epigallocatechin gallate, specifically for treating diabetic nephropathy.

Oral delivery of ursolic acid-loaded nanostructured lipid carrier coated with chitosan oligosaccharides: Development, characterization, in vitro and in vivo assessment for the therapy of leishmaniasis.

Visceral leishmaniasis (VL) is a life-threatening disease caused by Leishmania donovani due to uncontrolled parasitisation of liver, spleen, and bone marrow. Ursolic acid (UA), a promising anti-inflammatory, anti-bacterial and anti-diabetic drug used successfully for treatment of ailments. Development of new delivery system is extremely urgent for UA with better efficacy and fewer side effects. The aim of present research work was to formulate and evaluate the potential anti-leishmanial activity of UA loaded N-octyl-chitosan surface decorated nanostructured lipid carrier system (UA-NLC) for delivery to the macrophages for VL. UA-NLC were prepared and characterized for shape, size, fourier transforms scanning electron microscopy (FESEM), transmittance electron microscopy (TEM), entrapment efficiency and in vitro drug release. The results indicate that the formulated UA-NLC had nano size range (103.7±2.8nm to 143.0±3.8nm) with high drug loading capacity (12.05±0.54%) and entrapment efficiency (88.63±2.7%). Ex vivo drug uptake by macrophage was also evaluated. The UA-NLC was more effective against AG83 wild type (12 fold), SSG-R (4 fold), PMM-R (4 fold) and GE1 field isolated (3 fold) cellular amastigotes than its free form. In vivo study showed orally effective UA-NLC could suppress the parasite burden to 98.75%.

Development and evaluation of a cedrol-loaded nanostructured lipid carrier system for in vitro and in vivo susceptibilities of wild and drug resistant Leishmania donovani amastigotes.

Leishmaniasis is an epidemic in various countries, and the parasite Leishmania donovani is developing resistance against available drugs. In the present study the antileishmanial action of cedrol was evaluated in vitro and in vivo. Activity potentiation was achieved via nanostructured lipid carrier (NLC) complexation of cedrol. Cedrol-loaded NLC was prepared through the hot-melting emulsification-ultrasonication method. The cedrol- NLC prepared did not require the use of any organic solvents. The characterization of NLC-C1 and NLC-C2 revealed that particle size was 46.62nm and 54.73nm for 3.85%, and 7.48% drug loading, respectively and negative charge of -19.2mV and -23.7mV. The cedrol-loaded NLC were found to be spherical with a smooth surface. Drug-carrier interactions were clearly visualized in FT-IR studies. Incorporation of cedrol in NLC was ascertained in DSC and XRD analysis. Antileishmanial activities of free cedrol and cedrol-NLC were performed against L. donovani wild-type, sodium stibogluconate, paromomycin and field isolated resistant strains in axenic amastigotes and amastigotes in macrophage model. Coumarin-6 loaded NLC nanoparticles were assessed for macrophage internalization in confocal microscopic studies. Cedrol showed significant antileishmanial activity in wild-type (IC50=1.5µM), sodium stibogluconate resistant (IC50=2µM), paromomycin resistant (IC50=1.8µM) and field isolated resistant (IC50=1.35µM) strains in macrophage together with cytotoxicity (CC50=74µM) in mouse peritoneal macrophage cells. Incorporation of cedrol in NLC-C2 resulted in 2.1-fold and 2-fold increase in selectivity indexes (CC50/IC50) for wild-type and drug resistant strains, respectively. In addition, in vivo studies revealed that bioactivity of NLC-C2 were 2.3 to 3.8-fold increased in wild-type and 3 to 4.9-fold increased in drug resistant strains when compared with free cedrol; administered orally in mouse leishmaniasis model. Overall, NLC-C2 showed superior antileishmanial activity to free cedrol and miltefosine in oral dose. These findings support the use of NLCs for oral delivery of poorly water-soluble antileishmanial drugs in treatment of leishmaniasis. CHEMICAL COMPOUNDS: Cedrol (PubChem CID: 65575); Compritol® 888 ATO (PubChem CID: 62726); Triolein (PubChem CID: 5497163); Pluronic F68 (PubChem CID: 24751); Soya lecithin (PubChem CID: 57369748); Sodium deoxycholate (PubChem CID: 23668196); Miltefosine (PubChem CID: 3599); Paromomycin (PubChem CID: 165580); Amphotericin B (PubChem CID: 5280965); Sodium stibogluconate (PubChem CID: 16683012).