Abhishek Arya

Dynamic mechanical properties of multiwall carbon nanotube reinforced ABS composites and their correlation with entanglement density, adhesion, reinforcement and C factor

The dynamic mechanical properties of multiwalled carbon nanotube (MWCNTs) reinforced acrylonitrile butadiene styrene (ABS) high performance composites, which were prepared using a micro twin screw extruder with a back flow channel that enabled proper dispersion of MWCNTs into the polymer matrix are studied in detail. The dynamic characteristics of the MWCNTs/ABS composites, such as storage, loss modulus and damping factor were significantly affected by the incorporation of MWCNTs. The dynamic mechanical properties of polymers strongly depend on the adhesion of MWCNTs and polymer and entanglement density of the polymer chains in the presence of MWCNTs. Herein, the entanglement density and C-factor of MWCNTs/ABS composites are evaluated using the dynamic mechanical properties results obtained from a dynamic mechanical analyser and correlated with their mechanical properties. The entanglement density of the MWCNTs/ABS composites increased from 4.31 × 104 mol m−3 (pure ABS) to 7.6 × 104 mol m−3 (5 wt% MWCNTs/ABS composites). C-factor measures the effectiveness of the filler on the modulus of the composites, which decreased from 1.086 (1 wt% MWCNTs/ABS composites) to 0.78 (5 wt% MWCNTs/ABS composites), and beyond this loading, the value of C-factor began to increase; this showed that the utilization of 5 wt% MWCNTs in the ABS matrix is sufficient for their effective use. The “b” factor increased from 6.16 (1 wt% MWCNTs/ABS composites) to 7.625 (5 wt% MWCNT/ABS composites) and after that started to decrease. A larger value of “b” strengthens the MWCNTs/ABS matrix interaction. In addition, Cole–Cole analysis was carried out to understand the phase behaviour of the composites.

Investigation of salt formation between memantine and pamoic acid: Its exploitation in nanocrystalline form as long acting injection.

In the present work, we prepared memantine-pamoic acid (MEM-PAM) salt by counter ion exchange in the aqueous phase to reduce the water solubility of MEM hydrochloride (native form) to make it suitable for long acting injection. The ratio of MEM to PAM in salt formation was optimized to maximize the loading efficiency and complexation efficiency. The 2:1 molar ratio of MEM to PAM salt form displayed nearly 95% complexation efficiency and 50% drug loading. The solubility was decreased by a ∼1250 folds. Thermo Gravimetric Analysis (TGA), Differential Scanning Calorimetry (DSC), and Powder X-ray Diffraction Analysis (PXRD) studies revealed the formation of new solid phase. Additionally, Nuclear Magnetic Resonance (NMR) spectroscopy confirmed the anhydrous nature of the salt form. Through Fourier transformation infrared spectroscopy (FT-IR) we identified the molecular interactions. Further, the microcrystals of the salt were transformed into nanocrystals (NCs) using high pressure homogenization. The particle size distribution and atomic force microscopy confirmed the monodispersed and spherical shape of the NCs. The in vitro dissolution studies were performed under sink condition in phosphate buffer saline pH 6.8. The results of MTT assay in murine fibroblast 3T3 cell line show that the NCs were less cytotoxic and more tolerable than plain MEM HCl. The in vivo performance of NCs administered as i.m. injection at three different doses in female Sprague-Dawley rats showed that the plasma levels lasted till the 24th day of the study. The pharmacokinetic parameters AUC0-∞ and Cmax increased linearly with increasing dose. Therefore, the results suggest that injectable NCs could represent a therapeutic alternative for the treatment of AD.

PEGylated chitosan nanoparticles potentiate repurposing of ormeloxifene in breast cancer therapy.

AIM Development and optimization of ormeloxifene-loaded PEGylated chitosan nanoparticles (CNPs) for enhancing its literature profound therapeutic activity against breast cancer. METHODS CNPs were prepared by ionotropic gelation method and characterized. RESULTS Optimized formulation (CNPs10) had average 304 nm particle size with 0.247 polydispersity index and spherical shape with +31 mV surface charge. CNPs10 had 88.37% entrapment efficiency and 20.93% loading efficiency. CNPs10 demonstrated dose-dependent enhancement in cytotoxicity, cellular uptake, apoptosis, disruption of mitochondrial membrane potential and activation of caspase-3 in breast cancer MDA-MB-231 and MCF-7 cells over free ormeloxifene. In vivo studies divulged improved pharmacokinetic parameters, reduced toxicity, suppressed tumor burden and increased survival in CNPs10-treated female Sprague-Dawley rats. CONCLUSION PEGylated CNPs enhanced anticancer activity of ormeloxifene.

Phospholipid complexation of NMITLI118RT+: way to a prudent therapeutic approach for beneficial outcomes in ischemic stroke in rats

Abstract Withania somnifera Dunal (Solanaceae) known as Ashwagandha, a popular plant of Indian origin is known to possess tremedous medicinal potential, often used as anti-inflammatory, anti-platelet, antihypertensive, hypoglycemic, hypolipidemic and adaptogenic candidate. Some of its chemotypes developed by CSIR, India includes NMITLI-101, NMITLI-118, NMITLI-128. In this study the investigators have attempted development of a phytosomal complex of NMITLI118RT + (standardized ethanolic extract of a new chemotype of W. somnifera Dunal.), its pharmaceutical characterization and evaluation of its neuro-protective potential against experimenal stroke in rats in continuation with their previous work in this area. The phytosomal complex (NIMPLC) was prepared by following a cohesive optimization design and was characterized on the basis of solubility, dissolution profile, FT-IR, DSC-TGA analysis, zeta potential, physical stability, forced degradation and photolytic degradation. Results were suggestive of a pharmaceutically acceptable formulation. NIMPLC was taken up further for biological evaluation using the middle cerebral artery occlusion (MCAO) model in rats. It could be demonstrated that the beneficial effects of NMITLI118RT + could be augmented by NIMPLC in 1 h pre and 6 h post treatment as was evident from reduction in MDA levels, increment in GSH levels, reduction in neurological deficit (ND) scores and reduction in infarct size. The study could successfully demonstrate the beneficial effects of NIMPLC in brain function restoration following stroke.

Anticancer Effects of Extracts from the Fruit of Morinda Citrifolia (Noni) in Breast Cancer Cell Lines.

Morinda citrifolia L. (NONI) fruits have been used for thousands of years for the treatment of many health problems including cancer, cold, diabetes, flu, hypertension, and pain. Plant extracts have reported several therapeutic benefits, but extraction of individual compound from the extract often exhibits limited clinical utility as the synergistic effect of various natural ingredients gets lost. They generally constitute polyphenols and flavonoids. Studies have suggested that these phytochemicals, especially polyphenols, display high antioxidant properties, which help to reduce the risk of degenerative diseases, such as cancer and cardiovascular diseases. Several in-vitro and in-vivo studies have shown that Noni fruits have antioxidant, anti-inflammatory, anti-dementia, liver-protective, anticancer, analgesic, and immunomodulatory effects. Till date about 7 in vitro cancer studies have been done, but a detailed in vitro study including cell cycle and caspase activation assay on breast cancer cell line has not been done. In the present study different Noni fruit fractions have tested on cancer cell lines MCF-7, MDA-MB-231 (breast adenocarcinoma) and one non-cancer cell line HEK-293 (Human embryonic kidney). Out of which ethylacetate extract showed a higher order of in vitro anticancer activity profile. The ethylacetate extract strongly inhibited the proliferation of MCF-7, MDA-MB-231 and HEK-293 cell lines with IC50 values of 25, 35, 60 µg/ml respectively. The extract showed increase in apoptotic cells in MCF-7 and MDA-MB-231 cells and arrested the cell cycle in the G1/S phase in MCF-7 and G0/G1 phase in MDA-MB-231 cells. Noni extract also decreases the intracellular ROS generation and mitochondrial membrane potential.

Co-delivery of hesperetin enhanced bicalutamide induced apoptosis by exploiting mitochondrial membrane potential via polymeric nanoparticles in a PC-3 cell line

In this research, we reported the co-delivery of anti-androgen drug Bicalutamide (BCT) with Hesperetin (HSP) in chitosan (CS) coated polycaprolactone (PCL) nanoparticles (NPs) to increase their therapeutic efficacy against an androgen independent prostate cancer cell line. The PCL-BCT-HSP-CS NPs were prepared by anti-solvent precipitation followed by ionic gelation method, and showed narrow particle size distribution, high encapsulation efficiency (about 90%) and sustained drug release behavior for both drugs. During the preparation of NPs; HSP crystallinity was retained, whereas polymorphic transition of BCT from form I to form II was observed by thermogravimetric analysis. Additionally, DPPH radical scavenging assay confirmed the structural integrity of HSP in the NPs. The kinetic solubility of BCT and HSP in the NPs was increased by 61.66 and 6.75 fold, respectively, as compared to the free drugs. Further, the in vitro therapeutic efficacy of co-loaded PCL-BCT-HSP-CS NPs was compared with free BCT, HSP and their combination (BCT plus HSP) in androgen independent PC-3 cell lines. Interestingly, co-loaded NPs exhibited higher in vitro cytotoxicity by G1-S phase cell cycle arrest and apoptosis at equivalent concentrations. This superior activity may be attributed to enhanced mitochondrial membrane potential loss by co-loaded NPs. Cell uptake study showed significantly higher (P < 0.05) uptake of NPs by cancer cells. Additionally, in vivo pharmacokinetics of NPs were explored in SD male rats and revealed higher AUC0–t and Cmax of BCT (1.46 and 1.42 fold) and HSP (4.16 and 3.79 fold) than an aqueous suspension when administered orally at 20 mg kg−1. We demonstrated that co-delivery with HSP via polymeric NPs might have better therapeutic potential for in vitro management of androgen independent prostate cancer.

Validation of RP-HPLC Method for Simultaneous Quantification of Bicalutamide and Hesperetin in Polycaprolactone-Bicalutamide-Hesperetin-Chitosan Nanoparticles

Bicalutamide is a non-steroidal anti-androgen drug used for the treatment of androgen-dependent prostate cancer. Hesperetin is a natural bioflavonoid that can be used in combination with bicalutamide to improve efficacy and decrease tolerance. The aim of the present work was to develop and validate a simple, sensitive, rapid reverse phase-high performance liquid chromatographic method for simultaneous estimation of bicalutamide and hesperetin. The validation parameters such as specificity, linearity, precision and accuracy, limit of detection (LOD) and limit of quantification (LOQ) were determined according to International Conference on Harmonization ICH Q2 (R1) guidelines. Chromatographic separation was achieved on Lichrocart(®) CN column (250 × 4 mm, 5 µm, MERCK) with isocratic elution. The retention times and detection wavelength, for hesperetin and bicalutamide were 4.28 min, 288 nm and 5.90 min, 270 nm respectively. The intra-day and inter-day assay precision and accuracy were found to be <2% over linearity of 50-2000 ng/mL with R(2) 0.999. LOD and LOQ, of bicalutamide and hesperetin was 14.70, 44.57 ng/mL and 16.11, 48.84 ng/mL, respectively. The method was successfully applied for encapsulation efficiency and drug release studies from bicalutamide and hesperetin loaded nanoparticles.

CD44 targeting hyaluronic acid coated lapatinib nanocrystals foster the efficacy against triple-negative breast cancer

Lapatinib (LPT) is an orally administered drug for the treatment of metastatic breast cancer. For expanding its therapeutic horizon, we have prepared its nanocrystals (LPT-NCs) that were subsequently coated with hyaluronic acid (HA) to produce LPT-HA-NCs. The detailed in-vitro and in-vivo investigation of LPT-HA-NCs showed the superior anticancer activity due to active targeting to CD44 receptors than the counterparts LPT-NCs and free LPT. In the triple negative 4T1 cells induced breast tumor bearing female Balb/C mice; LPT-HA-NCs treatment caused significant retardation of tumor growth and overall increase in animal survival probability because of their higher tumor localization, increased residence time. Our findings clearly suggest that HA coated LPT-NCs formulation enhances the activity of LPT against triple negative breast cancer. It exhibited magnificent therapeutic outcome at low dose thus presenting a strategy to reduce dose administrations and minimize dose related toxicity.

Bioflavonoid hesperetin overcome bicalutamide induced toxicity by co-delivery in novel SNEDDS formulations: Optimization, in vivo evaluation and uptake mechanism

In the present study, we designed Bicalutamide (BCT) and Hesperetin (HSP) co-loaded self nano-emulsifying drug delivery system (SNEDDS) to encounter the problem of BCT induced toxicity, low solubility, and bioavailability. Optimized BCT-HSP SNEDDS would produce an emulsion of globule size 30.84±1.24nm with a high encapsulation efficiency of BCT (91.29%) and HSP (88.19%), and showed rapid drug release. DPPH assay confirmed the retention of antioxidant potential of HSP in SNEDDS. DCFH-DA confirmed intense green fluorescence in HSP treated groups due to the generation of reactive oxygen species. Thermogravimetric analysis showed the change in the polymorphic form of BCT. After 14days of sub-acute toxicity study, no significant increase (p>0.05) in the hepatotoxicity markers was observed but BCT-HSP SNEDDS significantly decreased (p<0.001) the levels of nephrotoxicity biochemical markers. Additionally, the histopathological study showed that pulmonary fibrosis and alteration in the bowmans by BCT treatment were conquered by co-administration of HSP. BCT-HSP SNEDDS revealed high AUC0-t of BCT (1.23 fold) and HSP (3.42 fold) than aqueous suspension in male Sprague-Dawley rats. The BCT-HSP SNEDDS were absorbed by clathrin-mediated endocytosis and lymphatic transport absorption pathway. Our results proposed that the co-delivery approach may be useful for in vivo management of prostate cancer.

Improved oral bioavailability of novel antithrombotic S002-333 via chitosan coated liposomes: a pharmacokinetic assessment

S002-333, a novel anti-thrombotic agent, exhibits excellent platelet mediated antithrombotic action and subsequently has no effect on the coagulation cascade. However, its oral bioavailability is hampered due to inherent low aqueous solubility. In order to circumvent this issue, chitosan coated liposomes were prepared by an ethanol injection method. S002-333 loaded liposomes (CH-LIP-F9) were reproduced with homogeneous particle sizes. The liposomal formulation was characterized with respect to size and surface morphology by transmission electron microscopy (TEM). The optimized formulation exhibited spherical shapes with a nano-metric size (249.64 ± 10.36 nm). The percentage entrapment efficiency (% EE) offered by the various developed formulations was found to be in the range between 72.36 ± 1.76 and 76.87 ± 2.32%. An in vitro release experiment demonstrated prolonged release of S002-333 from the optimized liposomal formulation. A cytotoxicity study represented that both blank liposomes (BLK-LIP) as well as the drug bearing liposomal formulation displayed negligible toxicity towards Caco-2 cells. The results of a pharmacokinetic study indicated that liposomal formulation significantly enhanced oral absorption of S002-333 in rats (AUC0–t; 7016.02 ± 128.96 h ng mL−1) compared to its aqueous suspension (AUC0–t; 2382.02 ± 77.17 h ng mL−1). These results together elicited that the developed liposomal formulation would improve preclinical and clinical application of S002-333.