Glioblastoma multiforme (GBM) is a typical category of the most common and aggressive brain tumors, with a high incidence in older adults, particularly in males. Although the etiology of GBM has not ...been fully elucidated, yet it is characterized by highly proliferative activity in the glial cells. Its complete resection is impossible, and radiotherapy is not always efficient for complete relief. Thus, GBM remains a therapeutic challenge in neurooncology as there is no treatment that provides significant improvement in the survival rate of patients. In this regard, the identification of newer drug therapy for the treatment of GBM is gaining popularity. However, identifying new targets and developing new leads for screening suitable drug candidates require the investment of resources like time, money, and efforts. It has been observed in many research studies that the use of polyunsaturated fatty acids (PUFAs) as therapeutic moieties for cancer treatment has yielded significant interest owing to their cost-effective availability, limited side effects, and insensitivity towards drug resistance. Nevertheless, the implications of nanostructured therapeutic systems in delivering the PUFAs can provide significant improvement in their biopharmaceutical performance and antitumor activity over the existing alkylating agents used as chemotherapeutic drugs in GBM. Currently, various studies have shown that PUFAs, especially γ-linolenic acid (GLA), have selective tumoricidal action and the ability to reduce antioxidant contents of the glioma tumor cells. In this regard, the present review endeavors to provide an insight into the applications of nanomedicinal drug carriers used for delivering the PUFAs for the effective treatment of GBM and associated diseases.
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•Hesperidin solid lipid nanoparticles (HES-SLNs) were developed by supercritical antisolvent technique.•HES-SLNs improves aqueous solubility and apparent permeability coefficient of ...HES.•HES-SLNs possess improved cardioprotective effects compared to hesperidin.•HES-SLNs effectively attenuates DOX-induced cardiotoxicity via suppression of oxidative stress and apoptosis.
Doxorubicin (DOX) is commonly used for the treatment of many types of cancers but its cardiotoxicity, owing to free radical formation, limits its clinical use. Hesperidin (HES), a flavanone glycoside, has been shown to exert multiple pharmacological actions including cardioprotective effects. Herein, we aim to formulate HES loaded solid lipid nanoparticles (SLNs) using supercritical antisolvent (SAS) technology to improve the oral delivery of HES. Process parameters were optimized to produce small size (175.3 ± 3.6 nm) HES-SLNs with high encapsulation efficiency (87.6 ± 3.8 %). DSC and XRD showed that HES is amorphously dispersed in SLNs. Compared to HES, HES-SLNs resulted in a nearly 20-fold increase in aqueous solubility and a nearly 5-fold increase in apparent permeability. Pharmacokinetics in rats revealed nearly 4.5-fold higher bioavailability of HES from SLN formulation compared to HES suspension. Data showed that HES-SLN significantly attenuated DOX-induced cardiotoxicity through lowering creatine kinase-muscle/brain, cardiac troponin I and improving histopathological scores as compared to the DOX group. HES-SLN also decreased malondialdehyde, increased catalase and superoxide dismutase of rats’ heart to levels relatively comparable to control. Marked reductions in caspase-3 were also observed following HES-SLN treatment. Conclusively, these results describe a cardioprotective effect for HES-SLN against DOX-induced cardiotoxicity likely facilitated via suppression of oxidative stress and apoptosis.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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•Hyaluronic acid (HA) coated irinotecan loaded lignin nanoparticles for colon cancer.•Optimization of ionic interaction by cationic bridging for HA coating.•Optimum levels of ...oxidative stress without compromising cytotoxicity and apoptosis.•Biodistribution studies indicate both active and passive drug targeting.•Chemotherapy assisted toxicities and cancer relapse aversion.
Hyaluronic acid (HA) coated irinotecan loaded lignin nanoparticles (HDLNPs) were synthesized using ionic interaction method. Optimized nanoparticles were characterized for their active chemotherapeutic targeting potential to CD44 receptors overly-expressed on cancer cells. Blood component interaction studies supported hemocompatible nature of HDLNPs and also demonstrated their sustained plasma residence property. Cell anti-proliferation and mitochondrial depolarization studies on HT-29 cells suggest significantly (p < 0.01) improved chemotherapeutic efficacy of HDLNPs. In vitro cell based studies showed that nanoparticles have retained antioxidant activity of lignin that can prevent cancer relapse. In vivo biodistribution studies in tumor-bearing Balb/c mice confirmed improved drug localization in tumor site for longer duration. Tumor regression and histopathological studies indicated the efficacy ofligand-assisted targeting chemotherapy over the conventional therapy. Hematological and biochemical estimation suggested that irinotecan-associated myelosuppression, liver steatosis and rare kidney failure can be avoided by its encapsulation in HA-coated lignin nanoparticles. HDLNPs were found to be stable over a period of 12 months.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Various preclinical and clinical studies exhibited the potential of cannabis against various diseases, including cancer and related pain. Subsequently, many efforts have been made to establish and ...develop cannabis-related products and make them available as prescription products. Moreover, FDA has already approved some cannabis-related products, and more advancement in this aspect is still going on. However, the approved product of cannabis is in oral dosage form, which exerts various limitations to achieve maximum therapeutic effects. A considerable translation is on a hike to improve bioavailability, and ultimately, the therapeutic efficacy of cannabis by the employment of nanotechnology. Besides the well-known psychotropic effects of cannabis upon the use at high doses, literature has also shown the importance of cannabis and its constituents in minimising the lethality of cancer in the preclinical models. This review discusses the history of cannabis, its legal aspect, safety profile, the mechanism by which cannabis combats with cancer, and the advancement of clinical therapy by exploiting nanotechnology. A brief discussion related to the role of cannabinoid in various cancers has also been incorporated. Lastly, the information regarding completed and ongoing trials have also been elaborated.
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DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
The present investigation intended to develop novel thermo-reversible gamma-linolenic acid-liposome-hydrogel (GLG) as an in-situ depot system for intratumoral chemotherapy.
Gamma-linolenic acid (GLA) ...entrapped liposomes (GL) were prepared by combination of ethanol injection method and homogenization and optimized using Box-Behnken design. To formulate the final GLG formulation, the GL was added to 22% w/v poloxamer hydrogel. The gel degradation test, in vitro release studies and characterization were carried simultaneously. In-depth in vivo biodistribution, anti-tumor efficacy, safety testing and histological investigation were conducted on DMBA-induced-solid tumor-bearing rats.
The optimized GL had a hydrodynamic particle size of 104.2 ± 2.15 nm, PDI of 0.234 ± 0.0019, % EE of 85.17 ± 2.05%, and %DL of 12.65 ± 1.33%. The TEM imaging revealed that GL were spherical and were uniformly dispersed. No significant changes in particle size, PDI, % EE, and gelation time were observed following loading of GL into poloxamer hydrogel. Further, GLG demonstrated sustained in vitro drug release over 120 h. In vivo studies demonstarted that intra-tumoral injection of GLG formed a depot, exhibited prolonged tumor retention, drug release lasting for 120 h, and significantly higher anti-tumor activity compared to free GLA and GL in solid tumor-bearing rats. In conclusion, GLG could be prospective and patient compliant therapeutics for the treatment of tumor.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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•Benzimidazole substituted oxindolinone hybrids as VEGFR-2 and EGFR inhibitors.•The IC50 value of 5b was found 6.81 and 13 nM against VEGFR-2 and EGFR, respectively.•The cytotoxicity ...was found as GI50 at 0.9 µM against epidermoid carcinoma cells.•Mechanistically 5b governs through VEGF/EGF, p53, bcl/bax and MMP9 signalling proteins.•Comparatively 5b was found more potent and safer than other dual inhibitors.•The dual inhibition was facilitated due to conformational switch in designed molecules.
Dual TK inhibitors have shown significant clinical effects against many tumors, but with unmanageable side effects. Design approach and selectivity of these inhibitors plays substantial role in their potency and side-effects. Understanding the homology of binding sites in targeted receptors, and involvement of signaling proteins after the inhibition might help in producing less toxic but effective inhibitors. Herein, we designed benzylideneindolon-2-one derivatives based on homology modeling in binding sites of VEGFR-2 and EGFR receptors as dual- inhibitor potent anticancer compounds with high selectivity. The benzylideneindolon-2-one derivatives were found to possess conformational switch in form of oxindole, substituted at 2-benzimidazole. Within synthesized compounds, 5b was found most active in in-vitro enzyme inhibition assay against VEGFR-2 and EGFR with highest IC50 value of 6.81 ± 2.55 and 13.04 ± 4.07 nM, respectively. Interestingly, cytotoxicity studies revealed selective toxicity of compound 5b against proliferation of A-431 cell lines (over expressed VEGFR-2 and EGFR) with GI50 value of 0.9 ± 0.66 µM. However, the compounds showed mild to moderate activity in all other cancer cell line in the range of 0.2–100 μM. Further mode of action studies by flow cytometry and western blot on A-431 indicated that they work via apoptosis at S- phase following Bcl/Bax pathway, and cell migration via MMP9. 5b not only suppressed tumor growth but also improved vandetanib associated with weight loss toxicity. Moreover, 5b was found safer than sunitinib and erlotinib with LD50 of 500 mg/kg body weight. These results propose 5b as potential anti-tumor drug with safer profile of conventional inhibitors of VEGFR-2 and EGFR for solid tumors.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Ziprasidone (ZP) is a novel atypical antipsychotic agent effective in the treatment of positive and negative symptoms of schizophrenia with low chances for extrapyramidal side effects (EPs) and ...cognitive deficits. ZP possesses poor oral bioavailability (~50%), short biological half-life (~2.5 h) and due to extensive first-pass metabolism, a repeated dose is administered which makes the therapy non-adherent, leading to patient non-compliance. Therefore, this is a first report of developing parenteral ZP loaded sustained release phospholipid based phase-transition system (ZP-LPS).
The ZP-LPS system was formulated by mixing of biocompatible materials including phospholipid E 80, medium chain triglyceride (MCT) and ethanol. Optimization was done by aqueous titration method using pseudo-ternary phase diagram and dynamic rheological measurements. In vivo depot formation was confirmed by gamma scintigraphy after subcutaneous injection. Biodegradation and biocompatibility studies were performed for its safety evaluation. Finally, the efficacy of the formulation was assessed by Morris water maze (MWM) test and dizocilpine (MK-801) was used to induce schizophrenia in Sprague-Dawley rats.
Optimized ZP-LPS showed rapid gelation (2 min), highest change in viscosity (~48000 mPa.s) and sustained release of ZP over a period of 1 month. Gamma scintigraphy depicted that the low-viscosity ZP-LPS system undergo rapid in situ gelation. Biodegradation and biocompatibility studies revealed gradual degradation in size of depot over a period of 28 days without any inflammation at the injection site. In MWM test, escape latency, time spent and total distance in target quadrant were significantly improved (p < 0.001) in the ZP-LPS group in comparison to the MK-801 group when evaluated at day 0, day 7 and day 28. However, significant improvement (p < 0.001) was observed only at day 0 in ZP suspension group.
The overall result indicates that the novel ZP-LPS system is safe, biodegradable, and effective for the management of schizophrenia.
Abstract
Borage oil that is extracted from (Borago officinalis Linn.) is a well-known medicinal plant having various medicinal benefits. In this work, an affordable, simple, reliable, rapid and ...easily accessible high-performance thin-layer chromatography (HPTLC) method was developed for the estimation of gamma-linolenic acid (GLA) in borage oil. HPTLC method employs thin-layer chromatography (TLC) aluminum plates precoated with silica gel (G60F254) as the stationary phase, and the mixture of hexane:toulene:glacial acetic acid (3:7:1, v/v/v) was used as the mobile phase. Densitometric analysis of the TLC plates was carried out at 200 nm. The developed method showed well-resolved spots with retention factor (Rf) value of 0.53 ± 0.04 for GLA. Various experimental conditions like saturation time for chamber, solvent phase migration and width of the band were studied intensely for selecting the optimum conditions. The method validation was performed for parameters like linearity, accuracy, specificity and precision. The values of limit of detection and limit of quantification for GLA were found to be 0.221 and 0.737 μg/band, respectively. In nutshell, the developed HPTLC method was found to be highly sensitive for the estimation of GLA in the herbal oil samples and formulations.
Multinationals from China and India courted the economies of both the North and the South and they had different advantages in doing so. After more than two decades of successful ...internationalization, can the survival of Chinese and Indian investments reveal the factors that are associated with the success of EMNC investments in the North and the South? This is the main question we explore in this paper. We find that there is a North-South divide in the survival of Chinese and Indian outward investments. Investments in the North are subject to more intense competitive pressure due to the stronger technological and managerial abilities of domestic firms and survival is markedly weaker there. In Southern locations, where Chinese and Indian firms enjoy competitive advantages and industrial leadership in several areas, they also have better rates of survival. Apart from highlighting the role of relative (to host country firms) firm-specific advantages in explaining survival in the North and South, we also find that a larger diaspora in Southern locations is associated with greater survival.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
We show that outward investment by Chinese firms with resource and asset seeking motives and Indian firms with market-seeking motives diverged after the financial crisis of 2008, due to different ...motives and the underlying financing structure of their outward investments. Indian firms faced export market contraction externally and cut back on outward investments as sales revenues shrank. In contrast, Chinese firms that relied on debt finance to seek out international assets expanded investment as investment targets became cheaper and the reliance on leverage inured Chinese firms to the fluctuations of stock markets and other financial implications of the crisis.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP