Identification of novel biomarkers and potential molecular targets for uterine cancer using network-based approach.

A better understanding of incidences at the cellular level in uterine cancer is necessary for its effective treatment and favourable prognosis. Till date, it lacks appropriate molecular target-based treatment because of unknown molecular mechanisms that proceed to cancer and no drug has shown the required results of treatment with less severe side effects. Uterine Cancer is one of the top five cancer diagnoses and among the ten most common death-causing cancer in the United States of America. There is no FDA-approved drug for it yet. Therefore, it became necessary to identify the molecular targets for molecular targeted therapy of this widely prevalent cancer type. For this study, we used a network-based approach to the list of the deregulated (both up and down-regulated) genes taking adjacent p-Value ≤ 0.05 as significance cut off for the mRNA data of uterine cancer. We constructed the protein-protein interaction (PPI) network and analyzed the degree, closeness, and betweenness centrality-like topological properties of the PPI network. Then we traced the top 30 genes listed from each topological property to find the key regulators involved in the endometrial cancer (ECa) network. We then detected the communities and sub-communities from the PPI network using the Cytoscape network analyzer and Louvain modularity optimization method. A set of 26 (TOP2A, CENPE, RAD51, BUB1, BUB1B, KIF2C, KIF23, KIF11, KIF20A, ASPM, AURKA, AURKB, PLK1, CDC20, CDKN2A, EZH2, CCNA2, CCNB1, CDK1, FGF2, PRKCA, PGR, CAMK2A, HPGDS, and CDCA8) genes were found to be key genes of ECa regulatory network altered in disease state and might be playing the regulatory role in complex ECa network. Our study suggests that among these genes, KIF11 and H PGDS appeared to be novel key genes identified in our research. We also identified these key genes interactions with miRNAs.

It Is All about Probiotics to Control Cervical Cancer.

Cervical cancer (CC) is the fourth most common malignancy in female patients. "Human papillomavirus" (HPV) contamination is a leading cause of all forms of cervical cancer, accounting for an expected 570,000 reported incidents in 2018. Two HPV strains (16 and 18) are responsible for 70% of CC and pre-cancerous cervical abnormalities. CC is one of the foremost reasons for the malignancy death rate in India among women ranging from 30 to 69 years of age in India, responsible for 17% of all cancer deaths. Currently approved cervical cancer treatments are associated with adverse reactions that might harm the lives of women affected by this disease. Consequently, probiotics can play a vital role in the treatment of CC. It is reflected from various studies regarding the role of probiotics in the diagnosis, prevention or treatment of cancer. In this review article, we have discussed the rationale of probiotics for treatment of CC, the role of probiotics as effective adjuvants in anti-cancer therapy and the combined effect of the anti-cancer drug along with probiotics to minimize the side effects due to chemotherapy.

Skin cancer: understanding the journey of transformation from conventional to advanced treatment approaches.

Skin cancer is a global threat to the healthcare system and is estimated to incline tremendously in the next 20 years, if not diagnosed at an early stage. Even though it is curable at an early stage, novel drug identification, clinical success, and drug resistance is another major challenge. To bridge the gap and bring effective treatment, it is important to understand the etiology of skin carcinoma, the mechanism of cell proliferation, factors affecting cell growth, and the mechanism of drug resistance. The current article focusses on understanding the structural diversity of skin cancers, treatments available till date including phytocompounds, chemotherapy, radiotherapy, photothermal therapy, surgery, combination therapy, molecular targets associated with cancer growth and metastasis, and special emphasis on nanotechnology-based approaches for downregulating the deleterious disease. A detailed analysis with respect to types of nanoparticles and their scope in overcoming multidrug resistance as well as associated clinical trials has been discussed.

Nanotechnology-empowered strategies in treatment of skin cancer.

In current scenario skin cancer is a serious condition that has a significant impact on world health. Skin cancer is divided into two categories: melanoma skin cancer (MSC) and non-melanoma skin cancer (NMSC). Because of its significant psychosocial effects and need for significant investment in new technology and therapies, skin cancer is an illness of global health relevance. From the patient's perspective chemotherapy considered to be the most acceptable form of treatment. However, significant negatives of chemotherapy such as severe toxicities and drug resistance pose serious challenges to the treatment. The field of nanomedicine holds significant promise for enhancing the specificity of targeting neoplastic cells through the facilitation of targeted drug delivery to tumour cells. The integration of multiple therapeutic modalities to selectively address cancer-promoting or cell-maintaining pathways constitutes a fundamental aspect of cancer treatment. The use of mono-therapy remains prevalent in the treatment of various types of cancer, it is widely acknowledged in the academic community that this conventional approach is generally considered to be less efficacious compared to the combination treatment strategy. The employment of combination therapy in cancer treatment has become increasingly widespread due to its ability to produce synergistic anticancer effects, mitigate toxicity associated with drugs, and inhibit multi-drug resistance by means of diverse mechanisms. Nanotechnology based combination therapy represents a promising avenue for the development of efficacious therapies for skin cancer within the context of this endeavour. The objective of this article is to provide a description of distinct challenges for efficient delivery of drugs via skin. This article also provides a summary of the various nanotechnology based combinatorial therapy available for skin cancer with their recent advances. This review also focuses on current status of clinical trials of such therapies.

Advanced multifunctional nano-lipid carrier loaded gel for targeted delivery of 5-flurouracil and cannabidiol against non-melanoma skin cancer.

Non-melanoma skin cancer is one of the most common malignancies reported around the globe. Current treatment therapies fail to meet the desired therapeutic efficacy due to high degree of drug resistance. Thus, there is prominent demand in advancing the current conventional therapy to achieve desired therapeutic efficacy. To break the bottleneck, nanoparticles have been used as next generation vehicles that facilitate the efficient interaction with the cancer cells. Here, we developed combined therapy of 5-fluorouracil (5-FU) and cannabidiol (CBD)-loaded nanostructured lipid carrier gel (FU-CBD-NLCs gel). The current investigation has been designed to evaluate the safety and efficacy of developed 5-Flurouracil and cannabidiol loaded combinatorial lipid-based nanocarrier (FU-CBD NLCs) gel for the effective treatment of skin cancer. Initially, confocal microscopy study results showed excellent uptake and deposition at epidermal and the dermal layer. Irritation studies performed by IR camera and HET cam shows FU-CBD NLCs was much more tolerated and less irritant compared to conventional treatment. Furthermore, gamma scintigraphy evaluation shows the skin retention behavior of the formulation. Later, in-ovo tumor remission studies were performed, and it was found that prepared FU-CBD NLCs was able to reduce tumor volume significantly compared to conventional formulation. Thus, obtained results disclosed that permeation and disposition of 5-FU and CBD into different layers of the skin FU-CBD NLCs gel could be more potential carrier than conventional gel. Furthermore, prepared formulation showed greater tumor remission, better survival rate, reduction in tumor number, area, and volume with improved biochemical profile. Thus, prepared gel could serve as a promising formulation approach for the skin cancer treatment.

Crafting ɣ-L-Glutamyl-l-Cysteine layered Human Serum Albumin-nanoconstructs for brain targeted delivery of ropinirole to attenuate cerebral ischemia/reperfusion injury via "3A approach".

Treatment of Ischemic Stroke is inordinately challenging due to its complex aetiology and constraints in shuttling therapeutics across blood-brain barrier. Ropinirole hydrochloride (Rp), a propitious neuroprotectant with anti-oxidant, anti-inflammatory, and anti-apoptotic properties (3A) is repurposed for remedying ischemic stroke and reperfusion (I/R) injury. The drug's low bioavailability in brain however, limits its therapeutic efficacy. The current research work has reported sub-100 nm gamma-L-Glutamyl-L-Cysteine coated Human Serum Albumin nanoparticles encapsulating Rp (C-Rp-NPs) for active targeting in ischemic brain to encourage in situ activity and reduce unwanted toxicities. Confocal microscopy and brain distribution studies confirmed the enhanced targeting potentiality of optimized C-Rp-NPs. The pharmacokinetics elucidated that C-Rp-NPs could extend Rp retention in systemic circulation and escalate bioavailability compared with free Rp solution (Rp-S). Additionally, therapeutic assessment in transient middle cerebral occlusion (tMCAO) model suggested that C-Rp-NPs attenuated the progression of I/R injury with boosted therapeutic index at 1000 times less concentration compared to Rp-S via reinstating neurological and behavioral deficits, while reducing ischemic neuronal damage. Moreover, C-Rp-NPs blocked mitochondrial permeability transition pore (mtPTP), disrupted apoptotic mechanisms, curbed oxidative stress and neuroinflammation, and elevated dopamine levels post tMCAO. Thus, our work throws light on fabrication of rationally designed C-Rp-NPs with enormous clinical potential.

RGB colorimetric method based detection of oxytocin in food samples using cysteamine functionalized gold nanoparticles.

In the present investigation, a colorimetric method has been demonstrated for detection of oxytocin using Cysteamine functionalized gold nanoparticles (Cys-AuNP). The analyte oxytocin which finds its use in medical field is purposefully injected in fruits and vegetables for their faster growth. Also, it is used in the milk letdown in cattles. The complexity of segregating oxytocin induced fruit and vegetables from naturally grown ones led to development of the method. The choice of spherical gold nanoparticles for development of sensor was influenced from its unique optical properties. Moreover, functionalization with cysteamine increased its sensitivity towards oxytocin detection. The method was coupled with RGB colorimetric technique which exhibited excellent linear correlation between Oxytocin concentration and RGB color values (R2 = 0.96). The RGB method used measured the intensity of color and a relation was established between measured RGB values and concentration of analyte (Oxytocin) present in the sample. This formed the basis for generation of simple colorimetric card that can be used to relate the color with amount present in the sample. More significantly, the Cys-AuNP shows excellent selectivity towards other coexisting substances present in the sample. This method with good precision (RSD>15%) offers suitability for onsite application without need for complex instrumentation.

Identification, analysis of deleterious SNPs of the human GSR gene and their effects on the structure and functions of associated proteins and other diseases.

Hereditary glutathione reductase deficiency, caused by mutations of the GSR gene, is an autosomal recessive disorder characterized by decreased glutathione disulfide (GSSG) reduction activity and increased thermal instability. This study implemented computational analysis to screen the most likely mutation that might be associated with hereditary glutathione reductase deficiency and other diseases. Using ten online computational tools, the study revealed four nsSNPs among the 17 nsSNPs identified as most deleterious and disease associated. Structural analyses and evolutionary confirmation study of native and mutant GSR proteins using the HOPE project and ConSruf. HOPE revealed more flexibility in the native GSR structure than in the mutant structure. The mutation in GSR might be responsible for changes in the structural conformation and function of the GSR protein and might also play a significant role in inducing hereditary glutathione reductase deficiency. LD and haplotype studies of the gene revealed that the identified variations rs2978663 and rs8190955 may be responsible for obstructive heart defects (OHDs) and hereditary anemia, respectively. These interethnic differences in the frequencies of SNPs and haplotypes might help explain the unpredictability that has been reported in association studies and can contribute to predicting the pharmacokinetics and pharmacodynamics of drugs that make use of GSR.

Thymoquinone Lipid Nanoparticles Cut the Gordian Knots of Depression via Neuroprotective BDNF and Downregulation of Neuro-inflammatory NF-κB, IL-6, and TNF-α in LPS Treated Rats.

BACKGROUND: In over 300 million clinical cases, antidepressant drugs seem to provide only symptomatic relief and limited protection in life-threatening depressive events. OBJECTIVES: To compare neuronal-signaling mechanism and neuroprotective roles of Thymoquinone (TQ) suspension and its SLN (TQSLN) against standard antidepressant drug fluoxetine. METHODS: This research investigated in-silico docking at NF-KB p50 active site, CLSM based gut permeation, screening of antidepressant activities and neurosignaling pathways involved. RESULTS: As compared to fluoxetine, TQ reporteda significantly better docking score (-6.83 v/s -6.22) and a better lower free binding energy of (-34.715 Kcal/mol v/s -28.537 Kcal/mol). While poorly oral bioavailable and P-gp substrate TQ reported approximately 250% higher gut permeation if delivered as TQSLN formulation. In locomotor studies, as compared to TQS, TQSLN favored more prominent (p< 0.010) elevation in average time, horizontalactivity, average-velocity, and total-movement with reduced rest time LPS treated groups. However, in the tail suspension test, TQSLN significantly reduced immobility time (p<0.010). Similarly, In the modified force swimming test, TQSLN also significantly reduced immobility time (p<0.010), but swimming time (p<0.010) and climbing time (p<0.050) were significantly elevated. Subsequently, TQSLN reported significantly elevated neuroprotective BDNF (p<0.010) as well as hippocampal 5HT/TRP; accompanied with reduced levels of hippocampal inflammatory markers TNF-α (p<0.001) and IL-6 (p<0.010) as well as lower kynurenine and tryptophan ratio (KYN/TRP). Similarly, the hippocampal CA1 region further revealed TQSL more predominantly attenuated NF-kB nuclear translocation in the brain. CONCLUSION: Despite the poor bioavailability of TQ, TQSLN potentially attenuates neuroinflammatory transmitters and favors BDNF to modulate depressive neurobehavioral states.

Co-encapsulation of docetaxel and thymoquinone in mPEG-DSPE-vitamin E TPGS-lipid nanocapsules for breast cancer therapy: Formulation optimization and implications on cellular and in vivo toxicity.

Rationally designed combination nano-therapy approaches have emerged as a promising strategy for resistant breast cancer treatment. This research reports the combination of Docetaxel (DTX) and Thymoquinone (THQ) co-encapsulated within long circulating sub-100 nm mPEG-DSPE-Vitamin E TPGS-Lipid nanocapsules (DxTq-LNCs). DxTq-LNCs with sufficient drug loading exhibited controlled drug release, enhanced protein binding resistance (confirming its long circulation in physiological environment and suitability for iv application) and retained the antioxidant effects of THQ. DxTq-LNCs were further subjected to cytotoxicity analysis against human breast cancer cells (MCF-7 & MDA-MB-231). The presence of multidrug resistance (MDR) reversal agents; Vitamin E TPGS and THQ, along with the nanoencapsulation, re-sensitized the resistant triple negative breast cancer (TNBC) cells to the anticancer effects of DTX. Greater inhibition of cell migration indicated improved anti-metastatic effects. Drastic changes in cellular morphology indicated by nuclear fragmentation (the hall marks of apoptosis), were observed upon DxTq-LNCs treatment to the breast cancer cells. In vivo toxicity studies indicated no substantial blood biochemical and histological changes with near normal appearance of kidney and liver tissue sections upon DxTq-LNCs treatment in contrast to free drug that showed parenchymal degeneration, areas of interstitial haemorrhage, glomerular atrophy and other histological changes, indicating hepato- and nephro-protective potential of DxTq-LNCs. Furthermore, enhanced antitumor efficacy was observed with DxTq-LNCs treatment to mice bearing ehrlich ascites carcinoma. Thus, nanocapsules presents a simple yet effective approach for successful combination chemotherapy with reduced unwanted toxicity.

Identification and evaluation of glutathione conjugate gamma-l-glutamyl-l-cysteine for improved drug delivery to the brain.

Glutathione (GU), an endogenous antioxidant tripeptide, is frequently transferred in the human brain through N-methyl-d-aspartate receptor (NMDAR), profusely expressed at the blood-brain barrier (BBB) junction. GU, also modifies the characteristics of tight junction proteins (occludin and claudin) at the site of BBB by depolarizing the enzyme, protein tyrosine phosphatase that manifests its usefulness for passive delivery of nanocarriers to the brain. GU, thus, represents itself as an ideal ligand for the surface decoration of nanocarriers to successfully administer them across the brain via receptor-mediated drug delivery pathway. Hence, we have employed here, in-silico approaches to identify the potential GU-like molecules, as appropriate ligand(s) for surface engineering of nanoconstruct with the purpose of attaining targeted drug delivery to the brain. Structure-based virtual screening methods was used to filter PubChem database for the identification of bioactive compounds with >95% structure similarity with GU. We have further screened the compounds against NMDAR using molecular docking approach. Top hits were selected based on their high binding affinities and selectivity towards NMDAR, and their binding pattern was analysed in detail. Finally, all atom molecular dynamics simulation for 100 ns was carried out on free NMDAR and in-presence of the selected GU-like compound, gamma-l-glutamyl-l-cysteine to evaluate complex stability and structural dynamics. In conclusion, gamma-l-glutamyl-l-cysteine may act as potential binding partner of NMDAR which can further be evaluated in drug delivery system to brain across the BBB.Communicated by Ramaswamy H. Sarma.

Improved chemotherapeutic efficacy against resistant human breast cancer cells with co-delivery of Docetaxel and Thymoquinone by Chitosan grafted lipid nanocapsules: Formulation optimization, in vitro and in vivo studies.

In recent years, multi-targeted chemotherapeutic combinations have received considerable attention in solid tumor chemotherapy. Here, we optimized low-molecular-weight chitosan (CS)-grafted lipid nanocapsules (LNCs, referred to as CLNCs) for the co-delivery of docetaxel (DTX) and thymoquinone (THQ) to treat drug-resistant breast cancer. We first screened size reduction techniques (homogenization vs ultrasonication), and then the 33-Box-Behnken design was employed to determine optimal conditions of the final LNCs with the desired quality attributes. Uncoated LNCs had a particle size of 141.7 ± 2.8 nm (Polydispersity index, PdI: 0.17 ± 0.02) with entrapment efficiency (%EE) of 66.1 ± 3.5 % and 85.3 ± 3.1 % for DTX and THQ, respectively. The CS functionalization of LNCs improved the uptake and endosomal escape effect, and led to a significantly higher cytotoxicity against MCF-7 and triple-negative (MDA-MB-231) breast cancer cells. Furthermore, an enhanced antiangiogenic effect was observed with DTX- and THQ-carrying CLNCs in the Chick embryo chorioallantoic membrane (CAM) assay.

Doxorubicin loaded carboxymethyl Assam bora rice starch coated superparamagnetic iron oxide nanoparticles as potential antitumor cargo.

In recent years, polysaccharide-decorated superparamagnetic iron oxide nanoparticles (SPIONs) have gained attention in the field of "nanotheranostics" with integrated diagnostic and therapeutic functions. Carboxymethyl Assam bora rice starch-stabilized SPIONs (CM-ABRS SPIONs), synthesized by co-precipitation method, has already shown exciting potential towards magnetic drug targeting potential. After establishing it as a promisable targeting carrier, the present study is focused on the next step i.e. to evaluate its In vitro anti-tumor potential by loading anticancer drug "Doxorubicin hydrochloride (DOX)" onto CM-ABRS SPIONs. DOX-loaded CM-ABRS SPIONs were physico-chemically characterized by DLS, zeta-potential, TEM, FT-IR, XRD, and VSM analysis. Spectroflourimetric analysis confirmed the maximum loading of DOX up to 6% (w/w) onto CM-ABRS SPIONs via electrostatic interactions. Further, molecular level drug performance was investigated by docking study against receptors (HER-2 and Folate receptor-α) over expressed in cancer cells and MTT assay (in MCF-7 and HeLa cell line), which conferred promisable results of DOX-CM-ABRS SPIONs as compared to standard DOX solution.

Daunorubicin oral bioavailability enhancement by surface coated natural biodegradable macromolecule chitosan based polymeric nanoparticles.

BACKGROUND: Daunorubicin hydrochloride (DAUN·HCl), due to low oral bioavailability poses the hindrance to be marketed as an oral formulation. AIM OF THE STUDY: To develop a natural biodegradable macromolecule i.e. Chitosan (CS)-coated-DAUN-PLGA-poly(lactic-co-glycolic acid)-Nanoparticles (NPs) with an aim to improve oral-DAUN bioavailability and to develop as well as validate UHPLC-MS/MS (ESI/Q-TOF) method for plasma quantification and pharmacokinetic analysis (PK) of DAUN. RESULTS: A particle size (198.3 ±â€¯9.21 nm), drug content (47.06 ±â€¯1.16 mg/mg) and zeta potential (11.3 ±â€¯0.98 mV), consisting of smooth and spherical shape was observed for developed formulation. Cytotoxicity studies for CS-DAUN-PLGA-NPs revealed; a comparative superiority over free DAUN-S (i.v.) in human breast adenocarcinoma cell lines (MCF-7) and a higher permeability i.e. 3.89 folds across rat ileum, as compared to DAUN-PLGA-NPs (p < 0.01) inhuman colon adenocarcinoma cell line (Caco-2). For PK, CS-DAUN-PLGA-NPs as compared to DAUN-S, exhibited a 10.0 fold higher bioavailability in Wister rat's plasma due to presence of a natural biodegradable macromolecule i.e. CS coated on the PLGA-NPs. With regard to bioanalytical method, easy as well as a rapid method for DAUN-plasma quantification was developed as; 2.75 min and 528.49/321.54 m/z for DAUN along with 1.94 min and 544.36/397.41 m/z for IS i.e. Doxorubicin, for elution time and transition, respectively. CONCLUSION: A novel natural biodegradable approach used in the preparation of CS coated DAUN-NPs for oral administration of DAUN is reported in this study which is can be utilized as an alternate for intravenous therapy.

Impact of ultrasonication techniques on the preparation of novel Amiloride-nanoemulsion used for intranasal delivery in the treatment of epilepsy.

AIM: To develop a nanoemulsion-nanoformulation in order to enhance brain bioavailability for Amiloride (Amilo) via intranasal (i.n.) drug delivery in the brain. MATERIAL AND METHODS: Oleic Acid, Tween-20 and Carbitol were selected as oil, surfactant and co-surfactant, respectively. For nanoemulsion preparation, an aqueous micro titration method followed by a high energy ultra-sonication method was used whereas three-factor three-level central composite design was employed to get the best formulation. The independent variables selected for the optimization were %oil, % Surfactant and co-surfactant (Smix) and sonication time (seconds). RESULTS: Based on the constraints applied for independent and dependent variables, the optimized formulation was selected with 2.5% oil, 10% Smix and a sonication time of 45 s. The experimental values observed for dependent variables such as hydrodynamic diameter (nm), % transmittance and % cumulative drug release were found to be 89.36 ± 11.18 nm, 99.23 ± 0.84% and 80.36 ± 5.48%, respectively. Results showed; a spherical shape (transmission electron microscopy and scanning electron microscopy - assisted morphological characterization), polydispersity index (0.231 ± 0.018), zeta potential (-9.83 ± 0.12 mV), refractive index (1.38 ± 0.042), viscosity (41 ± 5 cp), pH (6.4 ± 0.18) and drug content of 98.28 ± 0.29%, for optimized Amiloride-loaded-Nanoemulsion (Amilo-NE). For bioavailability evaluation, ultra-performance liquid chromatography-mass spectroscopy based bioanalytical method was developed and validated for pharmacokinetics, biodistribution, brain-targeting efficiency (1992.67 ± 45.63%) and nose-to-brain transport (586.18 ± 11.63%) whereby an enhanced Amilo-brain bioavailability was observed as compared to intravenous administration (i.v.). Furthermore, Amilo-NE enhanced the treatment in seizure threshold i.e. both rodent models of epilepsy (increasing current electroshock and pentylenetetrazole) induced seizures in mice. CONCLUSION: A significant role of Amilo-NE as observed after high targeting potential and efficiency of the formulation supports the easy brain targeting for Amilo-NE.

Polymeric nanoparticles as a platform for permeability enhancement of class III drug amikacin.

Amikacin (A), a water soluble aminoglycoside antibiotic is commercially available for intravenous administration only. Present investigation is aimed at the development of poly-lactic-co-glycolic acid (PLGA) nanoparticles (A-NPs).1 for oral permeability enhancement of amikacin. The pharmaceutical attributes of the A-NPs revealed particle size, 260.3 ±â€¯2.05 nm, zeta potential, -12.9 ±â€¯1.12 mV and drug content, 40.10 ±â€¯1.87 µg/mg with spherical shape and smooth surface. In vitro antibacterial studies showed that the A-NPs were active against P. aeruginosa, K. pneumoniae and E. coli. The permeation study across rat ileum showed 2.6-fold improvement in Papp for A-NPs than A-S2 This increase in permeability is due to the uptake of nanoparticles by Peyer's patches of intestinal epithelium and endocytic uptake via enterocytes. Flow cytometric analysis demonstrated 2.2-fold higher uptake of Rh B-NPs3 than Rh B-S4 and elucidated the dominance of enterocytes mediated endocytosis of nanoparticles. Furthermore, stability data collected as per ICH guidelines for three months under accelerated conditions had shown that the A-NPs were stable. The purported drug delivery system hence, seems a promising tool to replace successfully the current intravenous therapy and is used to support relevant patient compliance thereby, adding value to the "patient care at home".

Enhancement of oral bioavailability of doxorubicin through surface modified biodegradable polymeric nanoparticles.

BACKGROUND: Doxorubicin hydrochloride (DOX·HCl), an anthracycline glycoside antibiotic, exhibits low oral bioavailability due to active efflux from intestinal P-glycoprotein receptors. The oral administration of DOX remains a challenge hence; no oral formulation for DOX is marketed, till date. AIM OF THE STUDY: To improve the oral bioavailability of DOX through, preparation of a nanoformulation i.e. PEGylated-doxorubicin(DOX)-loaded-poly-lactic-co-glycolic acid (PLGA)-Nanoparticles (NPs) and to develop and validate an ultra-high performance liquid chromatography electrospray ionization-synapt mass spectrometric bioanalytical method (UHPLC/ESI-QTOF-MS/MS) for plasma (Wistar rats) DOX quantification. MATERIALS AND METHODS: For chromatography, Waters ACQUITY UPLC™ along with a BEH C-18 column (2.1 mm × 100 mm; 1.7 µm), mobile phase conditions (acetonitrile: 0.1% formic acid::1:1 v/v) and flow rate (0.20 ml/min) was used. For analyte recovery from rat plasma, a liquid-liquid extraction method (LLE), using Acetonitrile: 5 mM ammonium acetate in a ratio of 6:4 v/v at pH 3.5, was used. RESULTS: Nanoformulation with a particle size (183.10 ± 7.41 nm), zeta potential (- 13.10 ± 1.04 mV), drug content (42.69 ± 1.97 µg/mg) and a spherical shape and smooth surface was developed. An elution time of 1.61 and 1.75 min along with a transition at m/z 544.42/397.27 and 528.46/321.41 were observed for DOX and internal standard (IS) Daunorubicin, respectively. In addition, a linear dynamic range with r2 ≥ 0.9985 over a concentration range of 1.00-2500.0 ng/ml was observed for different processes and parameters used in the study. Similarly a marked improvement i.e. 6.8 fold was observed, in PEGylated-DOX-PLGA-NPs as compared to DOX-S, in pharmacokinetics studies. CONCLUSION: The promising approach of PEGylated-DOX-PLGA-NPs may provide an alternate to intravenous therapy for better patient care.

Synthesis and characterization of novel carboxymethyl Assam Bora rice starch for the controlled release of cationic anticancer drug based on electrostatic interactions.

Carboxymethyl Assam Bora rice starch (CM-ABRS) was chemically synthesized in non-aqueous medium with the optimum degree of substitution (DS) of 1.23, and physicochemically characterized by FT-IR, DSC, XRD, and SEM analysis. Comparative evaluation of CM-ABRS with native starch (ABRS) for powder flow characteristics, swelling index, apparent solubility, rheological properties, textural properties, and mucoadhesive studies were carried out. The aim of the current work was to investigate the potential of CM-ABRS as a novel carrier for the water-soluble chemotherapeutic, doxorubicin hydrochloride (DOX). Formation of drug/polymer complex (DOX-CM-ABRS) via electrostatic interaction has been evaluated for the controlled release of DOX in three different pH media (phosphate-buffered saline (PBS), pH 7.4, 6.8, and 5.5). In vitro drug release studies illustrated faster release of drug in PBS at pH 5.5 as compared to pH 6.8 and pH 7.4, respectively, indicating the importance of pH-sensitive drug release from the DOX-CM-ABRS complex in malignant tissues.

Insights into the Targeting Potential of Thymoquinone for Therapeutic Intervention Against Triple-negative Breast Cancer.

BACKGROUND: Thymoquinone (TQ) is a bioactive phytoconstituent obtained from Nigella sativa (black seeds). It has promising potential in cancer prevention. OBJECTIVE: Previous studies have shown that TQ can modulate signaling pathways responsible for cancer progression, thus enhancing the efficacy and improving the safety profile of clinically used anticancer drugs. METHOD: TQ acts on cell cycle and inhibits progression from G1 to S phase by targeting various proteins (cyclin D1, cyclin E, and p27). It also exhibits histone deacetylase (HDAC) inhibitory effects, targets p21 and Maspin, and induces pro-apoptotic gene, Bax and downregulates anti-apoptotic gene Bcl-2. Breast cancer (BC) is reported as one of the most common malignancies in women. RESULTS: Despite the research and advancement, it remains one of the most common causes of cancer related deaths among women. Recent advancements in molecular screening of BC led to the identification of clinically challenging condition of triple negative breast cancer (TNBC). TNBC is characterized by the absence of targetable receptors viz. estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) expressions. It is also characterized by reduced or absence of phosphatase and tensin homolog (PTEN) expression, a tumor suppressor gene having diverse functions including regulation of apoptosis, cell cycle, and metastasis. CONCLUSION: Since TQ has been reported to up-regulate several growth factors such as vascular endothelial growth factor (VEGF), EGF and PTEN expression, the present review article discusses the targeting potential of TQ for therapeutic intervention against such types of breast cancer.

Silymarin nanoemulsion against human hepatocellular carcinoma: development and optimization.

OBJECTIVE: Nanoemulsion of silymarin was developed and optimized. MATERIALS AND METHODS: Nanoemulsion was made by aqueous titration method. Sefsol 218 (5.8% v/v), Kolliphor RH40 and polyethylene glycol 400 (Smix; 2:1; 28.99% v/v) were used as oil phase, surfactant and co-surfactant while distilled water (65.22% v/v) acted as an aqueous phase. Nanoemulsion was characterized on the basis of particle size, viscosity, electrical conductivity and refractive index. Further, in vitro release, in vivo pharmacokinetic study, stability study and cancer cell line studies were also performed. RESULTS AND DISCUSSION: The optimized formulation (NE9) with mean particle size of 21.24 nm showed a minimum viscosity of 9.59 cps, maximum drug release (97.75%) in 24 h. The NE9 formulation also showed higher AUC (p < .01) and Cmax (p < .01) and shorter Tmax (p < .05) compared with conventional and standard suspensions of silymarin. The stability study also showed considerably stable formulations at refrigerator temperature as compared with room temperature (p > .05). The cancer cell line studies also confirmed that silymarin nanoemulsion reduced the cell viability and increased ROS intensity and chromatin condensation (p < .05). CONCLUSION: Our results concluded that nanoemulsion may be an efficient carrier for oral delivery of silymarin against human hepatocellular carcinoma without damaging normal cells.