Bis-arylidene oxindoles for colorectal cancer nanotherapy.

Oxindoles are potent anti-cancer agents and are also used against microbial and fungal infections and for treating neurodegenerative diseases. These oxindoles are earlier established as estrogen receptor (ER)-targeted agents for killing ER (+) cancer cells. Our previously developed bis-arylidene oxindole, Oxifen (OXF) exhibits effective targeting towards ER (+) cancer cells which has a structural resemblance with tamoxifen. Herein, we have designed and synthesized few structural analogues of OXF such as BPYOX, ACPOX and ACPOXF to examine its cytotoxicity in different cancer as well as non-cancer cell lines and its potential to form self- aggregates in aqueous solution. Among these series of molecules, ACPOXF showed maximum toxicity in colorectal cancer cell line which are ER (-) but it also kills non-cancer cell line HEK-293, thereby reducing its cancer cell selectivity. Incidentally, ACPOXF exhibits self-aggregation, without the help of a co-lipid with nanometric size in aqueous solution. ACPOXF self-aggregate was co-formulated with glucocorticoid receptor (GR) synthetic ligand, dexamethasone (Dex) (called, ACPOXF-Dex aggregate) which could selectively kill ER (-) colorectal cancer cells and also could increase survivability of colon-tumour bearing mice. ACPOXF-Dex induced ROS up-regulation followed by apoptosis through expression of caspase-3. Further, we observed upregulation of antiproliferative factor, p53 and epithelial-to-mesenchymal (EMT) reversal marker E-cadherin in tumour mass. In conclusion, a typical structural modification in ER-targeting Oxifen moiety resulted in its self-aggregation that enabled it to carry a GR-ligand, thus broadening its selective antitumor property especially as colon cancer therapeutics.

Cationic lipid-conjugated bis-arylidene oxindole derivatives as broad-spectrum breast cancer-selective therapeutics.

Breast cancer is a heterogeneous malignancy with wide-ranging variations in therapeutic responses, overall survival etc. Major challenges for available chemotherapeutic agents in achieving clinical success are in maintaining systemic bio-distribution and avoiding non-specific adverse effects. Bis-arylidene oxindoles are estrogen receptor (ER)-selective bioactive molecules with moderate potency. In here, we have designed, synthesized and evaluated a series of twin aliphatic chain cationic lipid-conjugated bis-arylidene oxindole molecules with variations in nature of linker, lengths of carbon spacer and hydrophobic twin chains. We observed that among the various structural analogues, C8 twin-chain containing molecules, PGC8, S2C8 and S3C8 showed effective cancer cell-selective cytotoxicity in different cancer cell lines with an IC50 ranging from 4 to 7 µM. These molecules selectively induced apoptosis, ROS production and cell cycle inhibition at G1/S phase in ER + breast cancer cells but not in non-cancer cells. Additionally, these molecules formed homogenous self-assemblies exhibiting effective hydrodynamic diameter with positive surface charge. The self-assemblies also showed prominent cancer cell-selective uptake and DNA-binding abilities. Hence, we have shown successful incorporation of dexamethasone to the self-assemblies, and its enhanced cytotoxicity even in ER-negative breast cancer cells. All these results indicate that PGC8, S2C8 and S3C8 molecules, albeit their potent and selective ER-positive anti-breast cancer activity, can be repurposed as targeted delivery systems and hold promise as unique, broader spectrum breast cancer cell-selective therapeutic payloads.

Deciphering the associated risk on soil microbes upon use of biopesticides in rice ecosystem.

Plant species, viz Cleistanthus collinus, Lantana camara, and Strychnos nux-vomica are being traditionally used for pest management in rice. However, limited investigation has been carried out to understand the toxic effect of these materials on soil microbes. Hot water extracts of these plants were evaluated for their effects on soil microbial population and enzyme activities along with neem oil and chlorpyrifos as check. Soil microbial population, viz bacteria, fungi, phosphate-solubilizing bacteria (PSB), and asymbiotic nitrogen fixers were unchanged after application of plant extracts. Maximum population of bacteria including PSB and asymbiotic nitrogen fixers were observed in control, whereas, S. nux-vomica, and C. collinus-treated soil had higher number of actinomycetes and fungal population, respectively. Soil microbial biomass did not vary differently among the plant extracts. Application of plant extracts did not alter dehydrogenase, ß-glycosidase, acid phosphatase, alkaline phosphatase, and urease content in soil. Secondary metabolites present in these plant extracts may be responsible for variable effects on soil microbes. Chlorpyrifos had a fleeting negative effect on soil microbes and enzymes in comparison to plant extracts. All the three plants did not have any negative effect on soil microbes and enzymes and can be safely recommended in rice pest management.

Comparison of Acute Gastrointestinal Toxicity of Intensity-Modulated Radiotherapy Versus Three-Dimensional Conformal Radiotherapy in Patients of Carcinoma Cervix.

Introduction Cervical cancer is the most common gynaecological malignancy worldwide, with a higher prevalence in middle- and low-income countries. Chemoradiotherapy, followed by intracavitary brachytherapy, is the treatment of choice in locally advanced cervical cancer. The most common acute side effect of external beam radiotherapy (EBRT) is bowel toxicity in the form of diarrhoea and abdominal cramps. The treatment techniques of EBRT were revolutionised with the advent of intensity modulation. This study aims to prospectively analyse whether the dosimetric advantage of intensity-modulated radiotherapy (IMRT) over three-dimensional conformal radiotherapy (3DCRT) is translated clinically into a decrease in acute toxicity. Method Twenty-four patients were randomised into two groups: the 3DCRT and the IMRT. Acute gastrointestinal (GI) toxicity was assessed during treatment using radiation therapy oncology group grading. The factors under consideration were age, stage of the disease, treatment technique, chemotherapy, and the intention of therapy (radical or adjuvant). The mean bowel bag dose of the two techniques was analysed. Result Among the factors under consideration, it was found that the treatment technique was the only factor that had a significant association with acute bowel toxicity in both univariate (p = 0.036) and multivariate analyses (p = 0.028). The mean V25 (the volume receiving 25 Gy), V45, and V50 of the bowel bag in the IMRT arm were significantly less than the 3DCRT arm. Grades 2 and 3 acute bowel toxicities were also higher in the 3DCRT arm. Conclusion The treatment technique is essential to determining acute GI toxicity during pelvic radiotherapy. With IMRT, the dose to the bowel bag and, in turn, the acute bowel toxicity can be reduced.

A Prospective Cohort Study Analyzing Radiation-Induced Xerostomia and Quality of Life of Head and Neck Cancer Patients Treated With Intensity-Modulated Radiotherapy and 3D Conformal Radiotherapy Techniques at a Tertiary Cancer Center in Eastern India.

Introduction Cancer of the head and neck is one of the most common cancers in India. Radiotherapy (RT) plays a vital role in the management of head and neck cancer both as a curative and adjuvant modality. Xerostomia is the most common acute and late toxicity. Therefore, this study aimed to analyze radiation-induced xerostomia and the quality of life of patients treated with intensity-modulated radiotherapy (IMRT) and three-dimensional (3D) conformal radiotherapy (3DCRT). Objectives We aim to evaluate radiation-induced acute xerostomia both subjectively and objectively at three-month and one-year post-radiotherapy follow-up period in patients who received radiotherapy in conformal technique (IMRT) to the head and neck region and compare it with those who received the 3DCRT technique. We also aim to assess the recovery of salivary flow in the third month post-radiotherapy by measuring the parotid scintigraphy excretion fraction. Materials and methods Forty patients with head and neck squamous cell carcinoma (SCC) were randomly assigned to the IMRT and 3DCRT arms. Xerostomia during radiation and at three-month and one-year post-radiotherapy follow-up was assessed subjectively using the xerostomia-related quality of life (XeQOL) questionnaire and objectively by measuring the salivary flow rate and parotid scintigraphy. Results The result is analyzed using an independent t-test, Mann-Whitney U test, and Fisher's exact test. The analysis showed that patients treated with radiation by IMRT showed better XeQOL scores (43.40±2.326 in IMRT and 52.10±2.573 in 3DCRT, p<0.001) and Eating Assessment Tool-10 (EAT-10) score (27.65±2.796 in IMRT and 33.80±1.936 in 3DCRT, p<0.001) compared to those treated with 3DCRT. Analysis of the excretion fraction (EF%) of parotid scintigraphy depicted improvement in EF% for both right and left parotids in the IMRT arm with statistical significance (for right parotid, 25.22±12.98 in IMRT and 19.60±10.17 in 3DCRT, p=0.136, and for left parotid, 28.03±12.51 in IMRT and 15.35±11.49 in 3DCRT, p=0.0019). The mean rate of flow (ROF) of saliva showed a declining trend during the end of radiotherapy treatment compared to baseline, but the mean ROF of saliva was better in IMRT compared to 3DCRT, and the difference was statistically significant. The ROF of saliva starts improving during the one-year post-radiotherapy follow-up period. Pearson's chi-square test was used to analyze the correlation between mean parotid dose with EF% of parotid scintigraphy, and it showed a negative correlation, which is statistically significant for both 3DCRT and IMRT arms. Conclusion Xerostomia can be reduced by precision radiotherapies such as the parotid-sparing IMRT technique in head and neck cancer patients, hence improving the quality of life.

Small-Molecule Probe for Sensing Serum Albumin with Consequential Self-Assembly as a Fluorescent Organic Nanoparticle for Bioimaging and Drug-Delivery Applications.

The recognition of a specific protein in blood serum amidst similar proteins is a challenging and vital endeavor in clinical diagnostics. Herein, we have described a small-molecule probe (DFPAC-OH) that can induce self-assembly of human serum albumin (HSA) and bovine serum albumin (BSA) to generate a highly sustainable fluorescent organic nanoparticle (NP), useful for imaging and in vitro drug-delivery applications. In the midst of similar proteins, DFPAC-OH selectively binds in a noncovalent manner to serum albumin. The specific binding tailors the fluorescence properties of DFPAC-OH. The lowest detection limit for BSA is 47 nM with a binding constant of 1.03 × 105 M-1. The probe can efficiently detect HSA in an artificial urine sample. Furthermore, the subsequent bovine albumin self-assembled nanoparticle (DFPAC-OH@BSA-NPs) displays a strong emission at 580 nm both in solution and in solid state. The nanoparticle is highly stable over a long pH range, covering the physiologic pH, and shows an excellent bioavailability to be used for sustainable cell imaging and drug-delivery applications. In addition, the cellular internalization and the pH-responsive drug-release behavior of a hydrophobic drug thymoquinone (TQ) encapsulated in DFPAC-OH@BSA-NPs (TQ-DFPAC-OH@BSA-NPs) have also been evaluated in A549 cell lines. The cytotoxic effect and quantification of intracellular reactive oxygen species (ROS) generation were further examined carefully to observe the anticancer property of TQ-DFPAC-OH@BSA-NPs. Therefore, the present system can simultaneously deliver drug molecules and image the event of delivery. The entire nanoparticles are characterized by transmission electron microscopy (TEM), scanning electron microscopy (SEM), dynamic light scattering (DLS), and infrared (IR) spectroscopy. The specific binding of DFPAC-OH is well supported by the molecular docking study, fluorescence lifetime measurement, and circular dichroism analysis.

Targeting the Trypanothione Reductase of Tissue-Residing Leishmania in Hosts' Reticuloendothelial System: A Flexible Water-Soluble Ferrocenylquinoline-Based Preclinical Drug Candidate.

Since inception, the magic bullets developed against leishmaniasis traveled a certain path and then dropped down due to either toxicity or the emergence of resistance. The route of administration is also an important concern. We developed a series of water-soluble ferrocenylquinoline derivatives, targeting Leishmania donovani, among which CQFC1 showed the highest efficacy even in comparison to other drugs, in use or used, both in oral and intramuscular routes. It did not induce any toxicity to splenocytes and on hematopoiesis, induced protective cytokines, and did not hamper the drug-metabolizing enzymes in hosts. It acts through the reduction and the inhibition of parasites' survival enzyme trypanothione reductase of replicating amastigotes in hosts' reticuloendothelial tissues. Unlike conventional drugs, this molecule did not induce the resistance-conferring genes in laboratory-maintained resistant L. donovani lines. Experimentally, this easily bioavailable preclinical drug candidate overcame all of the limitations causing the discontinuation of the other conventional antileishmanial drugs.