Tethering of Chemotherapeutic Drug/Imaging Agent to Bile Acid-Phospholipid Increases the Efficacy and Bioavailability with Reduced Hepatotoxicity.

Weakly basic drugs display poor solubility and tend to precipitate in the stomach's acidic environment causing reduced oral bioavailability. Tracing of these orally delivered therapeutic agents using molecular probes is challenged due to their poor absorption in the gastrointestinal tract (GIT). Therefore, we designed a gastric pH stable bile acid derived amphiphile where Tamoxifen (as a model anticancer drug) is conjugated to lithocholic acid derived phospholipid (LCA-Tam-PC). In vitro studies suggested the selective nature of LCA-Tam-PC for cancer cells over normal cells as compared to the parent drug. Fluorescent labeled version of the conjugate (LCA-Tam-NBD-PC) displayed an increased intracellular uptake compared to Tamoxifen. We then investigated the antitumor potential, toxicity, and median survival in 4T1 tumor bearing BALB/c mice upon LCA-Tam-PC treatment. Our studies confirmed a significant reduction in the tumor volume, tumor weight, and reduced hepatotoxicity with a significant increase in median survival on LCA-Tam-PC treatment as compared to the parent drug. Pharmacokinetic and biodistribution studies using LCA-Tam-NBD-PC witnessed the enhanced gut absorption, blood circulation, and tumor site accumulation of phospholipid-drug conjugate leading to improved antitumor activity. Therefore, our studies revealed that conjugation of chemotherapeutic/imaging agents to bile acid phospholipid can provide a new platform for oral delivery and tracing of chemotherapeutic drugs.

TANGO2 deficiency disease is predominantly caused by a lipid imbalance.

TANGO2 deficiency disease (TDD) is a rare genetic disorder estimated to affect ∼8000 individuals worldwide. It causes neurodegeneration often accompanied by potentially lethal metabolic crises that are triggered by diet or illness. Recent work has demonstrated distinct lipid imbalances in multiple model systems either depleted for or devoid of the TANGO2 protein, including human cells, fruit flies and zebrafish. Importantly, vitamin B5 supplementation has been shown to rescue TANGO2 deficiency-associated defects in flies and human cells. The notion that vitamin B5 is needed for synthesis of the lipid precursor coenzyme A (CoA) corroborates the hypothesis that key aspects of TDD pathology may be caused by lipid imbalance. A natural history study of 73 individuals with TDD reported that either multivitamin or vitamin B complex supplementation prevented the metabolic crises, suggesting this as a potentially life-saving treatment. Although recently published work supports this notion, much remains unknown about TANGO2 function, the pathological mechanism of TDD and the possible downsides of sustained vitamin supplementation in children and young adults. In this Perspective, we discuss these recent findings and highlight areas for immediate scientific attention.

Haem's relevance genuine? Re-visiting the roles of TANGO2 homologues including HRG-9 and HRG-10 in C. elegans.

Mutations in the TANGO2 gene cause severe illness in humans, including life-threatening metabolic crises; however, the function of TANGO2 protein remains unknown. In a recent publication in Nature, Sun et al. proposed that TANGO2 helps transport haem within and between cells, from areas with high haem concentrations to those with lower concentrations. Caenorhabditis elegans has two versions of TANGO2 that Sun et al. called HRG-9 and HRG-10. They demonstrated that worms deficient in these proteins show increased survival upon exposure to a toxic haem analog, which Sun et al. interpreted as evidence of decreased haem uptake from intestinal cells into the rest of the organism. We repeated several experiments using the same C. elegans strain as Sun et al. and believe that their findings are better explained by reduced feeding behavior in these worms. We demonstrate that hrg-9 in particular is highly responsive to oxidative stress, independent of haem status. Our group also performed several experiments in yeast and zebrafish models of TANGO2 deficiency and was unable to replicate key findings from these models reported in Sun et al.'s original study. Overall, we believe there is insufficient evidence to support haem transport as the primary function for TANGO2.

Current Breakthroughs in Structure-based Design of Synthetic and Natural Sourced Inhibitors Against Zika Viral Targets.

BACKGROUND: Zika is a worldwide pandemic dreadful viral transmission through Aedes mosquito vector. It significantly causes fever, joint pain or rash, and conjunctivitis. Pregnant mothers suffering from Zika viral infection may have fetal abnormalities due to severe neurological problems, characterized by microcephaly along with Guillain-Barré syndrome, issuing ZIKV a major public health concern as declared by the World Health Organization. There is hardly any FDA approved anti-Zika viral drugs available. OBJECTIVE: Therefore, it is a big panic for the scientists to destroy the virus completely by generating potent inhibitors. METHODS: For the purpose, various Zika viral targets were explored by structure-based design in the present review in connection with the discovery of various synthetic and natural sourced inhibitors against Zika virus. RESULTS: The structure-based drug design tools such as x-ray crystallography and molecular docking reported various co-crystallized ligands and Zika virus inhibitors. CONCLUSION: Such inhibitors could further be modified for the design of highly active leads to combat Zika virus utilizing chemoinformatics modules.

Injectable, Self-Healing Chimeric Catechol-Fe(III) Hydrogel for Localized Combination Cancer Therapy.

Conventional intravenous or oral administration of a combination of chemotherapeutics displays poor bioavailability and induces undesirable systemic toxicity. Therefore, localized delivery of such chemotherapeutic combinations using polymeric hydrogels is expected to help in enhancing drug efficacy and reducing systemic toxicity. In this manuscript, we have utilized a chitosan-catechol based hydrogel (CAT-Gel) assembled through catechol-Fe(III) coordinative interactions for localized combination therapy in murine lung and breast cancer models. CAT-Gel offers a unique blend of material properties such as injectability and self-healing along with useful biological attributes like their noncytotoxic and nonhemolytic nature. The amphipathic nature of this hydrogel enabled us to incorporate a recipe of hydrophilic doxorubicin hydrochloride (DOX) and hydrophobic docetaxel (DTX) anticancer drugs. Rheology studies confirmed the self-healing nature of this chimeric hydrogel even after drug loading. CAT-Gel was retained for more than 40 days in mice upon subcutaneous injection. The sequential and sustained release of the entrapped DOX and DTX from the hydrogel resulted in synergistic therapeutic effect with increased median survival against murine lung and breast cancer models. Therefore, CAT-Gel provides a new coordinatively assembled biocompatible scaffold for localized delivery of chemotherapeutic drugs.