No abstract

The aim of this work was to develop sustained local release systems for radioiodinated iodo-2'-deoxyuridine (125IUdR) from biodegradable polymeric microspheres to facilitate the controlled delivery of 125IUdR to brain tumours. The selective uptake of IUdR into the cell nucleus results in cell disruption over the short range of the low energy Auger electrons. The biodegradable microspheres can be precisely implanted in the brain by stereotactic techniques and the IUdR within the microspheres is protected from degradation and thus a sustained source of radiolabelled IUdR is available in the vicinity of the residual tumour cells. Poly(lactic-co-glycolic acid), PLGA (85:15), microspheres containing cold IUdR and the Auger-electron emitter 125I, as 125IUdR were prepared using the O/W, O/O and W/O/W emulsion-solvent evaporation methods. The W/O/W emulsion method was most effective in achieving good drug loading with the use of bovine plasma in the internal water phase. Also effective in improving the drug loading was the use of 20% acetone in the dichloromethane and the presence of Span 40 in the organic phase. Electrolytes (NaCl and IUdR) in the external aqueous phase also improved drug loading. After an initial rapid release from the microspheres, a sustained release was observed over 15 days for the 'cold' IUdR. The sustained release portions of the release curves showed Higuchi (t1/2), diffusion controlled release kinetics. The radiolabelled IUdR microspheres showed a burst release effect of 30-40% followed by a sustained release over 35 days.

No abstract

Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) is one of the most severe global pandemic due to its high pathogenicity and death rate starting from the end of 2019. Though there are some vaccines available against SAER-CoV-2 infections, we are worried about their effectiveness, due to its unstable sequence patterns. Therefore, beside vaccines, globally effective supporting drugs are also required for the treatment against SARS-CoV-2 infection. To explore commonly effective repurposable drugs for the treatment against different variants of coronavirus infections, in this article, an attempt was made to explore host genomic biomarkers guided repurposable drugs for SARS-CoV-1 infections and their validation with SARS-CoV-2 infections by using the integrated bioinformatics approaches. At first, we identified 138 differentially expressed genes (DEGs) between SARS-CoV-1 infected and control samples by analyzing high throughput gene-expression profiles to select drug target key receptors. Then we identified top-ranked 11 key DEGs (SMAD4, GSK3B, SIRT1, ATM, RIPK1, PRKACB, MED17, CCT2, BIRC3, ETS1 and TXN) as hub genes (HubGs) by protein-protein interaction (PPI) network analysis of DEGs highlighting their functions, pathways, regulators and linkage with other disease risks that may influence SARS-CoV-1 infections. The DEGs-set enrichment analysis significantly detected some crucial biological processes (immune response, regulation of angiogenesis, apoptotic process, cytokine production and programmed cell death, response to hypoxia and oxidative stress), molecular functions (transcription factor binding and oxidoreductase activity) and pathways (transcriptional mis-regulation in cancer, pathways in cancer, chemokine signaling pathway) that are associated with SARS-CoV-1 infections as well as SARS-CoV-2 infections by involving HubGs. The gene regulatory network (GRN) analysis detected some transcription factors (FOXC1, GATA2, YY1, FOXL1, TP53 and SRF) and micro-RNAs (hsa-mir-92a-3p, hsa-mir-155-5p, hsa-mir-106b-5p, hsa-mir-34a-5p and hsa-mir-19b-3p) as the key transcriptional and post- transcriptional regulators of HubGs, respectively. We also detected some chemicals (Valproic Acid, Cyclosporine, Copper Sulfate and arsenic trioxide) that may regulates HubGs. The disease-HubGs interaction analysis showed that our predicted HubGs are also associated with several other diseases including different types of lung diseases. Then we considered 11 HubGs mediated proteins and their regulatory 6 key TFs proteins as the drug target proteins (receptors) and performed their docking analysis with the SARS-CoV-2 3CL protease-guided top listed 90 anti-viral drugs out of 3410. We found Rapamycin, Tacrolimus, Torin-2, Radotinib, Danoprevir, Ivermectin and Daclatasvir as the top-ranked 7 candidate-drugs with respect to our proposed target proteins for the treatment against SARS-CoV-1 infections. Then, we validated these 7 candidate-drugs against the already published top-ranked 11 target proteins associated with SARS-CoV-2 infections by molecular docking simulation and found their significant binding affinity scores with our proposed candidate-drugs. Finally, we validated all of our findings by the literature review. Therefore, the proposed candidate-drugs might play a vital role for the treatment against different variants of SARS-CoV-2 infections with comorbidities, since the proposed HubGs are also associated with several comorbidities.

The pandemic threat of COVID-19 has severely destroyed human life as well as the economy around the world. Although, the vaccination has reduced the outspread, but people are still suffering due to the unstable RNA sequence patterns of SARS-CoV-2 which demands supplementary drugs. To explore novel drug target proteins, in this study, a transcriptomics RNA-Seq data generated from SARS-CoV-2 infection and control samples were analyzed. We identified 109 differentially expressed genes (DEGs) that were utilized to identify 10 hub-genes/proteins (TLR2, USP53, GUCY1A2, SNRPD2, NEDD9, IGF2, CXCL2, KLF6, PAG1 and ZFP36) by the protein–protein interaction (PPI) network analysis. The GO functional and KEGG pathway enrichment analyses of hub-DEGs revealed some important functions and signaling pathways that are significantly associated with SARS-CoV-2 infections. The interaction network analysis identified 5 TFs proteins and 6 miRNAs as the key regulators of hub-DEGs. Considering 10 hub-proteins and 5 key TFs-proteins as drug target receptors, we performed their docking analysis with the SARS-CoV-2 3CL protease-guided top listed 90 FDA approved drugs. We found Torin-2, Rapamycin, Radotinib, Ivermectin, Thiostrepton, Tacrolimus and Daclatasvir as the top ranked seven candidate drugs. We investigated their resistance performance against the already published COVID-19 causing top-ranked 11 independent and 8 protonated receptor proteins by molecular docking analysis and found their strong binding affinities, which indicates that the proposed drugs are effective against the state-of-the-arts alternatives independent receptor proteins also. Finally, we investigated the stability of top three drugs (Torin-2, Rapamycin and Radotinib) by using 100 ns MD-based MM-PBSA simulations with the two top-ranked proposed receptors (TLR2, USP53) and independent receptors (IRF7, STAT1), and observed their stable performance. Therefore, the proposed drugs might play a vital role for the treatment against different variants of SARS-CoV-2 infections.