Strategies and Approaches for siRNA Delivery

The present review discusses about RNA interference (RNAi) and its significance in gene therapy. The review mainly focuses on small interference RNA (siRNA) as a mediator of RNAi, its therapeutic benefits and various formulation strategies employed to overcome siRNA delivery hurdles. RNAi is a regulatory process which occurs endogenously within the cell wherein short double-stranded RNA (siRNA) effects sequence-specific posttranscriptional gene silencing. Even though siRNA assists researchers with its powerful therapeutic benefits, there are significant hurdles in developing efficient delivery systems for its systemic administration. These are extracellular and intracellular barriers for siRNA delivery. The present review addresses about pros and cons of gene therapy and superior advantages provided by siRNA over plasmid DNA in gene therapy. It also discloses about the discovery, mechanism of action, significance and applications of siRNA based gene therapies, challenges in its delivery and strategies for overcoming delivery hurdles. Furthermore, emphasis is provided on viral and non – viral vector based siRNA delivery and the significance of lipid based siRNA delivery, the lipoplexes over polymer based siRNA delivery - the polyplexes, followed by recent advances in siRNA based technologies directed against variety of diseases. Keywords: Endosomal escape, gene therapy, lipoplexes, polyplexes, siRNA, vectors

NOVEL FORMULATION STRATEGIES FOR INSULIN DELIVERY

Insulin is a hormone made by the pancreas that allows your body to use sugar (glucose) from carbohydrates in the food that you eat for energy or to store glucose for future use. Successful oral insulin delivery involves overcoming the enzymatic and physical barriers. Several companies across the globe are developing oral insulin based on different technology platforms. Insulin has been encapsulated in nanoparticles by mucoadhesive polymers such as chitosan, poly (lacticco-glycolic acid) (PLGA), and alginate which prevent enzymatic degradation and allow absorption across the epithelial layer in Peyer’s patches. Keywords: Novel Formulation Strategies, Insulin, hyperglycemia, Nanosphere-based oral insulin deliver

A REVIEW ON FRIEDREICH ATAXIA, A NEURODEGENERATIVE DISORDER

The present report discusses about the clinical trial requirements for Friedreich ataxia disease such as inclusion and exclusion criteria for the patients,primary/secondary outcome measuresrequired for assessing the efficacy of therapies viarating scales, physical activity tests, biomarkersand number of subjects/patients to be enrolled in each phase of the clinical trials of Friedreich ataxia (F.A.). These parameters have been selected from the ongoing and completed clinical trials for F.A. as reported in Clinical trials.gov and Friedreich Ataxia Research Alliance (FARA) official website. A total of 33 clinical trialdetails werereviewed for compilation of the above mentioned parameters. For the purpose of this report, the most useful and most commonly assessedprimary/secondary outcome measureswith respect to efficacy as well as inclusion and exclusion criteria have been selected and are being cited in this review.The outcome measures for the purpose of efficacy trials can broadly be classified as primary and secondaryoutcome measures and in each category, subclasses are being presented in the order of their priority as determined by their usefulness and common occurrence in all trials mentioned. These outcome measuresincludeRating Scales for Friedreich Ataxia, Physical Activity Tests and Biomarkers, evaluation of Cardiac functionality viz. left ventricular wall mass, non-invasive measures of systolic and diastolic ventricular function, echocardiography and immunogenicity.The genetic predisposition of Friedreich ataxia (epigenetics) leading to the pathogenesis of the disease is also discussed in this report. Based on above primary and secondary outcomes measures and inclusion and exclusion criteria, a tabular representation of the ongoing/ completed clinical trials representing the efficacy studies of the test molecules and the patient involvements in each clinical trial is also been listed. Various aspects of clinical trialsneeded for assessing ataxic stage in Friedreich ataxia disease is been reviewed in this article. Key words:Friedreich ataxia, Friedreich Ataxia Research Alliance (FARA), Inclusion and Exclusion criteria, primary and secondary outcome measures, rating scales, biomarkers, physical activity tests

Rod-shape theranostic nanoparticles facilitate antiretroviral drug biodistribution and activity in human immunodeficiency virus susceptible cells and tissues

Human immunodeficiency virus theranostics facilitates the development of long acting (LA) antiretroviral drugs (ARVs) by defining drug-particle cell depots. Optimal drug formulations are made possible based on precise particle composition, structure, shape and size. Through the creation of rod-shaped particles of defined sizes reflective of native LA drugs, theranostic probes can be deployed to measure particle-cell and tissue biodistribution, antiretroviral activities and drug retention. Methods: Herein, we created multimodal rilpivirine (RPV) 177lutetium labeled bismuth sulfide nanorods (177LuBSNRs) then evaluated their structure, morphology, configuration, chemical composition, biological responses and adverse reactions. Particle biodistribution was analyzed by single photon emission computed tomography (SPECT/CT) and laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS) imaging. Results: Nanoformulated RPV and BSNRs-RPV particles showed comparable physicochemical and cell biological properties. Drug-particle pharmacokinetics (PK) and biodistribution in lymphoid tissue macrophages proved equivalent, one with the other. Rapid particle uptake and tissue distribution were observed, without adverse reactions, in primary blood-derived and tissue macrophages. The latter was seen within the marginal zones of spleen. Conclusions: These data, taken together, support the use of 177LuBSNRs as theranostic probes as a rapid assessment tool for PK LA ARV measurements

Long-Acting Nanoformulated Antivirals for the Treatment and Prevention of HIV-1 and HBV infections

While antiretroviral therapy (ART) has revolutionized treatment and prevention of human immunodeficiency virus type one (HIV-1) infection, regimen adherence, viral mutations, drug toxicities, stigma and pill fatigue are limitations. These have led to the development of long acting (LA) ART. These include, but are not limited to, implantable devices, new chemical entities, prodrug modifications and nanoformulations. To these ends, this thesis focues on the transformation of nucleoside reverse transcriptase inhibitors (NRTIs) into LA parenterals, While elusive, data from our laboratories demonstrated that modifications to the PROdrug and nucleoTide technology (ProTide) enables improvements in drug apparent half-life and tissue and cell drug penetrance. Specifically, we now show that this modified ProTide approach could be applied successfully to emtricitabine (FTC) amongst other hydrophilic compounds to generate LA formulations. This advance can be seen as a principal part of commonly accepted antiretroviral and other antiviral treatment regimens

Rod-shape theranostic nanoparticles facilitate antiretroviral drug biodistribution and activity in human immunodeficiency virus susceptible cells and tissues

Human immunodeficiency virus theranostics facilitates the development of long acting (LA) antiretroviral drugs (ARVs) by defining drug-particle cell depots. Optimal drug formulations are made possible based on precise particle composition, structure, shape and size. Through the creation of rod-shaped particles of defined sizes reflective of native LA drugs, theranostic probes can be deployed to measure particle-cell and tissue biodistribution, antiretroviral activities and drug retention. Methods: Herein, we created multimodal rilpivirine (RPV) 177lutetium labeled bismuth sulfide nanorods (177LuBSNRs) then evaluated their structure, morphology, configuration, chemical composition, biological responses and adverse reactions. Particle biodistribution was analyzed by single photon emission computed tomography (SPECT/CT) and laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS) imaging. Results: Nanoformulated RPV and BSNRs-RPV particles showed comparable physicochemical and cell biological properties. Drug-particle pharmacokinetics (PK) and biodistribution in lymphoid tissue macrophages proved equivalent, one with the other. Rapid particle uptake and tissue distribution were observed, without adverse reactions, in primary blood-derived and tissue macrophages. The latter was seen within the marginal zones of spleen. Conclusions: These data, taken together, support the use of 177LuBSNRs as theranostic probes as a rapid assessment tool for PK LA ARV measurements

Simultaneous LC–MS/MS method for the quantitation of Azithromycin, Hydroxychloroquine and its metabolites in SARS-CoV-2(−/ +) populations using dried blood spots

Abstract Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) led to a global pandemic of coronavirus disease 2019 (COVID-19). Early in the pandemic, efforts were made to test the SARS-CoV-2 antiviral efficacy of repurposed medications that were already approved and available for other indications, including hydroxychloroquine (HCQ) and azithromycin (AZI). To reduce the risk of SARS-CoV-2 exposure for clinical-trial study participants and to conform with lockdowns and social distancing guidelines, biospecimen collection for HCQ and AZI included at-home dried blood spot (DBS) collection rather than standard venipuncture by trained clinicians. In this study, we developed and validated the first sensitive and selective simultaneous LC–MS/MS method to accurately quantitate the concentration of HCQ, HCQ metabolites (Desethylchloroquine [DCQ], Bisdesethylchloroquine [BDCQ], Monodesethylhydroxychloroquine [DHCQ]) and AZI extracted from DBS. The validated method was successfully applied for the quantification of over 2000 DBS specimens to evaluate the pharmacokinetic profile of AZI, HQC, and its metabolites. This new method has a small sample volume requirement (~ 10 µL), results in high sensitivity (1 ng/mL), and would facilitate remotely conducted therapeutic drug monitoring

Diagnostics for SARS-CoV-2 infections

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread to nearly every corner of the globe, causing societal instability. The resultant coronavirus disease 2019 (COVID-19) leads to fever, sore throat, cough, chest and muscle pain, dyspnoea, confusion, anosmia, ageusia and headache. These can progress to life-threatening respiratory insufficiency, also affecting the heart, kidney, liver and nervous systems. The diagnosis of SARS-CoV-2 infection is often confused with that of influenza and seasonal upper respiratory tract viral infections. Due to available treatment strategies and required containments, rapid diagnosis is mandated. This Review brings clarity to the rapidly growing body of available and in-development diagnostic tests, including nanomaterial-based tools. It serves as a resource guide for scientists, physicians, students and the public at large

Pharmacotherapeutics of SARS-CoV-2 Infections

The COVID-19 pandemic has affected more than 38 million people world-wide by person to person transmission of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Therapeutic and preventative strategies for SARS-CoV-2 remains a significant challenge. Within the past several months, effective treatment options have emerged and now include repurposed antivirals, corticosteroids and virus-specific antibodies. The latter has included convalescence plasma and monoclonal antibodies. Complete viral eradication will be achieved through an effective, safe and preventative vaccine. To now provide a comprehensive summary for each of the pharmacotherapeutics and preventative strategies being offered or soon to be developed for SARS-CoV-2. Graphical abstract: [Figure not available: see fulltext.].</p