Chitosan-Coated 5-Fluorouracil Incorporated Emulsions as Transdermal Drug Delivery Matrices

The purpose of the present study was to develop emulsions encapsulated by chitosan on the outer surface of a nano droplet containing 5-fluorouracil (5-FU) as a model drug. The emulsions were characterized in terms of size, pH and viscosity and were evaluated for their physicochemical properties such as drug release and skin permeation in vitro. The emulsions containing tween 80 (T80), sodium lauryl sulfate, span 20, and a combination of polyethylene glycol (PEG) and T20 exhibited a release of 88%, 86%, 90% and 92%, respectively. Chitosan-modified emulsions considerably controlled the release of 5-FU compared to a 5-FU solution (p < 0.05). All the formulations enabled transportation of 5-FU through a rat’s skin. The combination (T80, PEG) formulation showed a good penetration profile. Different surfactants showed variable degrees of skin drug retention. The ATR-FTIR spectrograms revealed that the emulsions mainly affected the fluidization of lipids and proteins of the stratum corneum (SC) that lead to enhanced drug permeation and retention across the skin. The present study concludes that the emulsions containing a combination of surfactants (Tween) and a co-surfactant (PEG) exhibited the best penetration profile, prevented the premature release of drugs from the nano droplet, enhanced the permeation and the retention of the drug across the skin and had great potential for transdermal drug delivery. Therefore, chitosan-coated 5-FU emulsions represent an excellent possibility to deliver a model drug as a transdermal delivery system.

Ultrasound-Responsive Smart Drug Delivery System of Lipid Coated Mesoporous Silica Nanoparticles

The immediate release of chemotherapeutics at the target site, along with no premature release in circulation is always challenging. The purpose of this study was to develop a stimuli responsive drug delivery system, composed of lipid supported mesoporous silica nanoparticles (MSNPs) for triggered drug release at the target site and simultaneously avoiding the premature release. MSNPs with a higher drug loading capacity and very slow release were designed so as to enhance release by FDA approved US-irradiation. Doxorubicin, as a model drug, and perfluoropentane (PFP) as a US responsive material, were entrapped in the porous structure of MSNPs. Lipid coating enhanced the cellular uptake and in addition provided a gatekeeping effect at the pore opening to reduce premature release. The mechanical and thermal effects of US induced the conversion of liquid PFP to a gaseous form that was able to rupture the lipid layer, resulting in triggered drug release. The prolonged stability profile and non-toxic behavior made them suitable candidate for the delivery of anticancer drugs. This smart system, with the abilities of better cellular uptake and higher cytotoxic effects on US-irradiation, would be a good addition to the applied side of chemotherapeutic advanced drug delivery systems.

Return to normal: COVID-19 vaccination under mitigation measures

Being unable to suppress SARS-CoV-2 transmission, the majority of countries worldwide have resorted to a mitigation approach towards COVID-19, allowing some degree of viral circulation in the population. Here, we investigate the expected outcomes of the interplay between vaccination rollout and adaptive mitigation measures constantly altering the epidemic trajectory and keeping the reproduction number around the unit. Using a novel mathematical modeling framework, we estimate that, for vaccination capacities of at least 4 daily doses administered per 1,000 inhabitants, a complete release of mitigation measures can be expected within 7 to 13 months since the start of vaccination, with a two-year cumulative incidence of deaths between 0.18 and 0.46 per 1,000 population. A heavier burden of deaths and a delayed <<return-to-normal>> is expected for lower vaccine capacities, if viral transmissibility exceeds by >60% the one estimated at the beginning of the pandemic, or if vaccine protection is short-lived. Failure to prioritize the elderly or a premature release of mitigation measures after vaccination of the most fragile will conspicuously increase the expected mortality. Finally, strategies oriented to prioritize the suppression of SARS-CoV-2 by maintaining strict restrictions will take a similar time as a mitigation approach, possibly resulting in acceptability issues. Persisting unknowns about the evolving epidemiology of SARS-CoV-2 variants and on the effectiveness of available and upcoming vaccines may warrant a future reassessment of these conclusions.

The arrested state of processing bodies supports mRNA regulation in early development

ABSTRACTBiomolecular condensates that form via liquid-liquid phase separation can exhibit diverse physical states. Despite considerable progress, the relevance of condensate physical states forin vivobiological function remains limited. Here, we investigated the physical properties ofin vivoprocessing bodies (P bodies) and their impact on mRNA storage in matureDrosophilaoocytes. We show that the conserved DEAD-box RNA helicase Me31B forms P body condensates which adopt a less dynamic, arrested physical state. We demonstrate that structurally distinct proteins and hydrophobic and electrostatic interactions, together with RNA and intrinsically disordered regions, regulate the physical properties of P bodies. Finally, using live imaging, we show that the arrested state of P bodies is required to prevent the premature release ofbicoid(bcd) mRNA, a body axis determinant, and that P body dissolution leads tobcdrelease. Together, this work establishes a role for arrested states of biomolecular condensates in regulating cellular function in a developing organism.

Analytical Methods for the Detection and Quantification of ADCs in Biological Matrices

Understanding pharmacokinetics and biodistribution of antibody–drug conjugates (ADCs) is a one of the critical steps enabling their successful development and optimization. Their complex structure combining large and small molecule characteristics brought out multiple bioanalytical methods to decipher the behavior and fate of both components in vivo. In this respect, these methods must provide insights into different key elements including half-life and blood stability of the construct, premature release of the drug, whole-body biodistribution, and amount of the drug accumulated within the targeted pathological tissues, all of them being directly related to efficacy and safety of the ADC. In this review, we will focus on the main strategies enabling to quantify and characterize ADCs in biological matrices and discuss their associated technical challenges and current limitations.

Collagen Hybrid Formulations for the 3D Printing of Nanostructured Bone Scaffolds: An Optimized Genipin-Crosslinking Strategy

Bone-tissue regeneration induced by biomimetic bioactive materials is the most promising approach alternative to the clinical ones used to treat bone loss caused by trauma or diseases such as osteoporosis. The goal is to design nanostructured bioactive constructs able to reproduce the physiological environment: By mimicking the natural features of bone tissue, the cell behavior during the regeneration process may be addressed. At present, 3D-printing technologies are the only techniques able to design complex structures avoiding constraints of final shape and porosity. However, this type of biofabrication requires complex optimization of biomaterial formulations in terms of specific rheological and mechanical properties while preserving high biocompatibility. In this work, we combined nano-sized mesoporous bioactive glasses enriched with strontium ions with type I collagen, to formulate a bioactive ink for 3D-printing technologies. Moreover, to avoid the premature release of strontium ions within the crosslinking medium and to significantly increase the material mechanical and thermal stability, we applied an optimized chemical treatment using ethanol-dissolved genipin solutions. The high biocompatibility of the hybrid system was confirmed by using MG-63 and Saos-2 osteoblast-like cell lines, further highlighting the great potential of the innovative nanocomposite for the design of bone-like scaffolds.

Conjugation of Doxorubicin to siRNA Through Disulfide-based Self-immolative Linkers

Co-delivery systems of siRNA and chemotherapeutic drugs have been developed as an attractive strategy to optimize the efficacy of chemotherapy towards cancer cells with multidrug resistance. In these typical systems, siRNAs are usually associated to drugs within a carrier but without covalent interactions with the risk of a premature release and degradation of the drugs inside the cells. To address this issue, we propose a covalent approach to co-deliver a siRNA-drug conjugate with a redox-responsive self-immolative linker prone to intracellular glutathione-mediated disulfide cleavage. Herein, we report the use of two disulfide bonds connected by a pentane spacer or a p-xylene spacer as self-immolative linker between the primary amine of the anticancer drug doxorubicin (Dox) and the 2′-position of one or two ribonucleotides in RNA. Five Dox-RNA conjugates were successfully synthesized using two successive thiol-disulfide exchange reactions. The Dox-RNA conjugates were annealed with their complementary strands and the duplexes were shown to form an A-helix sufficiently stable under physiological conditions. The enzymatic stability of Dox-siRNAs in human serum was enhanced compared to the unmodified siRNA, especially when two Dox are attached to siRNA. The release of native Dox and RNA from the bioconjugate was demonstrated under reducing conditions suggesting efficient linker disintegration. These results demonstrate the feasibility of making siRNA-drug conjugates via disulfide-based self-immolative linkers for potential therapeutic applications.

Doxorobicin as cargo in a redox-responsive drug delivery system capped with water dispersible ZnS nanoparticles

Redox-responsive drug delivery system was studied. ZnS nanoparticles served as pore capping agent to prevent premature release of anticancer drug. Such cargo can be monitored by magnetic field which opens possibilities its use in theranostics.

Gel granules from pectin callus Lupinus angustifolius prevent the premature release of mesalazine

The formation of cross-related pectin matrices on the base of physiologically active polysaccharides opens up new prospects for their application in medicine. The purpose of the study was to identify pectin gels that could retain the drag in an artificial gastric environment and did not have a cytotoxic effect. Here, pectins of apple, hogweed, thistle, rowan and lupine as well their gels were investigated. Pectin-gel granules were produced from 4% solutions of the pectins by ionotropic gelling. A metabolic activity of human cell cultures was evaluated in MTT test. The pectins at concentrations of less than 2 mg/mL were shown to be no cytotoxic. Pectin gels slightly reduced the metabolic activity of cells. The content of mesalazine in the gels and its releasing were evaluated by liquid chromatography-mass spectrometry method. Among pectines investigated, gel granules of lupine pectin retained the mesalazine most effectively. On the base of the results, one can consider the pectin polysaccharides of lupine as potential gel matrices for oral drag delivery systems. gel, pectins, HEK293, Caco-2, 5-aminosalicylic acid, gastric solution, chromatography-mass spectrometry

Woking of Advisory Boards in Maharashtra State: Serving Human Rights of Felons

Rationale behind construction of a “Sentence Review Board” in any State correctional institution in lies behind the progression of law originating from custodial and penal causes, to reformative and rehabilitative handling of lawbreakers wherein well-behaved and upright conduct, and rectified attitude are considered for as a key criterion for reduction of judicial sentence of imprisonment on personalized footing.In consonance of the statutory power granted, and focusing upon the guidelines issued by “Model Prison Manual 2003” through a notificationon December 1, 2015 the Home Department of the Government of Maharashtra formulated the amending rules to “Maharashtra Prisons (Review of Sentences) Rules, 1972” and restructured the “Advisory Boards,Special Advisory Boards and Medical Committees” constituted for the purpose of “pre-mature release” of the certain categorisedconvicts.As the provision for a premature release is “an executive exercise and not a judicial process”, “executive discretion in granting or denying” it raises certain grey areas in the criminal dispensation system in India. The present paper with an analytical and critical approach attempts to study the existing makeup of executive process of “pre-mature release of a felonwhich though is not a legal right, but is a human right to have his case considered for the grant of remission” in State of Maharashtra