Application of the Aqueous Porous Pathway Model to Quantify the Effect of Sodium Lauryl Sulfate on Ultrasound-Induced Skin Structural Perturbation

This study investigated the effect of sodium lauryl sulfate (SLS) on skin structural perturbation when utilized simultaneously with low-frequency sonophoresis (LFS). Pig full-thickness skin (FTS) and pig split-thickness skin (STS) treated with LFS/SLS and LFS were analyzed in the context of the aqueous porous pathway model to quantify skin perturbation through changes in skin pore radius and porosity-to-tortuosity ratio (ε/τ). In addition, skin treatment times required to attain specific levels of skin electrical resistivity were analyzed to draw conclusions about the effect of SLS on reproducibility and predictability of skin perturbation. We found that LFS/SLS-treated FTS, LFS/SLS-treated STS, and LFS-treated FTS exhibited similar skin perturbation. However, LFS-treated STS exhibited significantly higher skin perturbation, suggesting greater structural changes to the less robust STS induced by the purely physical enhancement mechanism of LFS. Evaluation of ε/τ values revealed that LFS/SLS-treated FTS and STS have similar transport pathways, whereas LFS-treated FTS and STS have lower ε/τ values. In addition, LFS/SLS treatment times were much shorter than LFS treatment times for both FTS and STS. Moreover, the simultaneous use of SLS and LFS not only results in synergistic enhancement, as reflected in the shorter skin treatment times, but also in more predictable and reproducible skin perturbation.National Institutes of Health (U.S.) (Grant EB-00351)Massachusetts Institute of Technology. Institute for Soldier Nanotechnologies (Grant DAAD-19-02-D-002)National Science Foundation (U.S.). Graduate Research Fellowship Progra

Low-Frequency Sonophoresis: Ultrastructural Basis for Stratum Corneum Permeability Assessed Using Quantum Dots

Low-frequency sonophoresis (LFS) has been well documented to enhance the permeability of skin to macromolecular drugs via induction of localized transport regions. However, the organizational details of epidermis, specifically stratum corneum (SC), during sonophoresis are beyond the resolution limit of common histo-optical microscopy tools, which fail to reveal any notable structural alterations in these regions at a submicroscopic scale. Here we report, using quantum dots (QDs) as a tracer and confocal microscopy and transmission electron microscopy (TEM) (with OsO4 and RuO4 post-fixation) as visualization methods, on LFS-induced permeation pathways in the SC. QDs (20nm diameter) penetrated well beyond the SC. TEM revealed that ultrasound significantly increased the frequency of occurrence of the otherwise scattered and separated lacunar spaces in the SC. A significant increase in lacunar dimensions was observed when 1% w/v sodium lauryl sulfate was added to the coupling medium. These studies show that LFS induces dilatation and higher connectivity of voids in the SC, possibly leading to formation of a three-dimensional porous network, which is capable of transporting QDs as well as macromolecules across the SC. This contention is consistent with previously conceived theoretical mechanistic understanding of LFS-induced enhanced transport across the skin

Интеллектуальный анализ данных на индийских фондовых рынках: создание портфелей с низким уровнем риска

Over the last five decades, business academics have identified over 300 determinants that potentially influence stock returns. However, we still do not know whether all return determinants are equally important, or whether there is a smaller set of determinants that has a disproportionately larger influence on stock returns. Can mining historical data help us find this smaller set of return determinants that has a disproportionately higher influence on stock returns? Using historical data from the Indian market, we build a large database of investments with more than 74,000 investments spread over a period of 132 months. From this database, using “association rule mining” method, we are able to mine a strong set of “association rules” that point to a smaller set of “return determinants” that are seen more frequently in investments that beat index returns. From a pool of thirty-seven return determinants, using “association rule mining”, we were able to find out a small set of key return determinants that are seen most frequently in investments that beat index returns in India. Portfolios created from these “association rules” have a portfolio risk lower than the market risk and provide index-beating returns. “Out-of-sample” portfolios created using these association rules have portfolio “Beta” less than one and provide returns that beat the market returns by a significant margin for all holding periods in the Indian market. Through this paper, we demonstrate how portfolio managers can mine “association rules” and build portfolios without any limits on the number of factors that can be included in the screening process. За последние 50 лет академики выявили более 300 факторов, которые потенциально влияют на доходность акций. Тем не менее мы по-прежнему не знаем, являются ли все факторы доходности одинаково важными или существует небольшой набор таких факторов, которые оказывают большее влияние на доходность акций. Помогут ли исторические данные по майнингу определить эти факторы доходности? Используя исторические данные индийского рынка, мы создали базу данных по 74 000 инвестициям в течение 132 месяцев. Из этой базы данных, используя метод «анализа ассоциативных правил», мы можем извлечь «факторы доходности», которые чаще встречаются в инвестициях и повышают индекс доходности. Из пула 37 факторов рентабельности, используя «ассоциативные правила», мы получили небольшой набор «ключевых» детерминирующих факторов, которые наиболее часто встречаются в инвестициях и повышают индекс доходности в Индии. Портфели, созданные на основе этих «правил ассоциации», имеют более низкий портфельный риск, чем рыночный риск, и обеспечивают большую отдачу от индексов. Портфели, созданные с использованием этих правил, имеют менее одного «Бета» в портфеле и обеспечивают прибыль, которая превосходит рыночную прибыль по полученной марже за весь период владения им на индийском рынке. С помощью этой статьи мы демонстрируем, как портфельные менеджеры могут использовать «правила ассоциации» и создавать портфели без каких-либо ограничений по количеству факторов, которые могут быть включены в процесс отбора

Effect of Surfactant Mixtures on Skin Structure and Barrier Properties

We investigated the effect of two commonly studied surfactants, sodium dodecyl sulfate (SDS) and dodecyl trimethylammonium bromide (C12TAB), on skin barrier properties. Using skin conductivity, FT-IR of stratum corneum samples, and penetration of radiolabelled SDS, we determined that addition of C12TAB lowers the ability of SDS to perturb skin’s barrier properties. Ultrafiltration experiments revealed that addition of C12TAB serves to decrease the concentration of monomers and sub-micellar aggregates. None of the measured skin properties including enhancement of skin conductivity, perturbation of lipid structure and skin concentration of SDS correlated with the total SDS concentration in the donor compartment (i.e., the total SDS concentration). However, all these parameters correlated well against the concentration of monomers and sub-micellar aggregates. These findings provide the evidence of the importance of monomer and sub-micellar components in altering skin barrier properties

An overview of clinical and commercial impact of drug delivery systems

Drug delivery systems are widely researched and developed to improve the delivery of pharmaceutical compounds and molecules. The last few decades have seen a marked growth of the field fueled by increased number of researchers, research funding, venture capital and the number of start-ups. Collectively, the growth has led to novel systems that make use of micro/nano-particles, transdermal patches, inhalers, drug reservoir implants and antibody-drug conjugates. While the increased research activity is clearly an indication of proliferation of the field, clinical and commercial translation of early-stage research ideas is critically important for future growth and interest in the field. Here, we will highlight some of the examples of novel drug delivery systems that have undergone such translation. Specifically, we will discuss the developments, advantages, limitations and lessons learned from: (i) microparticle-based depot formulations, (ii) nanoparticle-based cancer drugs, (iii) transdermal systems, (iv) oral drug delivery systems, (v) pulmonary drug delivery, (vi) implants and (vii) antibody-drug conjugates. These systems have impacted treatment of many prevalent diseases including diabetes, cancer and cardiovascular diseases, among others. At the same time, these systems are integral and enabling components of products that collectively generate annual revenues exceeding US $100 billion. These examples provide strong evidence of the clinical and commercial impact of drug delivery systems

Nanoparticles in the clinic: An update post COVID-19 vaccines

Nanoparticles are used in the clinic to treat cancer, resolve mineral deficiencies, image tissues, and facilitate vaccination. As a modular technology, nanoparticles combine diagnostic agents or therapeutics (e.g., elements, small molecules, biologics), synthetic materials (e.g., polymers), and biological molecules (e.g., antibodies, peptides, lipids). Leveraging these parameters, nanoparticles can be designed and tuned to navigate biological microenvironments, negotiate biological barriers, and deliver therapeutics or diagnostic agents to specific cells and tissues in the body. Recently, with the Emergency Use Authorization of the COVID-19 lipid nanoparticle vaccines, the advantages and potential of nanoparticles as a delivery vehicle have been displayed at the forefront of biotechnology. Here, we provide a 5-year status update on our original “Nanoparticles in the Clinic” review (also a 2-year update on our second “Nanoparticles in the Clinic” review) by discussing recent nanoparticle delivery system approvals, highlighting new clinical trials, and providing an update on the previously highlighted clinical trials

Cell-mediated delivery of nanoparticles: Taking advantage of circulatory cells to target nanoparticles

Cellular hitchhiking leverages the use of circulatory cells to enhance the biological outcome of nanoparticle drug delivery systems, which often suffer from poor circulation time and limited targeting. Cellular hitchhiking utilizes the natural abilities of circulatory cells to: (i) navigate the vasculature while avoiding immune system clearance, (ii) remain relatively inert until needed and (iii) perform specific functions, including nutrient delivery to tissues, clearance of pathogens, and immune system surveillance. A variety of synthetic nanoparticles attempt to mimic these functional attributes of circulatory cells for drug delivery purposes. By combining the advantages of circulatory cells and synthetic nanoparticles, many advanced drug delivery systems have been developed that adopt the concept of cellular hitchhiking. Here, we review the development and specific applications of cellular hitchhiking-based drug delivery systems

Particle Shape Enhances Specificity of Antibody-Displaying Nanoparticles

Monoclonal antibodies are used in numerous therapeutic and diagnostic applications; however, their efficacy is contingent on specificity and avidity. Here, we show that presentation of antibodies on the surface of nonspherical particles enhances antibody specificity as well as avidity toward their targets. Using spherical, rod-, and disk-shaped polystyrene nano- and microparticles and trastuzumab as the targeting antibody, we studied specific and nonspecific uptake in three breast cancer cell lines: BT-474, SK-BR-3, and MDA-MB-231. Rods exhibited higher specific uptake and lower nonspecific uptake in all cells compared with spheres. This surprising interplay between particle shape and antibodies originates from the unique role of shape in determining binding and unbinding of particles to cell surface. In addition to exhibiting higher binding and internalization, trastuzumab-coated rods also exhibited greater inhibition of BT-474 breast cancer cell growth in vitro to a level that could not be attained by soluble forms of the antibody. The effect of trastuzumab-coated rods on cells was enhanced further by replacing polystyrene particles with pure chemotherapeutic drug nanoparticles of comparable dimensions made from camptothecin. Trastuzumab-coated camptothecin nanoparticles inhibited cell growth at a dose 1,000-fold lower than that required for comparable inhibition of growth using soluble trastuzumab and 10-fold lower than that using BSA-coated camptothecin. These results open unique opportunities for particulate forms of antibodies in therapeutics and diagnostics