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Pulmonary drug delivery is governed by several biophysical parameters of delivery carriers, such as particle size, shape, density, charge, and surface modifications. Although much attention has been given to other parameters, particle shape effects have rarely been explored. In this work, we assess the influence of particle shape of inhaled delivery carriers on their aerodynamic properties and macrophage uptake by using polymeric microparticles of different geometries ranging in various sizes. Doxorubicin was conjugated to the polymer particles and the bioconjugates were characterized. Interestingly, the results of in-vitro lung deposition, performed using a next generation impactor, demonstrated a significant improvement in the aerodynamic properties of the rod-shaped particles with a high aspect ratio as compared to spherical particles with the same equivalent volume. The results of a macrophage uptake experiment demonstrate that the high aspect ratio particles were phagocytosed less than spherical particles. Furthermore, the cytotoxicity of these doxorubicin-conjugated particles was determined against murine macrophages, resulting in reduced toxicity when treated with high aspect ratio particles as compared to spherical particles. This project provides valuable insights into the influence of particle shape on aerodynamic properties and primary defense mechanisms in the peripheral lungs, while using polymeric microparticles of various sizes and geometries. Further systematic development can help translate these findings to preclinical and clinical studies for designing efficient inhalable delivery carriers., (Copyright © 2021 Elsevier B.V. All rights reserved.)

The measurement of UV-induced DNA damage as a dosimeter of exposure and predictor of skin cancer risk has been proposed by multiple groups. Although UV-induced mutations and adducts are present in normal-appearing UV-exposed epidermis, sampling normal nonlesional skin requires noninvasive methods to extract epidermal DNA for analysis. Here, we demonstrate the feasibility of such an approach, termed surfactant-based tissue acquisition for molecular profiling. Sampling in patients was performed using a felt-tip pen soaked in a mixture of surfactants (Brij-30/N-decyl-N,N-dimethyl-3-ammonio-1-propanesulfonate). In mice, we show that the epidermis can be selectively removed without scarring, with complete healing within 2 weeks. We exposed hairless mice to low-dose UV radiation over a period of 3 months and serially sampled them through up to 2 months following the cessation of UV exposure, observing a progressive increase in a UV signature mutational burden. To test whether surfactant-based tissue acquisition for molecular profiling could be applied to human patients, samples were collected from sun-exposed and sun-protected areas, which were then subjected to high-depth targeted exome sequencing. Extensive UV-driven mosaicism and substantially increased mutational loads in sun-exposed versus sun-protected areas were observed, suggesting that genomic measures, as an integrated readout of DNA damage, repair, and clonal expansion, may be informative markers of UV exposure., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

This study was aimed at developing a nanoparticle strategy to overcome acquired resistance against erlotinib in non-small cell lung cancer (NSCLC). To load erlotinib on biodegradable PLGA nanoparticles, erlotinib-cyclodextrin (Erlo-CD) complex was prepared using β-cyclodextrin sulfobutyl ether, which was in turn loaded in the core of PLGA nanoparticles using multiple emulsion solvent evaporation. Nanoparticles were characterized for size distribution, entrapment and loading efficiency, in-vitro release, and therapeutic efficacy against different lung cancer cells. Effect of formulation on cell cycle, apoptosis, and other markers was evaluated using flow cytometry and western blotting studies. The efficacy of optimized nanoformulation was evaluated using a clinically relevant in-vitro 3D-spheroid model. Results showed that Erlo-CD loaded nanoparticles (210 ± 8 nm in size) demonstrated 3-fold higher entrapment (61.5 ± 3.2% vs 21.9 ± 3.7% of plain erlotinib loaded nanoparticles) with ~5% loading efficiency and sustained release characteristics. Developed nanoparticles demonstrated significantly improved therapeutic efficacy against NSCLC cells in terms of low IC50 values and suppressed colony forming ability of cancer cells, increased apoptosis, and autophagy inhibition. Interestingly, 3D spheroid study demonstrated better anticancer activity of Erlo-CD nanoparticles compared to plain erlotinib. Present study has shown a premise to improve therapeutic efficacy against erlotinib-resistant lung cancer using modified nanoErlo formulations., (Copyright © 2018. Published by Elsevier B.V.)

A number of studies have reported on the activation energies of skin permeability. In this article, I summarize the literature data on activation energies and analyze their dependence on solute molecular properties, namely radius and lipophilicity. Theoretical equations are also presented to facilitate interpretation of the dependence of activation energy on molecular properties of the solute., (Copyright 2007 Wiley-Liss, Inc.)

Melanosomes, pigment granules in melanophores, play a principal role in physiological color adaptation of fish and frog. Melanophores regulate melanosome trafficking on cytoskeletal filaments to generate a range of spatiotemporal patterns. Here, we present the first comprehensive model of spatiotemporal evolution of melanosome patterns. The model encompasses both physical and biochemical aspects of melanosome dynamics. It consists of (i) a kinetic description of biochemical reactions involved in intracellular signaling, (ii) a system of macroscopic reaction-diffusion-convection equations for melanosome concentration, and (iii) a set of constitutive relationships for coupling transport with the biochemical network. The model relates molecular-level regulatory actions to cell-level melanosome distribution, allowing unification of existing experimental observations and qualitative hypotheses into an integrated, consistent framework. The model reproduces salient features of melanosome patterns, both during transient and steady state. It gives useful insights into how cells coordinate motor-assisted transport to maintain and adapt spatial organization of intracellular organelles. In particular, we calculate the optimal transition paths from aggregation to dispersion in fish melanophores. The calculations suggest that fish melanophores optimally control intracellular signaling to maximize the efficiency of motor-assisted transport during dispersion.

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 OsO(4) and RuO(4) post-fixation) as visualization methods, on LFS-induced permeation pathways in the SC. QDs (20 nm 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.

Application of low-frequency ultrasound has been shown to increase skin permeability, thereby facilitating delivery of macromolecules (low-frequency sonophoresis). In this study, we sought to determine a theoretical description of transdermal transport of hydrophilic permeants induced by low-frequency sonophoresis. Parameters such as pore size distribution, absolute porosity, and dependence of effective tortuosity on solute characteristics were investigated. Pig skin was exposed to low-frequency ultrasound at 58 kHz to achieve different skin resistivities. Transdermal delivery of four permeants [mannitol, luteinizing hormone releasing hormone (LHRH), inulin, dextran] in the presence and absence of ultrasound was measured. The porous pathway model was modified to incorporate the permeant characteristics into the model and to achieve a detailed understanding of the pathways responsible for hydrophilic permeant delivery. The slopes of the log kp(p) versus log R graphs for individual solutes changed with solute molecular area, suggesting that the permeability-resistivity correlation for each permeant is related to its size. The tortuosity that a permeant experiences within the skin also depends on its size, where larger molecules experience a less tortuous path. With the modified porous pathway model, the effective tortuosities and skin porosity were calculated independently. The results of this study show that low-frequency sonophoresis creates pathways for permeant delivery with a wide range of pore sizes. The optimum pore size utilized by solutes is related to their molecular radii., (Copyright 2003 Wiley-Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 92:381-393, 2003)

The application of low-frequency ultrasound enhances drug transport through the skin, a phenomenon referred to as low-frequency sonophoresis. This enhancement is mediated through cavitation, the formation and collapse of gaseous bubbles. We hypothesized that the efficacy of low-frequency sonophoresis can be significantly enhanced by provision of nuclei for cavitation. In this study, we used two porous resins, Diaion HP20 and Diaion HP2MG (2MG), as cavitation nuclei. We measured the effect of these resins on cavitation using pitting of aluminum foil. 2MG showed a higher efficacy in enhancing cavitation compared with Diaion HP20. 2MG was also effective in enhancing transdermal mannitol transport. These results confirm that the addition of cavitation nuclei such as porous resins further increases the effect of low-frequency ultrasound on skin permeability., (Copyright 2002 Wiley-Liss, Inc. and the American Pharmaceutical Association.)

The barrier properties of skin originate from its lipid bilayers whose ordered structure retards solute transport. The objective of this study is to develop a mathematical model that can predict skin permeability to small (MW < 500 Da), hydrophobic solutes based on the fundamental transport properties of skin lipid bilayers. We developed a mathematical model to predict two major transport properties (i.e., partition and diffusion coefficients) using important structural properties of lipid bilayers and molecular properties of the solute. The predictions are based on Scaled Particle Theory that calculates these properties using statistical mechanics of lipid chains. The calculations predict that solute partition coefficients in lipid bilayers are of the same order as those measured in isotropic solvents, such as octanol (K(o/w)). On the other hand, solute diffusion coefficients decrease exponentially with solute cross-sectional area. The resulting equation to predict skin permeability is given by P = 5.6 x 10(-6)K(0.7)(o/w)exp(-0.46r(2)(A1)--where r is solute molecular radius in Angstroms (A) and P is in cm/s. The predicted skin permeabilities compare well with the experimental data., (Copyright 2002 Wiley-Liss, Inc. and the American Pharmaceutical Association.)

Application of low-frequency ultrasound significantly enhances skin permeability. The enhancement of skin permeability is mediated by cavitation, oscillation, and collapse of gaseous cavities. In this article, we report detailed investigations of the occurrence of cavitation during low-frequency sonophoresis. Cavitation was monitored by recording pressure amplitudes of subharmonic emission and broadband noise at four different ultrasound frequencies in the range of 20-100 kHz and at various intensities in the range of 0-2.6 W/cm(2). Enhancement of skin conductivity, in the presence of sodium lauryl sulfate (SLS), was also measured under the same ultrasound conditions. Enhancement of skin conductivity correlated well with the amplitude of broadband noise, which suggests the role of transient cavitation in low-frequency sonophoresis. No correlation was found between the subharmonic pressure amplitude and conductivity enhancement., (Copyright 2002 Wiley-Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 91:444-453, 2002)

Low-frequency ultrasound (20 kHz) and surfactants have been individually shown to enhance transdermal drug transport. In this study, we investigated the synergistic effect of ultrasound and surfactants on transdermal drug delivery. Surfactants with different head group chemistries including anionic, cationic, and nonionic with varying tail lengths (8-16-carbon atoms) were studied. We found that surfactants possessing anionic and cationic head groups were more potent than those possessing nonionic head groups in increasing skin conductivity in the presence of ultrasound. Furthermore, for surfactants possessing the same head group, those with a 14-carbon tail length were found to be most effective in enhancing skin permeability. The data presented in this report show that ultrasound and surfactants synergistically enhance skin permeability. Two mechanisms are shown to play a role in this synergistic effect. First, ultrasound enhances surfactant delivery (enhanced delivery) into the skin and, second, ultrasound disperses surfactant (enhanced dispersion) within the skin. In general, surfactants that are potent enhancers by themselves are potent enhancers in the presence of ultrasound as well. We performed imaging experiments to assess the effect of ultrasound on delivery of a model permeant, sulforhodamine B, into the skin. These experiments show that ultrasound enhances surfactant delivery and dispersion in the skin., (Copyright 2002 Wiley-Liss, Inc.)

Application of ultrasound enhances transdermal transport of drugs (sonophoresis). The enhancement may result from enhanced diffusion due to ultrasound-induced skin alteration and/or from forced convection. To understand the relative roles played by these two mechanisms in low-frequency sonophoresis (LFS, 20 kHz), a theory describing the transdermal transport of hydrophilic permeants in both the absence and the presence of ultrasound was developed using fundamental equations of membrane transport, hindered-transport theory, and electrochemistry principles. With mannitol as the model permeant, the role of convection in LFS was evaluated experimentally with two commonly used in vitro skin models- human cadaver heat-stripped skin (HSS) and pig full-thickness skin (FTS). Our results suggest that convection plays an important role during LFS of HSS, whereas its effect is negligible when FTS is utilized. The theory developed was utilized to characterize the transport pathways of hydrophilic permeants during both passive diffusion and LFS with mannitol and sucrose as two probe molecules. Our results show that the porous pathway theory can adequately describe the transdermal transport of hydrophilic permeants in both the presence and the absence of ultrasound. Ultrasound alters the skin porous pathways by two mechanisms: (1) enlarging the skin effective pore radii, or (2) creating more pores and/or making the pores less tortuous. During passive diffusion, both HSS and FTS exhibit the same skin effective pore radii (r = 28 +/- 13 A). In contrast, during LFS, r within HSS is greatly enlarged (r > 125 A), whereas r within FTS does not change significantly (23 +/- 10 A). The observed different roles of convection during LFS across HSS and FTS can be attributed to the different degrees of structural alteration that these two types of skin undergo during LFS., (Copyright 2001 Wiley-Liss, Inc. and the American Pharmaceutical Association.)

Application of low-frequency ultrasound has been shown to enhance transdermal transport of drugs (low-frequency sonophoresis). In this paper, we show that the efficacy of low-frequency ultrasound in enhancing transdermal transport can be further increased by its combination with sodium lauryl sulfate (SLS), a well-known surfactant. The dependence of the ultrasound-SLS-mediated transport on ultrasound parameters, including intensity, net exposure time, and duty cycle, is discussed. The transdermal transport enhancement is proportional to ultrasound intensity as well as to exposure time, and is independent of duty cycle as long as the net exposure time is the same. The synergistic effect of SLS and ultrasound on transdermal transport increases linearly with SLS concentration. The enhancement is also proportional to the ultrasound energy density beyond a threshold value, which suggests that a certain minimum amount of energy density is required before noticeable changes in skin permeability occur. A similar dependence of the transdermal transport enhancement on energy density is observed in the case of the enhancement induced by ultrasound alone. Although the threshold energy density value in the presence of SLS is about 10 times lower than that in the case of ultrasound alone, the relationship between enhancement and energy density in the presence and in the absence of SLS is otherwise similar. Possible mechanisms for the synergistic effect of ultrasound and SLS are also discussed.

Over the last few decades, application of therapeutic ultrasound (frequency between 1 and 3 MHz and intensity between 1 and 2 W/cm2) has been attempted to enhance transdermal transport of several drugs, a method referred to as sonophoresis. The sonophoretic enhancement of transdermal drug transport was found to vary significantly from drug to drug. In certain cases, ultrasound did not induce any enhancement of transdermal drug transport. This variation in the efficacy of sonophoresis has raised a controversy regarding its applicability as a transdermal delivery enhancer. The objective of this paper is to provide a summary of the literature data on sonophoresis and an explanation for the observed variation of the sonophoretic enhancement from drug to drug. This paper also presents an equation to qualitatively predict whether therapeutic ultrasound may enhance transdermal transport of a given drug based on knowledge of the drug passive skin permeability and octanol-water partition coefficient.

The effects of (i) a series of chemical enhancers and (ii) the combination of these enhancers and therapeutic ultrasound (1 MHz, 1.4 W/cm2, continuous) on transdermal drug transport are investigated. A series of chemical enhancer formulations, including (i) polyethylene glycol 200 dilaurate (PEG), (ii) isopropyl myristate (IM), (iii) glycerol trioleate (GT), (iv) ethanol/pH 7.4 phosphate buffered saline in a 1:1 ratio (50% EtOH), (v) 50% EtOH saturated with linoleic acid (LA/EtOH), and (vi) phosphate buffered saline (PBS), as a control, are evaluated using corticosterone as a model drug. LA/EtOH is the most effective of these enhancers, increasing the corticosterone flux by 900-fold compared to that from PBS. Therapeutic ultrasound (1 MHz, 1.4 W/cm2, continuous) increases the corticosterone permeability from all of the enhancers examined by up to 14-fold (LA/EtOH) and increases the corticosterone flux from the saturated solutions by up to 13,000-fold (LA/EtOH), relative to that from PBS. Similar enhancements are obtained with LA/EtOH with and without ultrasound for four other model drugs, dexamethasone, estradiol, lidocaine, and testosterone. The permeability enhancements for all of these drugs resulting from the addition of linoleic acid to 50% EtOH increase with increasing drug molecular weight. Likewise, the permeability enhancement attained by ultrasound and LA/EtOH relative to passive EtOH exhibits a similar size dependence. A mechanistic explanation of this size dependence is provided. It is suggested that bilayer disordering agents, such as linoleic acid and ultrasound, transform the SC lipid bilayers into a fluid lipid bilayer phase or create a separate bulk oil phase. The difference in diffusivity of a given solute in SC bilayers and in either fluid bilayers or bulk oil is larger for larger solutes, thereby producing greater enhancements for larger solutes.

Although ultrasound has been shown to enhance the transdermal transport of a variety of drugs, the mechanisms underlying this phenomenon are not clearly understood. In this paper, we evaluate the roles played by various ultrasound-related phenomena, including cavitation, thermal effects, generation of convective velocities, and mechanical effects, in the ultrasonic enhancement of transdermal drug delivery (sonophoresis). Our experimental findings suggest that among all the ultrasound-related phenomena evaluated, cavitation plays the dominant role in sonophoresis using therapeutic ultrasound (frequency range, 1-3 MHz; intensity range, 0-2 W/cm2). Furthermore, confocal microscopy results indicate that cavitation occurs in the keratinocytes of the stratum corneum upon ultrasound exposure. It is hypothesized that oscillations of the cavitation bubbles induce disorder in the stratum corneum lipid bilayers, thereby enhancing transdermal transport. Evidence supporting this hypothesis is presented using skin electrical resistance measurements. Finally, a theoretical model is developed to predict the effect of ultrasound on the transdermal transport of drugs. The model predicts that sonophoretic enhancement depends most directly on the passive permeant diffusion coefficient, rather than on the permeability coefficient through the skin. Specifically, permeants passively diffusing through the skin at a relatively slow rate are expected to be preferentially enhanced by ultrasound. The experimentally measured sonophoretic transdermal transport enhancement for seven permeants, including estradiol, testosterone, progesterone, corticosterone, benzene, butanol, and caffeine, agree quantitatively with the model predictions. These experimental and theoretical findings provide quantitative guidelines for estimating the efficacy of sonophoresis in enhancing transdermal drug delivery.