Ultrasound-mediated transdermal drug delivery of fluorescent nanoparticles and hyaluronic acid into porcine skin in vitro

Transdermal drug delivery(TDD) can effectively bypass the first-pass effect. In this paper, ultrasound-facilitated TDD on fresh porcine skin was studied under various acoustic parameters, including frequency, amplitude, and exposure time. The delivery of yellow–green fluorescent nanoparticles and high molecular weight hyaluronic acid(HA) in the skin samples was observed by laser confocal microscopy and ultraviolet spectrometry, respectively. The results showed that,with the application of ultrasound exposures, the permeability of the skin to these markers(e.g., their penetration depth and concentration) could be raised above its passive diffusion permeability. Moreover, ultrasound-facilitated TDD was also tested with/without the presence of ultrasound contrast agents(UCAs). When the ultrasound was applied without UCAs,low ultrasound frequency will give a better drug delivery effect than high frequency, but the penetration depth was less likely to exceed 200 μm. However, with the help of the ultrasound-induced microbubble cavitation effect, both the penetration depth and concentration in the skin were significantly enhanced even more. The best ultrasound-facilitated TDD could be achieved with a drug penetration depth of over 600 μm, and the penetration concentrations of fluorescent nanoparticles and HA increased up to about 4–5 folds. In order to get better understanding of ultrasound-facilitated TDD, scanning electron microscopy was used to examine the surface morphology of skin samples, which showed that the skin structure changed greatly under the treatment of ultrasound and UCA. The present work suggests that, for TDD applications(e.g., nanoparticle drug carriers, transdermal patches and cosmetics), protocols and methods presented in this paper are potentially useful.     

A DFT‐based mechanistic study on the formation of oximes

Oxime chemistry has been proven to be a reliable bioconjugation method for biomedical applications. Because of its stable and bio‐orthogonal nature, a number of materials have been devised for in vitro and in vivo applications such as drug delivery, imaging, and biochemical assays. Polymers, synthetic molecules, nanoparticles, and biomolecules carrying alkoxyamine and aldehyde/ketone functional groups could be linked to each other through oxime bond, and a variety of modular platforms could be produced. Formation of oximes is catalyzed in acidic medium, and the proposed reaction mechanism follows classical imine formation pathways. Aniline has been found to accelerate the rate of oxime formation several orders of magnitude. In this computational study, we analyzed the proposed mechanism on model systems using DFT calculations including a solvation model. The energetics of the reaction steps in neutral and acidic conditions as well as in the presence of aniline was performed. Explicit water molecules were included in the calculations to study the energetics of solvent assisted proton transfer steps.     

The existence and stability of bulk nanobubbles:a long-standing dispute on the experimentally observed mesoscopic inhomogeneities in aqueous solutions

In theory,nanobubbles can stably exist with a lifetime of microseconds at most,but numerous experimental observations demonstrate that nanobubbles in bulk solution can be stable from hours to weeks.Although various conjectures on the stability mechanism of bulk nanobubbles,such as the contaminant mechanism,skin mechanism,surface zeta potential mechanism,are proposed,there has not yet been a unified conclusion.Since bulk nanobubbles show great potential in a wide spectrum of applications and are relevant to a number of unsolved questions on cavitation and nucleation,the debate over their stability mechanisms has been active.In the past,extensive studies have been carried out to understand the mechanism of nanobubble stability,and important insights have already been provided.This paper will provide a brief overview of our current understanding of the unexpected stability of bulk nanobubbles.     

Pharmaceutical and medical applications of polymer electrolytes

Classic methods of drug delivery have embraced a number of routes into the site of pharmacological action. Modern preference, wherever possible, is for a non-invasive route to minimise the chance of cross infection, especially of the AIDS virus. The skin, which is the largest organ in the human body, is a particularly appealing route as, in the absence of wounds and blemishes, it offers a natural, high-integrity, barrier to the outside world. Skin patches containing active drug that is allowed to diffuse passively across the external skin barrier into the bloodstream now enjoy wide application but a problem is that the rate of egress is often slow. For certain ionic drugs, including local anaesthetics and, more recently, peptides and gene-based, biotechnological engineered pharmaceuticals, it is possible substantially to enhance transdermal transport by iontophoresis. The technique of iontophoresis facilitates the passage of ionic drugs through the skin using an electric current. Ionically conducting polymers (polymer electrolytes) are potential candidates as hosts for drugs to be delivered iontophoretically. Key issues affecting iontophoretic delivery are reviewed in this paper and the potential role of polymer electrolyte materials in iontophoretic devices will be described. Paper presented at the 9th EuroConference on Ionics, Ixia, Rhodes, Greece, Sept. 15–21, 2002.     

Mechanisms underlying sonoporation: Interaction between microbubbles and cells

The past several decades have witnessed great progress in “smart drug delivery”, an advance technology that can deliver genes or drugs into specific locations of patients’ body with enhanced delivery efficiency. Ultrasound-activated mechanical force induced by the interactions between microbubbles and cells, which can stimulate so-called “sonoporation” process, has been regarded as one of the most promising candidates to realize spatiotemporal-controllable drug delivery to selected regions. Both experimental and numerical studies were performed to get in-depth understanding on how the microbubbles interact with cells during sonoporation processes, under different impact parameters. The current work gives an overview of the general mechanism underlying microbubble-mediated sonoporation, and the possible impact factors (e.g., the properties of cavitation agents and cells, acoustical driving parameters and bubble/cell micro-environment) that could affect sonoporation outcomes. Finally, current progress and considerations of sonoporation in clinical applications are reviewed also.     

Skin spectrophotometry under the islet photothermal effect on the epidermal permeability

The results of experimental investigation of an increase in the epidermal barrier permeability are presented. The results are obtained using the method based on the creation of permeability microzones (islets) during the local thermal action on stratum corneum. It is shown that the epidermal barrier permeability considerably increases under the island photothermal effect and application of various clearing agents. Detailed spectrophotometric investigations of skin under the conditions of a partial violation of the epidermis barrier functions due to the island effect and introduction of various immersion agents in the skin are presented. The effect of various conditions of the object illumination on the dynamics of spectra is analyzed. A common behavior of the dynamics of the spectra of all kinds during clearing is revealed. Possible mechanisms accompanying the optical clearing process under the island photothermal effect are discussed.     

Vascular permeability in cancer and infection as related to macromolecular drug delivery, with emphasis on the EPR effect for tumor-selective drug targeting

Tumor and inflammation have many common features. One hallmark of both is enhanced vascular permeability, which is mediated by various factors including bradykinin, nitric oxide (NO), peroxynitrite, prostaglandins etc. A unique characteristic of tumors, however, is defective vascular anatomy. The enhanced vascular permeability in tumors is also distinctive in that extravasated macromolecules are not readily cleared. We utilized the enhanced permeability and retention (EPR) effect of tumors for tumor selective delivery of macromolecular drugs. Consequently, such drugs, nanoparticles or lipid particles, when injected intravenously, selectively accumulate in tumor tissues and remain there for long periods. The EPR effect of tumor tissue is frequently inhomogeneous and the heterogeneity of the EPR effect may reduce the tumor delivery of macromolecular drugs. Therefore, we developed methods to augment the EPR effect without inducing adverse effects for instance raising the systemic blood pressure by infusing angiotensin II during arterial injection of SMANCS/Lipiodol. This method was validated in clinical setting. Further, benefits of utilization of NO-releasing agent such as nitroglycerin or angiotensin-converting enzyme (ACE) inhibitors were demonstrated. The EPR effect is thus now widely accepted as the most basic mechanism for tumor-selective targeting of macromolecular drugs, or so-called nanomedicine.     

Cavitation technology – A greener processing technique for the generation of pharmaceutical nanoemulsions

Novel nanoemulsion-based drug delivery systems (DDS) have been proposed as alternative and effective approach for the delivery of various types of poorly water-soluble drugs in the last decade. This nanoformulation strategy significantly improves the cell uptake and bioavailability of numerous hydrophobic drugs by increasing their solubility and dissolution rate, maintaining drug concentration within the therapeutic range by controlling the drug release rate, and reducing systemic side effects by targeting to specific disease site, thus offering a better patient compliance. To date, cavitation technology has emerged to be an energy-efficient and promising technique to generate such nanoscale emulsions encapsulating a variety of highly potent pharmaceutical agents that are water-insoluble. The micro-turbulent implosions of cavitation bubbles tear-off primary giant oily emulsion droplets to nano-scale, spontaneously leading to the formation of highly uniform drug contained nanodroplets. A substantial body of recent literatures in the field of nanoemulsions suggests that cavitation is a facile, cost-reducing yet safer generation tool, remarkably highlighting its industrial commercial viability in the development of designing novel nanocarriers or enhancing the properties of existing pharmaceutical products. In this review, the fundamentals of nanoemulsion and the principles involved in their formation are presented. The underlying mechanisms in the generation of pharmaceutical nanoemulsion under acoustic field as well as the advantages of using cavitation compared to the conventional techniques are also highlighted. This review focuses on recent nanoemulsion-based DDS development and how cavitation through ultrasound and hydrodynamic means is useful to generate the pharmaceutical grade nanoemulsions including the complex double or submicron multiple emulsions.     

Mechanistic Insights into a Non‐Classical Diffusion Pathway for the Formation of Hollow Intermetallics: A Route to Multicomponent Hollow Structures

Hollow nanostructures are used for various applications including catalysis, sensing, and drug delivery. Methods based on the Kirkendall effect have been the most successful for obtaining hollow nanostructures of various multicomponent systems. The classical Kirkendall effect relies on the presence of a faster diffusing species in the core; the resultant imbalance in flux results in the formation of hollow structures. Here, an alternate non‐Kirkendall mechanism that is operative for the formation of hollow single crystalline particles of intermetallic PtBi is demonstrated. The synthesis method involves sequential reduction of Pt and Bi salts in ethylene glycol under microwave irradiation. Detailed analysis of the reaction at various stages indicates that the formation of the intermetallic PtBi hollow nanoparticles occurs in steps. The mechanistic details are elucidated using control experiments. The use of microwave results in a very rapid synthesis of intermetallics PtBi that exhibits excellent electrocatalytic activity for formic acid oxidation reaction. The method presented can be extended to various multicomponent systems and is independent of the intrinsic diffusivities of the species involved.     

Versatile Preparation of Silica Nanocapsules for Biomedical Applications

Core–shell nanocapsules are receiving increasing interest for drug delivery applications. Silica nanocapsules have been the focus of intensive studies due to their biocompatibility, versatile silica chemistry, and tunable porosity. However, a versatile one-step preparation of silica nanocapsules with well-defined core–shell structure, tunable size, flexible interior loading, and tailored shell composition, permeability, and surface functionalization for site-specific drug release and therapeutic tracking remains a challenge. Herein, an interfacially confined sol–gel process in miniemulsion for the one-step versatile preparation of functional silica nanocapsules is developed. Uniform nanocapsules with diameters from 60 to 400 nm are obtained and a large variety of hydrophobic liquids are encapsulated in the core. When solvents with low boiling point are loaded, subsequent solvent evaporation converts the initially hydrophobic cavity into an aqueous environment. Stimuli-responsive permeability of nanocapsules is programmed by introducing disulfide or tetrasulfide bonds in the shell. Selective and sustained release of dexamethasone in response to glutathione tripeptide for over 10 d is achieved. Fluorescence labeling of the silica shell and magnetic loading in the internal cavity enable therapeutic tracking of nanocapsules by fluorescence and electron microscopies. Thus, silica nanocapsules represent a promising theranostic nanoplatform for targeted drug delivery applications.     

FTIR analysis of natural and synthetic collagen

Collagen is the most abundant protein in humans and animals, comprising of one third of the total proteins that accounts for three quarters of the dry weight skin in humans. Collagen containing a range of proteins has been reported for tissue engineering applications, but, only a small number of studies related to chemical structure evaluation of collagen are found in the literature. Collagen can be obtained from both the natural and synthetic sources and offers a wide range of biomedical applications due to its excellent biocompatibility and low immunogenicity. Hence, it is important to identify chemical structural properties of collagen and Fourier transform infrared (FTIR) appears to be a technique of choice to study their chemical structure. This review aims to highlight the use of FTIR to study collagen-based biomaterials, using it for characterization of collagen extracted from various sources. Characterization of collagen-based materials used in wound healing, skin substitutes, derma fillers, and aging of skin, collagen containing drug delivery agents, collagen-based materials used in tissue engineering, bone regeneration, and osteogenic differentiation is discussed in detail. FTIR analysis of collagen-containing materials used for dental applications, cleft-palate, and in alveolar-ridge preservation has also been highlighted.     

Therapeutic opportunities in biological responses of ultrasound

The therapeutic benefits of several existing ultrasound-based therapies such as facilitated drug delivery, tumor ablation and thrombolysis derive largely from physical or mechanical effects. In contrast, ultrasound can also trigger various time-dependent biochemical responses in the exposed biological milieu. Several biological responses to ultrasound exposure have been previously described in the literature but only a handful of these provide therapeutic opportunities. These include the use of ultrasound for healing of soft tissues and bones, the use of ultrasound for inducing non-necrotic tumor atrophy as well as for potentiation of chemotherapeutic drugs, activation of the immune system, angiogenesis and suppression of phagocytosis. A review of these therapeutic opportunities is presented with particular emphasis on their mechanisms. Overall, this review presents the increasing importance of ultrasound’s role as a biological sensitizer enabling novel therapeutic strategies.     

Sono-leather technology with ultrasound: a boon for unit operations in leather processing - review of our research work at Central Leather Research Institute (CLRI), India

Ultrasound is a sound wave with a frequency above the human audible range of 16Hz to 16kHz. In recent years, numerous unit operations involving physical as well as chemical processes are reported to have been enhanced by ultrasonic irradiation. There have been benefits such as improvement in process efficiency, process time reduction, performing the processes under milder conditions and avoiding the use of some toxic chemicals to achieve cleaner processing. These could be a better way of augmentation for the processes as an advanced technique. The important point here is that ultrasonic irradiation is physical method activation rather than using chemical entities. Detailed studies have been made in the unit operations related to leather such as diffusion rate enhancement through porous leather matrix, cleaning, degreasing, tanning, dyeing, fatliquoring, oil-water emulsification process and solid-liquid tannin extraction from vegetable tanning materials as well as in precipitation reaction in wastewater treatment. The fundamental mechanism involved in these processes is ultrasonic cavitation in liquid media. In addition to this there also exist some process specific mechanisms for the enhancement of the processes. For instance, possible real-time reversible pore-size changes during ultrasound propagation through skin/leather matrix could be a reason for diffusion rate enhancement in leather processing as reported for the first time. Exhaustive scientific research work has been carried out in this area by our group working in Chemical Engineering Division of CLRI and most of these benefits have been proven with publications in valued peer-reviewed international journals. The overall results indicate that about 2-5-fold increase in the process efficiency due to ultrasound under the given process conditions for various unit operations with additional benefits. Scale-up studies are underway for converting these concepts in to a real viable larger scale operation. In the present paper, summary of our research findings from employing this technique in various unit operations such as cleaning, diffusion, emulsification, particle-size reduction, solid-liquid leaching (tannin and natural dye extraction) as well as precipitation has been presented.     

中药透皮剂的研究

透皮给药比口服和注射给药具有避免肝脏首过效应、避免胃肠道降解、避免皮肤损伤、释药速率稳定、血药浓度可控,毒副作用小,停、用药方便和给药频率低等优点,利于长期治疗。本实验中草药组成复方以水提醇沉法、回流法、浸制法制得浸膏,采用改良的Franz扩散装置,以离体鸡皮为屏障生理盐水为接受介质,用紫外分光光度法测定中药复方在不同条件下的吸光度,来判断其透皮效果。结果表明,回流法制得透皮剂浸膏的吸光度最大。回流法所制透皮剂渗透效果最佳,随着时间的延长,渗透效果不断加强,其透皮效果明显优于水提醇沉法和浸渍法;水提醇沉法和浸渍法所制透皮剂效果不显著。     

Transportation of drug–gold nanocomposites by actinomyosin motor system

Nanotechnology is playing an important role in drug delivery to overcome limitations of conventional drug delivery systems in terms of solubility, in vivo stability, pharmacokinetics, and bio-distribution. The controlled transportation of drug into the cell and within the cell is a major challenge to be addressed. Cellular molecular motors have been exploited for their cargo carrying capacity for various applications including engineering and health care. Combination of nanotechnology and biomolecular motors can address some of the challenges in drug delivery. In the present study, transportation of drug nanocomposites has been demonstrated. Nanocomposites of 6-mercaptopurine and levodopa drugs (cancer and Parkinson’s disease, respectively) were prepared with gold nanoparticles (GNPs) by covalent attachment and these nanocomposites were attached to actin filaments. These nanocomposites were in-turn transported by actin filaments on myosin tracks. Characterization of drug nanocomposites formation was done by UV–Vis spectroscopy, field emission scanning electron microscopy, transmission electron microscopy, and confocal microscopy. GNP composites of 6-mercaptopurine and levodopa were formed by sulfide and amide bond formation, respectively. Average velocity of actin filament attached to nanocomposites was found to be 3.17 and 3.89 μm/s for levodopa and 6-mercaptopurine, respectively, as compared to actin filaments with velocity of 4.0–6.0 μm/s. Three concepts have been proposed for the study of drug transportation into the cell based on polycationic complex formation, interaction of actin with cellular myosin and Biomolecular Adaptor for Retrograde Transport (BART) technology. The aspects of this study heads toward the development of an approach to utilize molecular motors for nanoscale transportation endogenously.     

Ultrasound-driven titanium modification with formation of titania based nanofoam surfaces

Titanium has been widely used as biomaterial for various medical applications because of its mechanical strength and inertness. This on the other hand makes it difficult to structure it. Nanostructuring can improve its performance for advanced applications such as implantation and lab-on-chip systems. In this study we show that a titania nanofoam on titanium can be formed under high intensity ultrasound (HIUS) treatment in alkaline solution. The physicochemical properties and morphology of the titania nanofoam are investigated in order to find optimal preparation conditions for producing surfaces with high wettability for cell culture studies and drug delivery applications. AFM and contact angle measurements reveal, that surface roughness and wettability of the surfaces depend nonmonotonously on ultrasound intensity and duration of treatment, indicating a competition between HIUS induced roughening and smoothening mechanisms. We finally demonstrate that superhydrophilic bio-and cytocompatible surfaces can be fabricated with short time ultrasonic treatment.     

Fish oil based vitamin D nanoencapsulation by ultrasonication and bioaccessibility analysis in simulated gastro-intestinal tract

Recently, nanoemulsions have been employed for different applications including food and drug industries for efficient nutrient delivery system. In this study, vitamin D (a lipophilic molecule) was encapsulated in fish oil for higher oral bioavailability. The oil-in-water nanoemulsion was formulated by ultrasonication technique with a droplet size range of 300–450 nm and a shelf life of more than 90 days. The influence of oil, water and surfactant concentration was investigated by phase diagram. The formulated nanoemulsion had encapsulation efficiency in the range of 95.7–98.2%. Further, nanoemulsion passed through simulated gastro-intestinal tract revealed an increased bioavailability than non-encapsulated vitamin. Thus, the formulation can be used as a drug delivery vehicle for various lipophilic compounds. Till date, no one have fabricated an efficient nano-vehicle for the delivery of vitamin D as well as analyzed the efficient delivery system in simulated GI-tract, this is first of its kind study in this regard. This can be scaled up further after analyzing the safety aspects.     

Multidisciplinary Role of Mesoporous Silica Nanoparticles in Brain Regeneration and Cancers: From Crossing the Blood–Brain Barrier to Treatment

Mesoporous silica nanoparticles (MSNs) have gained wide attention for their role in biomedicine and as drug delivery vehicles. Their structural tunability, high surface area, and easy functionalization impart significant advantages over conventional materials. In this Review, recent advances in the synthesis, drug delivery, and therapeutic roles of MSNs in the treatment of various neurodegenerative and neuroinflammatory diseases are presented. The intention is to understand how MSN formulations that are capable of encapsulating drug molecules can enhance drug delivery by overcoming the blood–brain barrier (BBB) mediated by specific transport processes. The composition and characteristics of the BBB, and how alterations are observed in neurodegenerative diseases including Alzheimer's, epilepsy, and intracerebral hemorrhage are reviewed. Finally, the factors affecting efficient delivery of MSNs into the brain are summarized, and their most promising functional outcomes are discussed.     

肿瘤脂质体药物热靶向输送的数值研究

热作用可以提高肿瘤血管对脂质体药物的通透性,从而促进肿瘤内部的药物传输.本文建立了一个新的模型对热促进脂质体药物在肿瘤内输送的治疗方式进行了数值研究.模型将肿瘤划分为血管丰富的周边区域和无血管的中心区域.数值计算结果显示热作用能有效促进肿瘤内脂质体药物的传输.     

Variable‐temperature Raman spectro‐microscopy for a comprehensive analysis of the conformational order in PEGylated lipids

The investigation of phase transitions and associated changes in the conformational order of lipids is of importance in various research areas dealing with phenomena such as the formation and fusion of vesicles, transmembrane diffusion and membrane interactions with drugs and proteins. In this article, we have focused on the study of thermotropic phase behaviors and associated changes in the conformational order of two newly developed synthetic PEGylated lipids trademarked as QuSomes. In contrast to conventional phospholipids, this new kind of lipid forms liposomes spontaneously upon hydration, without the supply of external activation energy. Variable‐temperature Raman spectro‐microscopy has been employed in order to plot the transition temperature profiles showing the phase behavior of these new lipids composed of 1,2‐dimyristoyl‐rac‐glycerol‐3‐dodecaethylene glycol (GDM‐12) and 1,2‐distearoyl‐rac‐glycerol‐3‐triicosaethylene glycol (GDS‐23). Furthermore, several spectral indicators were calculated and correlated which allowed for the deduction of various aspects of molecular structure as well as intramolecular motion and intermolecular interactions. To confirm the observations, differential scanning calorimetry (DSC) was applied and revealed a good agreement with the Raman spectroscopy results. Finally, this information may find application in various studies including the development of lipid‐based novel substances and drug delivery systems. Copyright © 2008 John Wiley & Sons, Ltd.