Tissue Permeability Research Articles

Synthesis of near-infrared-responsive hexagonal-phase upconversion nanoparticles with controllable shape and luminescence efficiency for theranostic applications.

Over the past few decades, photodynamic therapy has been studied as a therapeutic method by generating singlet oxygen through activation of a photosensitizer (PS) to kill cancer cells. However, the light within the activating wavelength range of commercial photosensitizers has a low penetration depth. In this study, we designed multifunctional upconversion nanoparticles (UCNs) that can emit high-energy light by absorbing low-energy near-infrared (NIR) light with excellent tissue permeability through a fluorescence resonance energy transfer procedure. This process can produce reactive oxygen species by activating the PS. We aimed to optimize the thermal decomposition synthesis procedure to produce lanthanide-doped UCNs with a uniform size and improve the photoluminescence efficiency for an NIR-regulated theranostic system. It was confirmed that the morphologies of UCNs can be controlled by varying the reaction time, reaction temperature, and feed molar ratio of the solvent and reactant. The crystalline morphology of the synthesized UCNs showed a thermodynamically stable hexagonal phase. The photoluminescence efficiency of the UCNs also was influenced by size, surface area, crystalline property, and stability in aqueous solution. Furthermore, the surface-modified UCNs with a folic acid-conjugated block copolymer and PS exhibited enhanced singlet oxygen generation and significantly improved aqueous solubility and photoluminescence efficiency.

TAK-676 in combination with pembrolizumab after radiation therapy in patients (pts) with advanced non–small cell lung cancer (NSCLC), triple-negative breast cancer (TNBC), or squamous-cell carcinoma of the head and neck (SCCHN): Phase 1 study design.

TPS2698 Background: The cyclic GMP-AMP Synthase (cGAS)–STimulator of INterferon Genes (STING) pathway is an important modulator of the innate immune system via induction of type I interferon (IFN-I). Cytosolic DNA generated as a result of tumor cell death following radiation therapy has been demonstrated to activate the cGAS-STING signaling axis resulting in antitumor immunogenicity. TAK-676 is a novel, synthetic STING agonist and it has been shown in preclinical studies to potently modulate the innate immune system and subsequently activate the adaptive immune system to produce antitumor responses. TAK-676 is designed for prolonged half-life in serum and enhanced tissue permeability compared with other STING agonists designed for intratumoral injection, allowing for systemic IV delivery with access to tumor sites and lymphatic tissue. IFN signaling impairment has been linked to checkpoint inhibitor (CPI) resistance in tumors. Treatment with TAK-676 after radiation therapy has the potential to stimulate T cell-mediated antitumor immunity via STING-mediated IFN-I release, particularly when used with anti-PD-1/PD-L1 therapies. Preclinical data support the addition of STING agonists to reverse resistance in tumors with prior exposure to CPIs. TAK-676 is being investigated (+/- pembrolizumab) in an ongoing first-in-human phase 1 study (NCT04420884). Here, we describe another phase 1 trial to investigate the safety and preliminary antitumor activity of TAK-676 plus pembrolizumab following radiation therapy in pts with advanced or metastatic NSCLC, TNBC, or SCCHN (NCT04879849). Methods: Adult pts with progressive disease (PD) following CPI treatment and who have ≥2 lesions, 1 of which can be targeted with radiation, are being enrolled. Pts receive 8 Gy x 3 fractions of image-guided radiation followed (after ≥40 hours) by IV pembrolizumab 200 mg on day 1 plus escalating doses of IV TAK-676 on days 1, 8, and 15 of a 21-day cycle. TAK-676 dose escalation is guided by the Bayesian optimal interval design. Pts receive TAK-676 plus pembrolizumab until PD, intolerance to treatment, or withdrawal. Pts enrolled at TAK-676 dose levels shown to have pharmacodynamic activity, and who have a safely accessible lesion outside the radiation field, will have paired biopsies collected at screening and between days 15 and 21 of cycle 1. The primary objective is to determine the safety and tolerability of TAK-676 plus pembrolizumab following radiation therapy; secondary objectives are to establish the recommended phase 2 dose of TAK-676 plus pembrolizumab following radiation therapy, and to assess preliminary antitumor activity both locally (within the radiation field) and systemically (non-radiated lesions). As of February 2022, we have enrolled ̃10% of the planned pts. Clinical trial information: NCT04879849.

Sequential Dual Delivery System Based on siCOX-2-Loaded Gold Nanostar and Thermal-Sensitive Liposomes Overcome Hypoxia-Mediated Multidrug Resistance in Tumors.

Reversing hypoxia-mediated multidrug resistance (MDR) presents a unique challenge in clinical chemotherapy. Here, a sequential dual delivery system composited with Cyclooxygenase-2 siRNA (siCOX-2) in poly-d-arginine (9R)/2-deoxyglucose (DG)-loaded gold nanostar (GNS) (siCOX-2@RDG) and paclitaxel (PTX)-loaded thermosensitive liposome (PTSL) was proposed to conquer the hypoxia-mediated MDR in tumors. As a result, the prepared siCOX-2@RDG exhibited a starlike morphology with a uniform particle size of 194.36 ± 1.44 nm and a ζ-potential of -11.83 ± 2.01 mV. In vitro, PTSL displayed expected thermal-responsive release properties. As expected, siCOX-2@RDG displayed exceptional DG-mediated hypoxia-targeting capability both in vitro and in vivo and downregulated the expression of COX-2 successfully. Meanwhile, GNS-triggered hyperthermia elevated the cellular uptake of PTSL in PTX-resistant HepG2(HepG2/PTX) cells in vitro and enhanced the permeability of tumor tissues, thus elevating the valid retention of PTX into solid tumors. Finally, we demonstrated that the sequential dual systems composed of siCOX-2@RDG and PTSL could reverse hypoxia-mediated MDR and exhibit excellent synergistic antitumor effects both in vitro and in vivo, prolonging the survival of tumor-bearing mice. The devised sequential dual systems, composed of two independent nanosystems, have a promising potential to overcome hypoxia-mediated MDR in clinical practice.

Mathematical modelling of haemorrhagic transformation within a multiscale microvasculature network

Objective. Haemorrhagic transformation (HT) is one of the most common complications after ischaemic stroke, caused by damage to the blood–brain barrier (BBB) that could be the result of stroke progression or a complication of stroke treatment with reperfusion therapy. The aim of this study is to develop further a previous simple HT mathematical model into an enlarged multiscale microvasculature model in order to investigate the effects of HT on the surrounding tissue and vasculature. In addition, this study investigates the relationship between tissue displacement and vascular geometry. Approach. By modelling tissue displacement, capillary compression, hydraulic conductivity in tissue and vascular permeability, we establish a mathematical model to describe the change of intracranial pressure (ICP) surrounding the damaged vascular bed after HT onset, applied to a 3D multiscale microvasculature. The use of a voxel-scale model then enables us to compare our HT simulation with available clinical imaging data for perfusion and cerebral blood volume () in the multiscale microvasculature network. Main results. We showed that the haematoma diameter and the maximum tissue displacement are approximately proportional to the diameter of the breakdown vessel. Based on the voxel-scale model, we found that perfusion reduces by approximately and reduces by around after HT onset due to the effect of capillary compression caused by increased interstitial pressure. The results are in good agreement with the limited experimental data. Significance. This model, by enabling us to bridge the gap between the microvascular scale and clinically measurable parameters, providing a foundation for more detailed validation and understanding of HT in patients.

Analysis of the effectiveness of the protective properties of woven materials of overalls designed to work in conditions of high microbial contamination

The role of tissue hygroscopicity in violation of the protective qualities of tissues made of natural fibers, associated with increased tissue permeability by microorganisms, is shown. The ability of the studied tissues to absorb moisture was determined. An original program was used to assess the hygroscopicity of fabrics intended for the manufacture of special clothing. Recommendations have been developed for the use of cotton fabrics in conditions of high microbial contamination.

Epithelial response to vocal fold microflap injury in a preclinical model.

Functional outcomes following microflap surgery for vocal fold pathology are favorable. Although the stratified squamous epithelium appears to heal rapidly, persistent physiologic tissue alterations are likely. We sought to elucidate key biochemical processes including recruitment of immune cells, regulation of cellular junction proteins, and long-term alterations to epithelial tissue permeability following microflap with an eye toward enhanced clinical outcomes. Forty New Zealand rabbits were assigned to eight groups (n=5/group): no-injury control or bilateral microflap with survival for 0 h, 12 h, 1 day, 3 days, 7 days, 30 days, and 60 days post-microflap. The epithelium was dissected from one vocal fold and transepithelial resistance was quantified. The contralateral fold was subjected to transmission electron microscopy. Images were evaluated by a blinded rater and paracellular space dilation was quantified using ImageJ. Immune cell infiltration was evaluated and recorded qualitatively. Increased innate immune response was observed 12 h as well as 7 and 30 days after microflap. At 60 days following injury, decreased epithelial resistance was observed. Paracellular spaces were dilated at all time-points following injury. The vocal fold epithelium was significantly altered at 60 days following microflap. The implications for this tissue phenotype are unclear. However, compromised epithelial barrier function is implicated in various diseases and may increase the risk of subsequent injury. NA Laryngoscope, 133:350-356, 2023.

A Gene Encoding a SHINE1/WAX INDUCER1 Transcription Factor Controls Cuticular Wax in Barley

All land plants seal their above ground body parts with a lipid-rich hydrophobic barrier called the cuticle to protect themselves from dehydration and other terrestrial threats. Mutational studies in several model species have identified multiple loci regulating cuticular metabolism and development. Of particular importance are the eceriferum (cer) mutants characterized by a loss of cuticular wax. Some barley cer mutants, including cer-x, show defects in the distinctive β-diketone-enriched wax bloom on reproductive stage leaf sheaths, stems, and spikes. We exploited extensive allelic populations, near-isogenic lines, and powerful genotyping platforms to identify variation in the HvWAX INDUCER1 (HvWIN1) gene, encoding a SHINE transcription factor, as underlying cer-x. Comparing the cer-x allelic glossy sheath4.l Bowman Near Isogenic Line BW407 to cv. Bowman revealed an increased cuticular permeability in tissues showing reduced accumulation of β-diketones and altered cuticular metabolic gene expression in BW407. Analyses across the barley pangenome and hundreds of exome-capture datasets revealed high sequence conservation of HvWIN1 and two non-synonymous variants exclusive to the cultivated germplasm. Taken together, we suggest that variation in HvWIN1 controls multiple cuticular features in barley.

Impact of Zwitterionic Polymers on the Tumor Permeability of Molecular Bottlebrush-Based Nanoparticles.

Biocompatible polymers possessing antifouling properties for biomolecules are necessary to be combined with nanoparticles for cancer chemotherapy to improve their retention in blood and subsequent tumor accumulation. However, these properties simultaneously lead to poor affinity to cells, and low tumor tissue permeability subsequently, which is one of the major barriers in achieving efficient anticancer efficacy. To address this, we try to elucidate the tumor permeability of nanoparticles using molecular bottlebrushes (MBs) as model polymeric nanoparticles composed of various biocompatible polymers. An MB comprising nonionic poly[(ethylene glycol) methyl ether methacrylate] (PEGMA) shows no tumor permeability at all, whereas zwitterionic MBs composed of poly(phosphobetaine methacrylate), poly(sulfobetaine methacrylate), or poly(carboxybetaine methacrylate) penetrate deeply into tumor tissues. The carboxybetaine-based MBs showed an efficient cellular uptake into cancer cells while the other MBs did not, which enable them to penetrate into tumor tissues via the transcytosis pathway. Additionally, their permeability is based on intercellular or intracellular pathways, which might be related to the zwitterionic betaine properties that recognize protein transporters on cancer cells. Surprisingly, incorporating only 10 mol % of the zwitterionic betaine polymers into PEGMA-based MBs significantly enhances their tissue permeability. This platform technology enables us to redesign the PEG-based nanoparticles developed for cancer chemotherapy in clinical applications.

Fluorescent Nanosystems for Drug Tracking and Theranostics: Recent Applications in the Ocular Field.

The greatest challenge associated with topical drug delivery for the treatment of diseases affecting the posterior segment of the eye is to overcome the poor bioavailability of the carried molecules. Nanomedicine offers the possibility to overcome obstacles related to physiological mechanisms and ocular barriers by exploiting different ocular routes. Functionalization of nanosystems by fluorescent probes could be a useful strategy to understand the pathway taken by nanocarriers into the ocular globe and to improve the desired targeting accuracy. The application of fluorescence to decorate nanocarrier surfaces or the encapsulation of fluorophore molecules makes the nanosystems a light probe useful in the landscape of diagnostics and theranostics. In this review, a state of the art on ocular routes of administration is reported, with a focus on pathways undertaken after topical application. Numerous studies are reported in the first section, confirming that the use of fluorescent within nanoparticles is already spread for tracking and biodistribution studies. The first section presents fluorescent molecules used for tracking nanosystems’ cellular internalization and permeation of ocular tissues; discussions on the classification of nanosystems according to their nature (lipid-based, polymer-based, metallic-based and protein-based) follows. The following sections are dedicated to diagnostic and theranostic uses, respectively, which represent an innovation in the ocular field obtained by combining dual goals in a single administration system. For its great potential, this application of fluorescent nanoparticles would experience a great development in the near future. Finally, a brief overview is dedicated to the use of fluorescent markers in clinical trials and the market in the ocular field.

Role of Tissue Hydraulic Permeability in Convection-Enhanced Delivery of Nanoparticle-Encapsulated Chemotherapy Drugs to Brain Tumour

PurposeTissue hydraulic permeability of brain tumours can vary considerably depending on the tissue microstructure, compositions in interstitium and tumour cells. Its effects on drug transport and accumulation remain poorly understood.MethodsMathematical modelling is applied to predict the drug delivery outcomes in tumours with different tissue permeability upon convection-enhanced delivery. The modelling is based on a 3-D realistic tumour model that is extracted from patient magnetic resonance images.ResultsModelling results show that infusing drugs into a permeable tumour can facilitate a more favourable hydraulic environment for drug transport. The infused drugs will exhibit a relatively uniform distribution and cover a larger tumour volume for effective cell killing. Cross-comparisons show the delivery outcomes are more sensitive to the changes in tissue hydraulic permeability and blood pressure than the fluid flow from the brain ventricle. Quantitative analyses demonstrate that increasing the fluid gain from both the blood and brain ventricle can further improve the interstitial fluid flow, and thereby enhance the delivery outcomes. Furthermore, similar responses to the changes in tissue hydraulic permeability can be found for different types of drugs.ConclusionsTissue hydraulic permeability as an intrinsic property can influence drug accumulation and distribution. Results from this study can deepen the understanding of the interplays between drug and tissues that are involved in the drug delivery processes in chemotherapy.

Immersion optical clearing of adipose tissue in rats: ex vivo and in vivo studies.

Optical clearing (OC) of adipose tissue has not been studied enough, although it can be promising in medical applications, including surgery and cosmetology, for example, to visualize blood vessels or increase the permeability of tissues to laser beams. The main objective of this work is to develop technology for OC of abdominal adipose tissue in vivo using hyperosmotic optical clearing agents (OCAs). The maximum OC effect (77%) was observed for ex vivo rat adipose tissue samples exposed to OCA on fructose basis for 90 minutes. For in vivo studies, the maximum effect of OC (65%) was observed when using OCA based on diatrizoic acid and dimethylsulfoxide for 120 minutes. Histological analysis showed that in vivo application of OCAs may induce a limited local necrosis of fat cells. The efficiency of OC correlated with local tissue damage through cell necrosis due to accompanied cell lipolysis.

Bamboo-based composites: A review on fundamentals and processes of bamboo bonding

Sustainable development and applications of bamboo and bamboo-wood composites require better understanding and optimization of bamboo bonding. This paper provides a critical review of bamboo composite bonding in relation to wood bonding characteristics and processes. A polylamellate cell wall structure, low tissue porosity and permeability, and poor surface wettability hamper bamboo bonding with most wood adhesives. Bamboo element preparation, treatment and adhesive modification must be optimized in conjunction with more efficient material utilization and processes. Development of bond qualification standards similar to engineered wood products but tailored to stronger bamboo tissues are essential for structural bamboo composites. While phenolics are still commonly used for structural bamboo composite bonding, the industry is shifting away from formaldehyde systems. Isocyanate-based resins offer viable solutions, especially for bamboo strand composites. Changes in bamboo surface pH and wettability after industrial treatments like bleaching and pressure-steaming likely explain the variations in bonding performance with common wood adhesives. Hybrid bamboo-wood composites are promising cost-effective approaches for the engineered bamboo industry leading to viable building products. Future research subjects related to bamboo composite bonding are also discussed.

TANTALUM OXIDE NANOPARTICLES FOR CONTRAST ENHANCED COMPUTED TOMOGRAPHY IMAGING OF CARTILAGE

Purpose: Contrast-enhanced computed tomography (CECT) allows detection of changes in cartilage structure and function via use of a contract agent, which diffuses into cartilage. The aim of this study is to investigate potential of a novel nanoparticle contrast agent for computed tomography (CT) diagnosis of osteoarthritis. An early indicator of cartilage degeneration is the loss of collagens and proteoglycans (PG) leading to enhanced tissue permeability and decreased tissue mechanical integrity.

Theranostic nanomotors for tumor multimode imaging and photothermal/photodynamic synergistic therapy

Efficient nanotheranostic reagents for cancer has attracted extensive attention. Herein we report nanomotors UCNPs@mSiO2-Au-Cys for tumor multimode imaging and photothermal (PTT)/photodynamic (PDT) combined therapy. Firstly, the photothermal agent Au NPs and photosensitizer Cy-S-Ph-NH2 (Cys) are loaded by upconversion nanoparticles (UCNPs) with the mesoporous silica shell. Nanomotors generate autonomous motion under 808 nm laser irradiation, which can significantly increase their tumor tissue permeability. Meanwhile, Au NPs provide photothermal conversion, photothermal imaging, and act as nanocatalytic enzyme that can enhance the efficacy of oxygen dependent PDT. Cys also can increase the photothermal effect. In addition, the two emission of UCNPs at 659 and 800 nm under 980 nm excitation are offered respectively the possibility to realize real-time online monitoring of therapeutic effect and the tumor fluorescence imaging. This nano-therapeutics platform based on the optical properties of UCNPs and nano-motor technology will provide potential methods for tumor treatment.

INFLUENCE OF COLD ARGON PLASMA ON DIELECTRIC PARAMETERS OF RAT SKIN

The purpose of this study was a comparative study of dielectric parameters of rat skin treated with argon and cold argon plasma. The experiment was carried out on 40 male Wistar rats divided into 4 equal groups. The first group of animals (n=10) was the control (intact). A pre-epilated area of the back skin (area = 1*1 cm) of the rats of the remaining groups (n=10 in each) was treated daily. The course duration for all experimental groups was 10 procedures. Animals of the second group received treatment with non-ionized argon flow (the duration of one procedure is 1 minute), rats of the third and fourth groups received cold argon plasma (1 and 2 minutes, respectively). Cold plasma was generated using a device that uses the principle of microwave ionization of a gas stream. As the latter, high purity argon (99.99%) was used. The assessment of the dielectric parameters of the skin in the treated area (for rats of the control group - in a similar part of the back) was carried out after the completion of the full course of the exposure. A specialized software and hardware complex was used for this, which provides near-field resonant microwave sounding of biological tissues. It was established that the course treatment of the skin area of the rats’ back with gas flows with different ionization causes formation of a specific functional-metabolic and morphostructural response. Its character is determined by the parameters of the gas flow used: non-ionized argon significantly reduces the dielectric parameters (permeability and conductivity), and the result of the action of cold argon plasma depends on the exposure. In case of one-minute treatment, the preservation of tissue permeability at an intact level was observed with a moderate decrease of conductivity. In the case of 2 minute exposure, the dielectric capacitivity increased, while the conductivity remained unchanged.

Development of Stable Nano-Sized Transfersomes as a Rectal Colloid for Enhanced Delivery of Cannabidiol.

Current cannabidiol (CBD) formulations are challenged with unpredictable release and absorption. Rational design of a rectal colloid delivery system can provide a practical alternative. In this study the inherent physiochemical properties of transferosomes were harnessed for the development of a nano-sized transfersomes to yield more stable release, absorption, and bioavailability of CBD as a rectal colloid. Transfersomes composed of soya lecithin, cholesterol, and polysorbate 80 were synthesized via thin film evaporation and characterized for size, entrapment efficiency (%), morphology, CBD release, ex vivo permeation, and physicochemical stability. The optimized formulation for rectal delivery entrapped up to 80.0 ± 0.077% of CBD with a hydrodynamic particle size of 130 nm, a PDI value of 0.285, and zeta potential of −15.97 mV. The morphological investigation via SEM and TEM revealed that the transfersomes were spherical and unilamellar vesicles coinciding with the enhanced ex vivo permeation across the excised rat colorectal membrane. Furthermore, transfersomes improved the stability of the encapsulated CBD for up to 6 months at room temperature and showed significant promise that the transfersomes promoted rectal tissue permeation with superior stability and afforded tunable release kinetics of CBD as a botanical therapeutic with inherent poor bioavailability.

The pathogens of secondary infection in septic patients share a similar genotype to those that predominate in the gut

BackgroundSecondary nosocomial infections, which are commonly caused by carbapenem-resistant Klebsiella pneumoniae (CRKP) and vancomycin-resistant Enterococcus faecium (VRE), often develop in septic patients. This study aimed to identify the origin of secondary systemic pathogens and reveal the underlying mechanism of infection.MethodsIn this prospective, observational case–control study, a total of 34 septic patients, 33 non-septic intensive care unit (ICU) patients and 10 healthy individuals serving as controls were enrolled. Three hundred and twelve fecal samples were collected and subjected to 16S rRNA gene amplicon sequencing. Metagenome sequencing was performed to identify the homology between dominant CRKP or VRE in the intestine and pathogens isolated from secondary infectious sites. C57/BL mice were established as pseudo germ-free animal model by pretreatment with broad-spectrum antibiotics for two weeks.ResultsThe abundance and diversity of the gut microbiota in septic patients was drastically decreased one week after ICU admission, potentially leading to the enrichment of antibiotic-resistant bacteria, such as CRKP. Furthermore, secondary bloodstream and abdominal infections caused by CRKP or VRE in septic patients occurred after intestinal colonization with the predominant bacterial species. Genomic analysis showed that bacteria isolated from secondary infection had high homology with the corresponding predominant intestinal opportunistic pathogens. In addition, animal model experiments validated the hypothesis that the administration of antibiotics caused the enrichment of CRKP and VRE among the intestinal microbiota, increasing the likelihood of permeation of other tissues and potentially causing subsequent systemic infection in pseudo germ-free mice.ConclusionOur study indicated that the pathogens causing secondary infection in septic patients might originate from the intestinal colonization of pathogens following broad-spectrum antibiotic treatment.

Cold and exogenous calcium alter Allium fistulosum cell wall pectin to depress intracellular freezing temperatures.

De-methyl esterification of homogalacturonan and subsequent cross-linking with Ca2+ is hypothesized to enhance the freezing survival of cold acclimated plants by reducing the porosity of primary cell walls. To test this theory, we collected leaf epidermal peels from non- (23/18 °C) and cold acclimated (2 weeks at 12/4 °C) Japanese bunching onion (Allium fistulosum L.). Cold acclimation enhanced the temperature at which half the cells survived freezing injury by 8 °C (LT50 =-20 °C), and reduced tissue permeability by 70-fold compared with non-acclimated epidermal cells. These effects were associated with greater activity of pectin methylesterase (PME) and a reduction in the methyl esterification of homogalacturonan. Non-acclimated plants treated with 50mM CaCl2 accumulated higher concentrations of galacturonic acid, Ca2+ in the cell wall, and a lower number of visible cell wall pores compared with that observed in cold acclimated plants. Using cryo-microscopy, we observed that 50mM CaCl2 treatment did not lower the LT50 of non-acclimated cells, but reduced the lethal intracellular ice nucleation to temperatures observed in cold acclimated epidermal cells. We postulate that the PME-homogalacturonan-mediated reduction in cell wall porosity is integral to intracellular freezing avoidance strategies in cold acclimated herbaceous cells.

Development and Evaluation of Nanoparticles-in-Film Technology to Achieve Extended In Vivo Exposure of MK-2048 for HIV Prevention.

MK-2048 is a second-generation integrase inhibitor active against HIV, which has been applied vaginally using ring formulations. In this work, a nanoparticle-in-film technology was developed as a discrete pre-exposure prophylactic product option against HIV for an extended duration of use. A film platform loaded with poly (lactic-co-glycolic acid) nanoparticles (PNP) encapsulating MK-2048 was engineered. MK-2048 PNPs were loaded into films that were manufactured via the solvent casting method. Physicochemical and mechanical properties, in vitro efficacy, Lactobacillus compatibility, in vitro and ex vivo permeability, and in vivo pharmacokinetics in macaques were evaluated. PNPs with a mean diameter of 382.2 nm and −15.2 mV zeta potential were obtained with 95.2% drug encapsulation efficiency. PNP films showed comparable in vitro efficacy to free MK-2048 (IC50 0.46 vs. 0.54 nM) and were found to have no impact on Lactobacillus. MK-2048 encapsulated in PNPs showed an increase in permeability (>4-fold) compared to the free MK-2048 in MDCKII cell lines. Furthermore, PNPs had higher ectocervical tissue permeability (1.7-fold) compared to free MK-2048. PNP films showed sustained drug levels for at least 3 weeks in the macaque vaginal fluid. This work demonstrates the synergy of integrating nanomedicine and polymeric film technology to achieve sustained vaginal drug delivery.

New Frontiers of Extracorporeal Shock Wave Medicine in Urology from Bench to Clinical Studies.

A shock wave (SW), which carries energy and propagates through a medium, is a type of continuous transmitted sonic wave that can achieve rapid energy transformations. SWs have been applied for many fields of medical science in various treatment settings. In urology, high-energy extracorporeal SWs have been used to disintegrate urolithiasis for 30 years. However, at lower energy levels, SWs enhance the expression of vascular endothelial growth factor (VEGF), endothelial nitric oxide synthase (eNOS), proliferating cell nuclear antigen (PCNA), chemoattractant factors, and the recruitment of progenitor cells, and inhibit inflammatory molecules. Low energy extracorporeal shock wave (LESW) therapy has been used in urology for treating chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS), interstitial cystitis/bladder pain syndrome (IC/BPS), overactive bladder, stress urinary incontinence, and erectile dysfunction through the mechanisms of anti-inflammation, neovascularization, and tissue regeneration. Additionally, LESW have been proven to temporarily increase tissue permeability and facilitate intravesical botulinum toxin delivery for treating overactive bladders in animal studies and in a human clinical trial. LESW assisted drug delivery was also suggested to have a synergistic effect in combination with cisplatin to improve the anti-cancer effect for treating urothelial cancer in an in vitro and in vivo study. LESW assisted drug delivery in uro-oncology is an interesting suggestion, but no comprehensive clinical trials have been conducted as of yet. Taken together, LESW is a promising method for the treatment of various diseases in urology. However, further investigation with a large scale of clinical studies is necessary to confirm the real role of LESW in clinical use. This article provides information on the basics of SW physics, mechanisms of action on biological systems, and new frontiers of SW medicine in urology.