Microenvironmental pH Research Articles

Antilipogenesis Effect of Rutin-Loaded Liposomes Using a Microneedle Delivery System.

Rutin, a flavonoid glycoside phytochemical compound, has a remarkable antiobesity effect. However, its therapeutic potential is hindered by its poor water solubility and low oral bioavailability. In this study, rutin was loaded into liposomes (LR) through the self-assembly of lecithin and cholesterol. It was discovered that liposomes improved the water solubility and cellular uptake of rutin in adipocytes. These rutin-loaded liposomes were then incorporated into a microneedle patch (MP) system formed by polyvinylpyrrolidone and poly(vinyl alcohol), and the MP-LR showed an increased release percentage in the adipose tissue microenvironment of pH 6.5 and achieved local delivery of rutin into adipocytes. Next, the therapeutic potentials of rutin, LR, and MP-LR were investigated in a high-fat diet (HFD)-induced obese mouse model. The MP-LR formulation decreased the weight of the HFD mice the most significantly. The antilipogenesis mechanisms of MP-LR are downregulating the lipid synthesis-related proteins (PPAR γ and C/EBP α) in adipocytes and promoting the expression of the beige adipogenesis-related proteins (UCP 1 and Cyt C). The MP systems further promote the local penetration of LR into the adipose tissue specifically, which again elevates their antiobesity effect. Overall, this study suggests that MP-delivered liposome-based formulation is a promising approach to enhance the antiobesity efficacy of antilipogenesis bioactive compounds.

Contribution of the Dynamic Intestinal Absorption Model (Diamod) to the Development of a Patient-Centric Drug Formulation.

Compound X is a weak basic drug targeting the early stages of Parkinson's disease, for which a theoretical risk assessment has indicated that elevated gastric pH conditions could potentially result in reduced plasma concentrations. Different in vitro dissolution methodologies varying in level of complexity and a physiologically based pharmacokinetic (PBPK) absorption model demonstrated that the dissolution, solubility, and intestinal absorption of compound X was indeed reduced under elevated gastric pH conditions. These observations were confirmed in a crossover pharmacokinetic study in Beagle dogs. As a result, the development of a formulation resulting in robust performance that is not sensitive to the exposed gastric pH levels is of crucial importance. The dynamic intestinal absorption MODel (Diamod), an advanced in vitro gastrointestinal transfer tool that allows to study the gastrointestinal dissolution and interconnected permeation of drugs, was selected as an in vitro tool for the formulation optimization activities given its promising predictive capacity and its capability to generate insights into the mechanisms driving formulation performance. Different pH-modifiers were screened for their potential to mitigate the pH-effect by decreasing the microenvironmental pH at the dissolution surface. Finally, an optimized formulation containing a clinically relevant dose of the drug and a functional amount of the selected pH-modifier was evaluated for its performance in the Diamod. This monolayer tablet formulation resulted in rapid gastric dissolution and supersaturation, inducing adequate intestinal supersaturation and permeation of compound X, irrespective of the gastric acidity level in the stomach. In conclusion, this study describes the holistic biopharmaceutics approach driving the development of a patient-centric formulation of compound X.

Mycobacterium tuberculosis Fatty Acyl-CoA Synthetase fadD33 Promotes Bacillus Calmette-Guérin Survival in Hostile Extracellular and Intracellular Microenvironments in the Host.

Tuberculosis, caused by Mycobacterium tuberculosis (M. tb), remains a significant global health challenge. The survival of M. tb in hostile extracellular and intracellular microenvironments is crucial for its pathogenicity. In this study, we discovered a Bacillus Calmette-Guérin (BCG) mutant B1033 that potentially affected mycobacterium pathogenicity. This mutant contained an insertion mutation gene, fadD33, which is involved in lipid metabolism; however, its direct role in regulating M. tb infection is not well understood. Here, we found that the absence of fadD33 reduced BCG adhesion and invasion into human pulmonary alveolar epithelial cells and increased the permeability of the mycobacterial cell wall, allowing M. tb to survive in the low pH and membrane pressure extracellular microenvironment of the host cells. The absence of fadD33 also inhibited the survival of BCG in macrophages by promoting the release of proinflammatory cytokines, such as interleukin (IL)-1β, IL-6, and tumors necrosis factor-α, through the mitogen-activated protein kinase p38 signaling pathway. Overall, these findings provide new insights into M. tb mechanisms to evade host defenses and might contribute to identifying potential therapeutic and vaccine targets for tuberculosis prevention.

Investigating in-vitro degradation, fatigue behavior, and fracture toughness of electrical discharge-processed Mg alloys for biodegradable implant applications

Biodegradable magnesium (Mg) alloys hold great potential for revolutionizing the field of biomedical engineering by offering temporary support during tissue healing and degrading without leaving permanent residues. However, their clinical applications have been limited due to their relatively high degradation rate. This study focuses on evaluating the in-vitro degradation, fatigue resistance, and fracture toughness properties of Mg alloys under cyclic loading conditions, mimicking real-life scenarios. Wire Electrical Discharge Machining (WEDM) was used to prepare spark-processed Mg samples with complex surface texture, and fine-polished Mg samples were used for comparison. The structural characterization, electrochemical corrosion behavior, degradation assessment, and mechanical integrity of the samples were comprehensively analysed. The results show that the Electrical Discharge processed (EDed) Mg sample exhibited uniformly distributed overlapped craters on the surface, which led to a lower charge transfer resistance and higher corrosion potential compared to the Pristine Mg sample. The rough surface topography and alkaline pH microenvironment of the EDed Mg sample facilitated rapid apatite mineralization, but the resulting Ca-deficient apatite compromised its structural stability. Both EDed and Pristine Mg samples exhibited a significant reduction in fatigue life and lower fracture toughness with prolonged immersion. These findings provide valuable insights into the performance of Mg alloys and their potential applications in biodegradable implants, guiding the design of robust implant materials for enhanced patient outcomes.

Acidification of intracellular pH in MM tumor cells overcomes resistance to hypoxia-mediated apoptosis in vitro and in vivo.

Multiple myeloma (MM) is an incurable cancer of malignant plasma cells that engraft in the bone marrow (BM). It is more than likely that the poorly investigated physical parameters of hypoxia and pH in the tumor microenvironment (TME) is critical for MM survival. Here, we explore the effects of a hypoxic environment on pH regulation and its role in MM survival. We used in vitro models of MM, in which the culturing medium was modified to specific pH and pO2 levels and then measured the effects on cell survival that was correlated with changes in intracellular (pHi) and extracellular pH (pHe). In a MM xenograft model, we used PET/CT to study hypoxia-mediated effects on tumor growth. Hypoxia-mediated apoptosis of MM cells is correlated with acidic intracellular pHi (less than < 6.6) that is dependent on HIF activity. Using a polyamide HIF responsive element binding compound, a carbonic anhydrase inhibitor (acetazolamide), and an NHE-1 inhibitor (amiloride) acidified the pHi and lead to cell death. In contrast, treatment of cells with an alkalization agent, Na-lactate, rescued these cells by increasing the pHi (pH > 6.6). Finally, treatment of mice with acetazolamide decreased cell growth in the tumor nodules. Targeting hypoxia and HIF have been proposed as an anti-tumor therapy but the clinical efficacy of such strategies are modest. We propose that targeting the pHi may be more effective at treating cancers within a hypoxic TME.

Dual-switched carbon monoxide nano gas tank for auto-diagnosis and precision therapy of osteoarthritis

Carbon monoxide (CO) has great potential in the therapy of osteoarthritis (OA), but its controllable delivery in vivo is still an intractable problem. To optimize CO gas therapy for OA, a stable CO release platform with multi-stimulus responsiveness must be designed. Herein, we describe a local delivery system (Fe3(CO)12 @Croc-PEG5K) for near-infrared fluorescence (NIRF) imaging-guided photothermal treatment and CO gas synergistic therapy. As a nano gas tank, Fe3(CO)12 @Croc-PEG5K releases CO on-demand under near infrared (NIR) laser irradiation, scavenges free radicals and regulates the pH in the OA microenvironment, and relieves the inflammatory response of macrophages to maintain the vitality of chondrocytes. Furthermore, the pH-dependent NIRF imaging properties of Fe3(CO)12 @Croc-PEG5K can be exploited to determine the administration interval and auto-monitor the curative effects during the therapeutic process. Owing to these merits, the photothermal and CO gas synergistic therapy mediated by Fe3(CO)12 @Croc-PEG5K can be optimized to deliver outstanding therapeutic performance in vivo, as demonstrated by the OA rat model. Our study is the first to validate the therapeutic effect of CO against OA in vivo, reveals a promising strategy for precision medicine pertaining to the treatment of OA and broadens the scope of CO gas therapy.

Integrating Liquification of The Gelated Tumor Interstitium Around Nanomedicines with Biconditional GD2-targeting for Precise And Safe Chemotherapy.

The quick diffusion of nanomedicines in the polysaccharide-gel-filling tumor interstitium and precise active targeting are two major obstacles that have not yet been overcome. Here, we developed a poly(L-glutamyl-L-lysine(EK) (p(EK))-camouflaged, doxorubicin (Dox)-conjugated nanomedicine to demonstrate the underlying mechanism of zwitterionic shell in synchronous barrier-penetration and biconditional active targeting. The zwitterionic p(EK) shell liquifies its surrounding water molecules in the polysaccharide gel of tumorinterstitium, leading to 5 times faster diffusion than the pegylated Doxil® with similar size in tumor tissue. Its doped sulfonate groups lead to more precise active tumor-targeting than disialoganglioside (GD2) antibody by meeting the dual requirements of tumor microenvironment (TME) pH and overexpression of GD2 on tumor. Consequently, the concentrations of the nanomedicine in tumor are always higher than in life-supported organs in whole accumulation process, reaching over 10 times higher Dox in GD2-overexpressing MCF-7 tumors than in life-supporting organs. Furthermore, the nanomedicine also avoids anti-GD2-like accumulation in GD2-expressing kidney in a mouse model. Thus, the nanomedicine expands the therapeutic window of Doxil® by more than 3 times and eliminates tumors with negligible myocardial and acute toxicity. This new insight paves an avenue to design nanodelivery systems for highly precise and safe chemotherapy. This article is protected by copyright. All rights reserved.

The Role of pH in Cancer Biology and its Impact on Cellular Repair, Tumor Markers, Tumor Stages, Isoenzymes, and Therapeutics

The intriguing connection between pH and cancer is explored in this manuscript. The role of pH in cancer biology, including its impact on cellular repair, tumor markers, tumor stages, isoenzymes, and therapies, is highlighted. pH variations can affect cellular repair processes, potentially leading to cancer development. Changes in pH also disrupt various cellular functions, such as enzyme activity and DNA modifications, impacting cancer biology. The acidic tumor microenvironment resulting from pH changes promotes tumor growth and affects surrounding normal tissue. Additionally, pH variations influence specific isoenzymes activity, aiding in cancer diagnosis and targeted therapies. Targeting the pH microenvironment in cancer treatment shows promise, utilizing strategies like pH-sensitive nanoparticles and inhibitors. However, considerations must be made regarding normal cell impact and systemic pH balance. An innovative approach involving a glucose derivative, glucosodiene, inhibits tumor glucose metabolism and restores cellular pH balance. Understanding the intricate relationship between pH and cancer provides insights for diagnostics and treatments. Further research in this field can lead to innovative approaches to combat cancer and improve patient outcomes.

The Role of pH in Cancer Biology and its Impact on Cellular Repair, Tumor Markers, Tumor Stages, Isoenzymes, and Therapeutics

The intriguing connection between pH and cancer is explored in this manuscript. The role of pH in cancer biology, including its impact on cellular repair, tumor markers, tumor stages, isoenzymes, and therapies, is highlighted. pH variations can affect cellular repair processes, potentially leading to cancer development. Changes in pH also disrupt various cellular functions, such as enzyme activity and DNA modifications, impacting cancer biology. The acidic tumor microenvironment resulting from pH changes promotes tumor growth and affects surrounding normal tissue. Additionally, pH variations influence specific isoenzymes activity, aiding in cancer diagnosis and targeted therapies. Targeting the pH microenvironment in cancer treatment shows promise, utilizing strategies like pH-sensitive nanoparticles and inhibitors. However, considerations must be made regarding normal cell impact and systemic pH balance. An innovative approach involving a glucose derivative, glucosodiene, inhibits tumor glucose metabolism and restores cellular pH balance. Understanding the intricate relationship between pH and cancer provides insights for diagnostics and treatments. Further research in this field can lead to innovative approaches to combat cancer and improve patient outcomes.

The Role of pH in Cancer Biology and its Impact on Cellular Repair, Tumor Markers, Tumor Stages, Isoenzymes, and Therapeutics

The intriguing connection between pH and cancer is explored in this manuscript. The role of pH in cancer biology, including its impact on cellular repair, tumor markers, tumor stages, isoenzymes, and therapies, is highlighted. pH variations can affect cellular repair processes, potentially leading to cancer development. Changes in pH also disrupt various cellular functions, such as enzyme activity and DNA modifications, impacting cancer biology. The acidic tumor microenvironment resulting from pH changes promotes tumor growth and affects surrounding normal tissue. Additionally, pH variations influence specific isoenzymes activity, aiding in cancer diagnosis and targeted therapies. Targeting the pH microenvironment in cancer treatment shows promise, utilizing strategies like pH-sensitive nanoparticles and inhibitors. However, considerations must be made regarding normal cell impact and systemic pH balance. An innovative approach involving a glucose derivative, glucosodiene, inhibits tumor glucose metabolism and restores cellular pH balance. Understanding the intricate relationship between pH and cancer provides insights for diagnostics and treatments. Further research in this field can lead to innovative approaches to combat cancer and improve patient outcomes.

On-demand release of enrofloxacin-loaded chitosan oligosaccharide-oxidized hyaluronic acid composite nanogels for infected wound healing

In this study, enrofloxacin (ENR) was encapsulated by oxidized hyaluronic acid (OHA) containing aldehyde groups and chitosan oligosaccharide (COS) containing amino groups through Schiff's base reaction to achieve on-demand release in the micro-environment (pH 5.5 and HAase) of bacterial-infected wounds (Escherichia coli and Staphylococcus aureus). The formation mechanism, physicochemical characterization, responsive release performance, in vitro and in vivo antimicrobial activities, and in vivo regeneration in full-thickness wounds in a bacterial-infected mouse model of the ENR nanogels were systematically studied. According to the single-factor experiment and Design-Expert software, the optimized formula was 3.8 mg/ml COS, 0.5 mg/ml OHA, and 0.3 mg/ml ENR, respectively. The mean particle diameter, polydispersity index, zeta potential, loading capacity, and encapsulation efficiency were 35.6 ± 1.7 nm, −6.7 ± 0.5 mV, 0.25 ± 0.02, 30.4 % ± 1.3 %, and 76.3 % ± 2.6 %, respectively. The appearance, optical microscopy images, SEM, TEM, PXRD, and FTIR showed that the ENR nanogels were successfully prepared. The ENR nanogels exhibited obvious pH and HAase-responsiveness by swelling ratios and in vitro release and had stronger antibacterial activity with time-dependent and concentration-dependent effects, as well as accelerating infected wound healing. In vitro and in vivo biosafety studies suggested the great promise of ENR nanogels as biocompatible wound dressings for infected wounds.

Magnetic-field-assisted electrodeposition regulates the Ni:Fe ratio for water oxidation

Nickel iron (oxygen) hydroxide (NiFeOx(OH)y) has been extensively studied as a promising electrocatalyst for oxygen evolution reaction (OER). Reasonable control of the ratio of Ni to Fe can improve its catalytic performance but has not yet been effectively achieved. In this work, we designed a magnetic-field-assisted electrodeposition method, which combined the magnetohydrodynamic effect and the corrosion effect of nickel foam substrate in the electrolyte to adjust the mass transfer and surface microenvironment (pH), thereby adjusting the Ni and Fe ratio in a large range. As a result, we use the foamed nickel substrate as the nickel source. As the deposition magnetic field increases, the composition of the catalyst evolves from Ni-doped FeOOH (Ni–FeOOH) to Ni–FeOOH/Ni(OH)2 p-n junction. The introduction of Ni and the p-n junction are beneficial to the electron transfer during the OER process. The sample Ni–FeOOH/Ni(OH)2-500 has an overpotential of only 264 mV at a current density of 20 mA/cm2, which is 34 mV lower than Ni–FeOOH-0.

One-Pot Synthesis of Tumor-Microenvironment Responsive Degradable Nanoflower-Medicine for Multimodal Cancer Therapy with Reinvigorating Antitumor Immunity.

Multimodal cancer therapies show great promise in synergistically enhancing anticancer efficacy through different mechanisms. However, most current multimodal therapies either rely on complex assemblies of multiple functional nanomaterials and drug molecules or involve the use of nanomedicines with poor in vivo degradability/metabolizability, thus restricting their clinical translatability. Herein, a nanoflower-medicine using iron ions, thioguanine (TG), and tetracarboxylic porphyrin (TCPP) are synthesized as building blocks through a one-step hydrothermal method for combined chemo/chemodynamic/photodynamic cancer therapy. The resulting nanoflowers, consisting of low-density Fe2 O3 core and iron complex (Fe-TG and Fe-TCPP compounds) shell, exhibit high accumulation at the tumor site, desirable degradability in the tumor microenvironment (TME), robust suppression of tumor growth and metastasis, as well as effective reinvigoration of host antitumor immunity. Triggered by the low pH in tumor microenvironment, the nanoflowers gradually degrade after internalization, contributing to the effective drug release and initiation of high-efficiency catalytic reactions precisely in tumor sites. Moreover, iron ions can be eliminated from the body through renal clearance after fulfilling their mission. Strikingly, it is also found that the multimodal synergistic therapy effectively elicits the host antitumor immunity without inducing additional toxicity. This easy-manufactured and degradable multimodal therapeutic nanomedicine is promising for clinical precision oncology.

PH-sensitivity of a hybrid ionotronic device-based self-diagnostic hydrogel for sensing and therapeutic activity

Here, we report a cancer-microenvironment monitoring pH-responsive mineralized hydrogel (PRM-gel) sensor, aimed at producing a model construct that forms the basis of a functional bio-inspired hybrid ionotronic device capable of self-diagnosis and therapy. The sensor was designed with the ability to self-detect, in real-time, the changes caused by extracellular pH of cancer cells to the pliability and fluidity of the PRM-gel visible to the naked eye. Structural changes to pH-responsive complexed nanoparticle (cPDA-BPD) in cancer microenvironment (pH 6.8) resulted in carbonized polydopamine (cPDA) release, which influenced the fluorescence, adhesiveness (373% increase) and macroporous morphology of the PRM-gel. Subsequently, the structural changes in cPDA-BPD altered the H-bonding in the matrix causing increased water uptake-assisted alterations in viscosity (99.2% decrease in G’) and stretchability (552.6 to 803.8%) of the hydrogel; this demonstrated the self-diagnostic capabilities of the sensor. Further, the cPDA release regulated the conductivity (ΔR ≈ 26.4 ± 1.4 kΩ) and this in combination with pliable mechanics could detect delicate pressure changes via LCR [water drop: ΔR/R0 ≈ 0.038 (HeLa) and 0 (CHO-K1)] and wireless sensing. Finally, the sensor showed therapeutic potential under cancer conditions when irradiated with NIR light (808 nm) owing to cPDA-generated hyperthermia. Therefore, the PRM-gel sensor is an easy-to-use sensing platform promising for reliable cancer diagnosis.

Study on Sulfamethoxazole-Piperazine Salt: A Mechanistic Insight into Simultaneous Improvement of Physicochemical Properties.

Multidrug salts represent more than one drug in a crystal lattice and thus could be used to deliver multiple drugs in a single dose. It showcases unique physicochemical properties in comparison to individual components, which could lead to improved efficacy and therapeutic synergism. This study presents the preparation and scale-up of sulfamethoxazole-piperazine salt, which has been thoroughly characterized by X-ray diffraction and thermal and spectroscopic analyses. A detailed mechanistic study investigates the impact of piperazine on the microenvironmental pH of the salt and its effect on the speciation profile, solubility, dissolution, and diffusion profile. Also, the improvement in the physicochemical properties of sulfamethoxazole due to the formation of salt was explored with lattice energy contributions. A greater ionization of sulfamethoxazole (due to pH changes contributed by piperazine) and lesser lattice energy of sulfamethoxazole-piperazine contributed to improved solubility, dissolution, and permeability. Moreover, the prepared salt addresses the stability issues of piperazine and exhibits good stability behavior under accelerated stability conditions. Due to the improvement of physicochemical properties, the sulfamethoxazole-piperazine salt demonstrates better pharmacokinetic parameters in comparison to sulfamethoxazole and provides a strong suggestion for the reduction of dose. The following study suggests that multidrug salts can concurrently enhance the physicochemical properties of drugs and present themselves as improved fixed-dose combinations.

Conditionally Active, pH-Sensitive Immunoregulatory Antibodies Targeting VISTA and CTLA-4 Lead an Emerging Class of Cancer Therapeutics.

Immune checkpoints and other immunoregulatory targets can be difficult to precisely target due to expression on non-tumor immune cells critical to maintaining immune homeostasis in healthy tissues. On-target/off-tumor binding of therapeutics results in significant pharmacokinetic and pharmacodynamic problems. Target-mediated drug disposition (TMDD) significantly limits effective intratumoral drug levels and adversely affects anti-tumor efficacy. Target engagement outside the tumor environment may lead to severe immune-related adverse events (irAEs), resulting in a narrowing of the therapeutic window, sub-optimal dosing, or cessation of drug development altogether. Overcoming these challenges has become tractable through recent advances in antibody engineering and screening approaches. Here, we review the discovery and development of conditionally active antibodies with minimal binding to target at physiologic pH but high-affinity target binding at the low pH of the tumor microenvironment by focusing on the discovery and improved properties of pH-dependent mAbs targeting two T cell checkpoints, VISTA and CTLA-4.

Generating high-valent iron-oxo ≡FeIV=O complexes by calcium sulfite activation in neutral microenvironments for enhanced degradation of CIP

Although alkaline sulfite activation of ferrate (Fe(VI)) has advantages of fast response and high activity for degradation of organic contaminants, the specific production pathways of active species and the pH conditions still hinder its widespread application. Based on this, our study constructed a novel advanced oxidation process of calcium sulfite (CaSO3) could activated Fe(VI) continuously by Ca2+ buffering and investigated the mechanism under different pH values and CaSO3 dosages with ciprofloxacin as a target organic pollutant. The results showed that Ca2+ stabilized the process at a neutral/weakly alkaline microenvironment of pH 7–8, which could alleviate the hydrolysis of ≡FeIV=O by protons and iron hydroxyl groups. Besides, the removal of pollutants occurred efficiently when sulfate (SO32−) was excessive and had a 3:1 ratio of SO32− to Fe(VI), achieving more than 99% removal of electron-rich phenolic organic pollutants within 2 min. By adding different radical scavengers and combining electrochemical analysis methods and electron paramagnetic resonance spectroscopy techniques to revealed that the main active species in Fe(VI)/CaSO3 process were ≡FeIV=O/≡FeV=O. Furthermore, the reactivity of various sulfate species (such as SO32−, SO3•−, SO4•−, SO5•−) with Fe(VI) was calculated using density functional theory (DFT), and it was found that Fe(VI)–SO32− reaction has a much lower energy barrier (−36.08 kcal/mol), indicating that SO32− can readily activate Fe(VI) and generate ≡FeIV=O to attack the atoms with high Fukui index (f -) in organic pollutants. The above results confirm the feasibility of Fe(VI)/CaSO3 process. Thus, this study can theoretically and practically prove that the main active species is ≡FeIV=O, rather than SO4•− or •OH in Fe(VI)/CaSO3 process.

Amorphous solid dispersions of lidocaine and lidocaine HCl produced by ball milling with well-defined RAFT-synthesised methacrylic acid polymers

This study focuses on the use of methacrylic acid polymers synthesised via the Reversible Addition Fragmentation chain Transfer (RAFT) polymerisation method for the production of amorphous solid dispersions (ASDs) by ball milling, to kinetically solubilize a poorly water-soluble model drug. The solid-state characteristics and the physical stability of the formulations were investigated using X-ray diffraction, differential scanning calorimetry, and infrared spectroscopy. This was followed by dissolution studies in different media. It was discovered that the acidic polymers of methacrylic acid were capable of interacting with the weakly basic drug lidocaine and its hydrochloride salt form to produce ASDs when a polymer to drug ratio of 70:30 w/w was used. The ASDs remained amorphous following storage under accelerated aging conditions (40 °C and 75% relative humidity) over 8 months. Fast dissolution and increased lidocaine solubility in different media were obtained from the ASDs owing to the reduced microenvironment pH and enhanced solubilization of the drug caused by the presence of the acidic polymer in the formulation. Production of ASDs using well-defined RAFT-synthesised acidic polymers is a promising formulation strategy to enhance the pharmaceutical properties of basic poorly water-soluble drugs.

PH-Mediated Mucus Penetration of Zwitterionic Polydopamine-Modified Silica Nanoparticles.

Zwitterionic polymers have emerged as promising trans-mucus nanocarriers due to their superior antifouling properties. However, for pH-sensitive zwitterionic polymers, the effect of the pH microenvironment on their trans-mucus fate remains unclear. In this work, we prepared a library of zwitterionic polydopamine-modified silica nanoparticles (SiNPs-PDA) with an isoelectric point of 5.6. Multiple-particle tracking showed that diffusion of SiNPs-PDA in mucus with a pH value of 5.6 was 3 times faster than that in mucus with pH value 3.0 or 7.0. Biophysical analysis found that the trans-mucus behavior of SiNPs-PDA was mediated by hydrophobic and electrostatic interactions and hydrogen bonding between mucin and the particles. Furthermore, the particle distribution in the stomach, intestine, and lung demonstrated the pH-mediated mucus penetration behavior of the SiNPs-PDA. This study reveals the pH-mediated mucus penetration behavior of zwitterionic nanomaterials, which provides rational design strategies for zwitterionic polymers as nanocarriers in various mucus microenvironments.

Effect of 2-deoxyglucose-mediated inhibition of glycolysis on migration and invasion of HTR-8/SVneo trophoblast cells

The proper invasion of trophoblasts is crucial for embryo implantation and placental development, which is helpful to establish a correct maternal-fetal relationship. Trophoblasts can produce a large amount of lactate through aerobic glycolysis during early pregnancy. Lactate creates a low pH microenvironment around the embryo to help uterine tissue decompose and promote the invasion of trophoblasts. The purpose of this study is to reveal the the potential mechanism of aerobic glycolysis regulating the invasiveness of trophoblasts by investigating the effect of 2-Deoxy-D-glucose (2-DG), a glycolysis inhibitor, on the biological function of HTR-8/SVneo trophoblast cells, the expressions of epithelial mesenchymal transformation (EMT) markers and invasion-related factors. 2-DG could inhibit the aerobic glycolysis of trophoblasts and decrease the activity of trophoblasts in a dose-dependent manner. Moreover, 2-DG inhibited the EMT of HTR-8/SVneo cells, down-regulated the expression of invasion-related factors matrix metalloproteinase 2/9 (MMP2/9) and up-regulated the expression of tissue inhibitor of matrix metalloproteinases 1/2 (TIMP1/2), thus inhibiting cell migration and invasion. This paper provides a foundation in the significance of aerobic glycolysis of trophoblasts in the process of invasion, and also provides ideas and insights for the promotion of embryo implantation.