Design of in vitro biomimetic experimental system and simulation analysis for transvascular transport of nano-preparation.

Recently, the enhanced penetration and retention (EPR) effect of nano-preparations has been questioned. Whether the vascular endothelial cell gap (VECG) is the main transport pathway of nano-preparations has become a hot issue at present. Therefore, we propose an in vitro biomimetic experimental system that demonstrates the transvascular transport of nano-preparation. Based on the tumor growth process, the experimental system was used to simulate the change process of abnormal factors (vascular endothelial cell gap and interstitial fluid pressure (IFP)) in the tumor microenvironment. The influence of change in the abnormal factors on the enhanced penetration and retention effect of nano-preparation was explored, and simulation verification was performed. The results show that when the interstitial fluid pressure is close to the vascular fluid pressure (VFP), the transport of nano-preparation is obstructed, resulting in the disappearance of enhanced penetration and retention effect of the nano-preparation. This indicates that the pressure gradient between vascular fluid pressure and interstitial fluid pressure determines whether the enhanced penetration and retention effect of nano-preparations can exist.

Relaxin-Loaded Inhaled Porous Microspheres Inhibit Idiopathic Pulmonary Fibrosis and Improve Pulmonary Function Post-Bleomycin Challenges.

Idiopathic pulmonary fibrosis (IPF) causes worsening pulmonary function, and no effective treatment for the disease etiology is available now. Recombinant Human Relaxin-2 (RLX), a peptide agent with anti-remodeling and anti-fibrotic effects, is a promising biotherapeutic candidate for musculoskeletal fibrosis. However, due to its short circulating half-life, optimal efficacy requires continuous infusion or repeated injections. Here, we developed the porous microspheres loading RLX (RLX@PMs) and evaluated their therapeutic potential on IPF by aerosol inhalation. RLX@PMs have a large geometric diameter as RLX reservoirs for a long-term drug release, but smaller aerodynamic diameter due to their porous structures, which were beneficial for higher deposition in the deeper lungs. The results showed a prolonged release over 24 days, and the released drug maintained its peptide structure and activity. RLX@PMs protected mice from excessive collagen deposition, architectural distortion, and decreased compliance after a single inhalation administration in the bleomycin-induced pulmonary fibrosis model. Moreover, RLX@PMs showed better safety than frequent gavage administration of pirfenidone. We also found RLX-ameliorated human myofibroblast-induced collagen gel contraction and suppressed macrophage polarization to the M2 type, which may be the reason for reversing fibrosis. Hence, RLX@PMs represent a novel strategy for the treatment of IPF and suggest clinical translational potential.

Bioinspired Nanocomplexes Comprising Phenolic Acid Derivative and Human Serum Albumin for Cancer Therapy.

Inspired by the natural phenomenon of phenolic-protein interactions, we translate this "naturally evolved interaction" to a "phenolic acid derivative based albumin bound" technology, through the synthesis of phenolic acid derivatives comprising a therapeutic cargo linked to a phenolic motif. Phenolic acid derivatives can bind to albumin and form nanocomplexes after microfluidic mixing. This strategy has been successfully applied to different types of anticancer drugs, including taxanes, anthraquinones, etoposides, and terpenoids. Paclitaxel was selected as a model drug for an in-depth study. Three novel paclitaxel-phenolic acid conjugates have been synthesized. Molecular dynamics simulations provide insights into the self-assembled mechanisms of phenolic-protein nanocomplexes. The nanocomplexes show improved pharmacokinetics, elevated tolerability, decreased neurotoxicity, and enhanced anticancer efficacies in multiple murine xenograft models of breast cancer, in comparison with two clinically approved formulations, Taxol (polyoxyethylated castor oil-formulated paclitaxel) and Abraxane (nab-paclitaxel). Such a robust system provides a broadly applicable platform for the development of albumin-based nanomedicines and has great potential for clinical translation.

[A comparative study of raw Aurantii Fructus Immaturus and bran-fried products on dryness of rats with slow-transit constipation].

The differences in dryness between raw Aurantii Fructus Immaturus(AFI) and bran-fried products were investigated based on a slow-transit constipation(STC) model. Seventy healthy SPF-grade rats were randomly divided into a blank group(K), a positive drug group(Y), a model group(M), low-and high-dose raw AFI groups(SD and SG), and low-and high-dose bran-fried AFI groups(FD and FG). During the experiment, it was found that compared with the K group, the groups with drug treatment had little effect on the daily body weight of the STC rats. The first defecation time of black stool in the M group was significantly higher than that in the K group, and the 24-hour fecal output significantly decreased starting from the 13th day, indicating successful modeling. The SG group showed a significant increase in the first defecation time, fecal water content, urine output, and water intake than other groups with drug treatment. The FG group had the highest fecal output than other groups with drug treatment. The FD group had the highest salivary secretion than other groups with drug treatment. The levels of cAMP/cGMP, VIP, 5-HT, AQP1, and AQP5 were measured in each group with drug treatment, and the expression of c-Kit and SCF mRNA in gastric antrum tissue and AQP3 mRNA in the kidney and colon were detected by RT-PCR. The results showed that the SD and SG groups had a more significant impact on AQP1, AQP5, and other water channel indexes in STC rats than the FD and FG groups. The FD and FG groups had a more significant impact on c-Kit, SCF, VIP, 5-HT, and other gastrointestinal motility indicators than the SD and SG groups. This study, through in vitro biological observations, immunological detection, and gene expression analysis, found that raw AFI had strong dryness property, while bran-fried AFI could alleviate its dryness property.

Inhibition of the adenosinergic pathway: the indispensable part of oncological therapy in the future.

In recent years, immunotherapy has produced many unexpected breakthroughs in oncological therapy; however, it still has many deficiencies. For example, the number of patients who are unresponsive to anti-programmed death-ligand 1 (PD-L1), anti-cytotoxic T-like antigen-4 (CTLA4), and anti-programmed death-1 (PD1) therapies cannot be ignored, and the search for an undiscovered immunosuppressive pathway is imminent. Five decades ago, researchers found that activation of the adenosinergic pathway was negatively correlated with prognosis in many cancers. This review describes the entire process of the adenosinergic pathway in the tumor microenvironment and the mechanism of immunosuppression, which promotes tumor metastasis and drug resistance. Additionally, the review explores factors that regulate this pathway, including signaling factors secreted by the tumor microenvironment and certain anti-tumor drugs. Additionally, the combination of adenosinergic pathway inhibitors with chemotherapy, checkpoint blockade therapy, and immune cell-based therapy is summarized. Finally, certain issues regarding treatment via inhibition of this pathway and the use of targeted nanoparticles to reduce adverse reactions in patients are put forward in this review. Graphical Abstract The inhibitors of adenosinergic pathway loaded nanoparticles enter tumor tissue through EPR effect, and inhibit adenosinergic pathway to enhance or restore the effect of immune checkpoint blockade therapy, chemotherapies and immune cell-based therapy. Note: EPR means enhanced penetration and retention, × means blockade.

Smart polymeric nanoparticles for cancer gene delivery.

The massive amount of human genetic information already available has accelerated the identification of target genes, making gene and nucleic acid therapy the next generation of medicine. Nanoparticle (NP)-based anticancer gene therapy treatment has received significant interest in this evolving field. Recent advances in vector technology have improved gene transfection efficiencies of nonviral vectors to a level similar to viruses. This review serves as an introduction to surface modifications of NPs based on polymeric structural improvements and target moieties. A discussion regarding the future perspective of multifunctional NPs in cancer therapy is also included.

Disulfide bond bridge insertion turns hydrophobic anticancer prodrugs into self-assembled nanomedicines.

It is commonly observed that hydrophobic molecules alone cannot self-assemble into stable nanoparticles, requiring amphiphilic or ionic materials to support nanoparticle stability and function in vivo. We report herein newly self-assembled nanomedicines through entirely different mechanisms. We present proof-of-concept methodology and results in support of our hypothesis that disulfide-induced nanomedicines (DSINMs) are promoted and stabilized by the insertion of a single disulfide bond into hydrophobic molecules, in order to balance the competition between intermolecular forces involved in the self-assembly of nanomedicines. This hypothesis has been explored through diverse synthetic compounds, which include four first-line chemotherapy drugs (paclitaxel, doxorubicin, fluorouracil, and gemcitabine), two small-molecule natural products and their derivatives, as well as a fluorescent probe. Such an unprecedented and highly reproducible system has the potential to serve as a synthetic platform for a wide array of safe and effective therapeutic and diagnostic nanomedicine strategies.

Antitumor mechanisms of S-allyl mercaptocysteine for breast cancer therapy.

BACKGROUND: S-allyl mercaptocysteine (SAMC), a water-soluble component derived from garlic, has been found to exert multi-antitumor activities. This study was to investigate the responsible molecular mechanisms of SAMC in human breast cancer cell lines. METHODS: Sulforhodamine B assay was used to determine cell viability, flow cytometry was applied for the analysis of cell cycle and cell apoptosis, the change of protein was detected by Western blot. RESULTS: It was found that SAMC exhibited an effective cell growth inhibition of human breast cancer cell lines MCF-7 (ER positive) and MDA-MB-231 (ER negative) in a dose- and time-dependent manner by inducing cell cycle arrested in G0/G1 phase, the block of cell cycle was associated with the up-regulation of p53 and p21. Furthermore, the SAMC-mediated cell cycle arrest was accompanied with promotion of apoptosis, as indicated by the changes in the nuclear morphology and expressions of apoptosis-related proteins. SAMC clearly triggered the mitochondrial apoptotic pathway as indicated by activation of Bax, decreased expression of Bcl-2 and Bcl-XL, and subsequent activation of caspase-9 and caspase-3. CONCLUSION: These results highlight the value of a continued investigation into the use of SAMC as a potential antitumor candidate for breast cancer.

Recent advances in transdermal insulin delivery technology: A review.

Transdermal drug delivery refers to the administration of drugs through the skin, after which the drugs can directly act on or circulate through the body to the target organs or cells and avoid the first-pass metabolism in the liver and kidneys experienced by oral drugs, reducing the risk of drug poisoning. From the initial singular approach to transdermal drug delivery, there has been a shift toward combining multiple methods to enhance drug permeation efficiency and address the limitations of individual approaches. Technological advancements have also improved the accuracy of drug delivery. Optimizing insulin itself also enables its long-term release via needle-free injectors. In this review, the diverse transdermal delivery methods employed in insulin therapy and their respective advantages and limitations are discussed. By considering factors such as the principles of transdermal penetration, drug delivery efficiency, research progress, synergistic innovations among different methods, patient compliance, skin damage, and posttreatment skin recovery, a comprehensive evaluation is presented, along with prospects for potential novel combinatorial approaches. Furthermore, as insulin is a macromolecular drug, insights gained from its transdermal delivery may also serve as a valuable reference for the use of other macromolecular drugs for treatment.

Advancements in gradient bone scaffolds: enhancing bone regeneration in the treatment of various bone disorders.

Bone scaffolds are widely employed for treating various bone disorders, including defects, fractures, and accidents. Gradient bone scaffolds present a promising approach by incorporating gradients in shape, porosity, density, and other properties, mimicking the natural human body structure. This design offers several advantages over traditional scaffolds. A key advantage is the enhanced matching of human tissue properties, facilitating cell adhesion and migration. Furthermore, the gradient structure fosters a smooth transition between scaffold and surrounding tissue, minimizing the risk of inflammation or rejection. Mechanical stability is also improved, providing better support for bone regeneration. Additionally, gradient bone scaffolds can integrate drug delivery systems, enabling controlled release of drugs or growth factors to promote specific cellular activities during the healing process. This comprehensive review examines the design aspects of gradient bone scaffolds, encompassing structure and drug delivery capabilities. By optimizing the scaffold's inherent advantages through gradient design, bone regeneration outcomes can be improved. The insights presented in this article contribute to the academic understanding of gradient bone scaffolds and their applications in bone tissue engineering.

Immunotherapeutic hydrogel for co-delivery of STAT3 siRNA liposomes and lidocaine hydrochloride for postoperative comprehensive management of NSCLC in a single application.

Despite standard treatment for non-small cell lung cancer (NSCLC) being surgical resection, cancer recurrence and complications, such as induction of malignant pleural effusion (MPE) and significant postoperative pain, usually result in treatment failure. In this study, an alginate-based hybrid hydrogel (SOG) is developed that can be injected into the resection surface of the lungs during surgery. Briefly, endoplasmic reticulum-modified liposomes (MSLs) pre-loaded with the signal transducer and activator of transcription 3 (STAT3) small interfering RNA and lidocaine hydrochloride are encapsulated in SOG. Once applied, MSLs strongly downregulated STAT3 expression in the tumor microenvironment, resulting in the apoptosis of lung cancer cells and polarization of tumor-associated macrophages towards the M1-like phenotype. Meanwhile, the release of lidocaine hydrochloride (LID) was beneficial for pain relief and natural killer cell activation. Our data demonstrated MSL@LID@SOG not only efficiently inhibited tumor growth but also potently improved the quality of life, including reduced MPE volume and pain relief in orthotopic NSCLC mouse models, even with a single administration. MSL@LID@SOG shows potential for comprehensive clinical management upon tumor resection in NSCLC, and may alter the treatment paradigms for other cancers.

Wound-induced pectin methylesterases enhance banana (Musa spp. AAA) susceptibility to Fusarium oxysporum f. sp. cubense.

Recent studies suggest that plant pectin methylesterases (PMEs) are directly involved in plant defence besides their roles in plant development. However, the molecular mechanisms of PME action on pectins are not well understood. In order to understand how PMEs modify pectins during banana (Musa spp.)-Fusarium interaction, the expression and enzyme activities of PMEs in two banana cultivars, highly resistant or susceptible to Fusarium, were compared with each other. Furthermore, the spatial distribution of PMEs and their effect on pectin methylesterification of 10 individual homogalacturonan (HG) epitopes with different degrees of methylesterification (DMs) were also examined. The results showed that, before pathogen treatment, the resistant cultivar displayed higher PME activity than the susceptible cultivar, corresponding well to the lower level of pectin DM. A significant increase in PME expression and activity and a decrease in pectin DM were observed in the susceptible cultivar but not in the resistant cultivar when plants were wounded, which was necessary for successful infection. With the increase of PME in the wounded susceptible cultivar, the JIM5 antigen (low methyestrified HGs) increased. Forty-eight hours after pathogen infection, the PME activity and expression in the susceptible cultivar were higher than those in the resistant cultivar, while the DM was lower. In conclusion, the resistant and the susceptible cultivars differ significantly in their response to wounding. Increased PMEs and thereafter decreased DMs acompanied by increased low methylesterified HGs in the root vascular cylinder appear to play a key role in determination of banana susceptibility to Fusarium.

Advances in Mechanical Properties of Hydrogels for Cartilage Tissue Defect Repair.

Numerous factors, such as degeneration and accidents, frequently cause cartilage deterioration. Owing to the absence of blood vessels and nerves in cartilage tissue, the ability of cartilage tissue to heal itself after an injury is relatively low. Hydrogels are beneficial for cartilage tissue engineering owing to their cartilage-like structure and advantageous properties. Due to the disruption of its mechanical structure, the bearing capacity and shock absorption of cartilage are diminished. The tissue should possess excellent mechanical properties to ensure the efficacy of cartilage tissue repair. This paper discusses the application of hydrogels in the fields of cartilage repair, the mechanical properties of hydrogels used for cartilage repair, and the materials used for hydrogels in cartilage tissue engineering. In addition, the challenges faced by hydrogels and future research directions are discussed.

Novel coatings for the continuous repair of human bone defects.

Bone defects are the second most common tissue grafts after blood. However, bone grafts face several problems, such as bone scaffolds, which have low bioactivity and are prone to corrosion. Much of the current research on bone scaffolds is focused on the mechanical aspects such as structure and strength. Surface modification of the bone scaffold is carried out in terms of the mechanical structure or structural design of the bone scaffold with reference to a bionic structure. However, with the development of mechanical designs, materials science, and medicine, many studies have reported that promoting bone growth by modifying the structure of the scaffold or coating is not possible. Therefore, the application of a bioactive coating to the surface of the bone scaffold is particularly important to generate a synergistic effect between the structure and active coating. In this article, we present several perspectives to improve the bioactivity of bone scaffolds, including corrosion resistance, loading of bioactive coatings or drugs on bone scaffolds, improved adhesion to the surface of the bone scaffolds, immune response modulation, and drawing on bionic structures during manufacturing.

Recent progress in the fabrication of flexible materials for wearable sensors.

Wearable sensors have been widely studied because of their small size, light weight, and potential for the noninvasive tracking and monitoring of human physiological information. Wearable flexible sensors generally consist of two parts: a flexible substrate in contact with the skin and a signal processing module. At present, wearable electronics cover many fields, such as machinery, physics, chemistry, materials science, and biomedicine. The design concept and selection of materials are very important to the function of a sensor. In this review, we summarize the latest developments in flexible materials for wearable sensors, including developments in flexible materials, electrode materials, and new flexible biodegradable materials, and describe the important role of innovation in material and sensor design in the development of wearable flexible sensors. Strategies and challenges related to the improvement of the performances of wearable flexible sensors, as well as the development prospects of wearable devices based on flexible materials, are also discussed.

Metal complex-based liposomes: Applications and prospects in cancer diagnostics and therapeutics.

Metal complexes are of increasing interest as pharmaceutical agents in cancer diagnostics and therapeutics, while some of them suffer from issues such as limited water solubility and severe systemic toxicity. These drawbacks severely hampered their efficacy and clinical applications. Liposomes hold promise as delivery vehicles for constructing metal complex-based liposomes to maximize the therapeutic efficacy and minimize the side effects of metal complexes. This review provides an overview on the latest advances of metal complex-based liposomal delivery systems. First, the development of metal complex-mediated liposomal encapsulation is briefly introduced. Next, applications of metal complex-based liposomes in a variety of fields are overviewed, where drug delivery, cancer imaging (single photon emission computed tomography (SPECT), positron emission tomography (PET), and magnetic resonance imaging (MRI)), and cancer therapy (chemotherapy, phototherapy, and radiotherapy) were involved. Moreover, the potential toxicity, action of toxic mechanisms, immunological effects of metal complexes as well as the advantages of metal complex-liposomes in this content are also discussed. In the end, the future expectations and challenges of metal complex-based liposomes in clinical cancer therapy are tentatively proposed.

Molecular dynamics simulation of hyaluronic acid hydrogels: Effect of water content on mechanical and tribological properties.

BACKGROUND AND OBJECTIVE: Recently conducted biomedical studies have shown that the drug diffusivity of hyaluronic acid hydrogel plays an important role in the treatment of joint diseases. The drug diffusivity is closely related to the water content of hydrogel. In addition, different water content will not only affect its mechanical and tribological properties, but also change the effect of drug release. METHODS: In this work, a Molecular dynamics simulation was used to investigate the effect of water content on spatial distribution, tribological and mechanical properties of a hyaluronic acid hydrogel network. This paper focuses on the analysis and calculation of the radial distribution function of 20, 40, 60, and 80% water content model and the friction force and mechanical parameters under the influence of different load and friction speed. RESULTS: The results show that at 20 and 40% water content, the spatial distribution is loose and the intermolecular force is not strong, resulting in a major lack in tribological and mechanical properties; whereas at 60 and 80% water content, the spatial distribution becomes gradually compact and the intermolecular force is gradually increased. The tribological and mechanical properties manifest a marked improvement. CONCLUSIONS: The calculations reveal that the hydrogel model has the best wear resistance, pressure resistance, and plastic deformation resistance at 80% water content. In the range of 20-80% water content, the mechanical properties and friction properties of hydrogels become better and better with the increase of water content.

CFD simulation of porous microsphere particles in the airways of pulmonary fibrosis.

BACKGROUND AND OBJECTIVE: Pulmonary fibrosis (PF) is a chronic progressive disease with an extremely high mortality rate and is a complication of COVID-19. Inhalable microspheres have been increasingly used in the treatment of lung diseases such as PF in recent years. Compared to the direct inhalation of drugs, a larger particle size is required to ensure the sustained release of microspheres. However, the clinical symptoms of PF may lead to the easier deposition of microspheres in the upper respiratory tract. Therefore, it is necessary to understand the effects of PF on the deposition of microspheres in the respiratory tract. METHODS: In this study, airway models with different degrees of PF in humans and mice were established, and the transport and deposition of microspheres in the airway were simulated using computational fluid dynamics. RESULTS: The simulation results showed that PF increases microsphere deposition in the upper respiratory tract and decreases bronchial deposition in both humans and mice. Porous microspheres with low density can ensure deposition in the lower respiratory tract and larger particle size. In healthy and PF humans, porous microspheres of 10 µm with densities of 700 and 400 kg/m³ were deposited most in the bronchi. Unlike in humans, microspheres larger than 4 µm are completely deposited in the upper respiratory tract of mice owing to their high inhalation velocity. For healthy and PF mice, microspheres of 6 µm with densities of and 100 kg/m³ are recommended. CONCLUSIONS: The results showed that with the exacerbation of PF, it is more difficult for microsphere particles to deposit in the subsequent airway. In addition, there were significant differences in the deposition patterns among the different species. Therefore, it is necessary to process specific microspheres from different individuals. Our study can guide the processing of microspheres and achieve differentiated drug delivery in different subjects to maximize therapeutic effects.

Combination of oxaliplatin and POM-1 by nanoliposomes to reprogram the tumor immune microenvironment.

Some chemotherapy can damage tumor cells, releasing damage-related molecular patterns including ATP to improve immunological recognition against the tumor by immunogenic cell death (ICD). However, the immune-stimulating ATP may be rapidly degraded into immunosuppressive adenosine by highly expressed CD39 and CD73 in the tumor microenvironment, which leads to immune escape. Based on the above paradox, a liposome nanoplatform combined with ICD inducer (oxaliplatin) and CD39 inhibitor (POM-1) is designed for immunochemotherapy. The liposomes efficiently load the phospholipid-like oxaliplatin prodrug, and the cationic charged surface could adsorb POM-1. Rationally designed DSPE-PEGn-pep, on the one hand, could cover and hide POM-1 to avoid systematic toxicity and, on the other, achieve a response and charge reversal to favor POM-1 shedding and tumor deep penetration. This combination maximizes the ICD effect, and takes two-pronged advantage of stimulating the immune response and relieving immune suppression. The designed POL can effectively inhibit the growth of in situ, lung metastasis and postoperative recurrence melanoma model and form long-term immune memory. With the powerful clinical transformation potential of nanoliposome platforms, this new synergistic strategy is expected to enhance anticancer effects safely and effectively.

Nanobubbles loaded with carbon quantum dots for ultrasonic fluorescence dual detection.

To increase the efficiency and accuracy of clinical tumor detection, we explored multiple imaging by preparing carbon quantum dot (CQD)-loaded nanobubbles for ultrasonic fluorescence dual detection. In this experiment, we prepared 1,2-dioleoyl3-trimethylammonium-propane chloride (DOTAP) cationic liposomes using the film dispersion method and chose perfluoropentane as the core gas material of the nanobubbles. The nanobubbles were coupled with the negatively charged CQDs through the charge effect to prepare the testing agent for two-way diagnosis with ultrasound contrast and fluorescence detection. The formulation and preparation of the loaded CQD liposome nanobubbles were screened. In vivo experiments showed that nanobubbles can be enriched to the tumor site within 5 min, which enables clearer ultrasound imaging and is conducive to tumor detection. We expect CQD-loaded liposome (Lip-CQD) nanobubbles to become a new ultrasonic contrast agent for clinical applications that can provide a basis for early tumor diagnosis and thus earlier treatment.