Intestinal Colonized Silkworm Chrysalis-Like Probiotic Composites for Multi-Crossed Comprehensive Synergistic Therapy of Inflammatory Bowel Disease.

Inspired by the timely emergence of silkworm pupae from their cocoons, silkworm chrysalis-like probiotic composites (SCPCs) are developed for the comprehensive therapy of inflammatory bowel disease (IBD), in which probiotics are enveloped as the "pupa" in a sequential layering of silk sericin (SS), tannic acid (TA), and polydopamine, akin to the protective "cocoon". Compared to unwrapped probiotics, these composites not only demonstrate exceptional resistance to the harsh gastrointestinal environment and exhibit over 200 times greater intestinal colonization but also safeguard probiotics from the damage of IBD environment while enabling probiotics sustained release. The probiotics, in synergy with SS and TA, provide a multi-crossed comprehensive therapy for IBD that simultaneously addresses various pathological features of IBD, including intestinal barrier disruption, elevated pro-inflammatory cytokines, heightened oxidative stress, and disturbances in the intestinal microbiota. SCPCs exhibit remarkable outcomes, including a 9.7-fold reduction in intestinal permeability, an 8.9-fold decrease in IL-6 levels, and a 2.9-fold reduction in TNF-α levels compared to uncoated probiotics. Furthermore, SCPCs demonstrate an impressive 92.25% reactive oxygen species clearance rate, significantly enhance the richness of beneficial intestinal probiotics, and effectively diminish the abundance of pathogenic bacteria, indicating a substantial improvement in the overall therapeutic effect of IBD.

Ultrasound-assisted brain delivery of nanomedicines for brain tumor therapy: advance and prospect.

Nowadays, brain tumors are challenging problems, and the key of therapy is ensuring therapeutic drugs cross the blood-brain barrier (BBB) effectively. Although the efficiency of drug transport across the BBB can be increased by innovating and modifying nanomedicines, they exert insufficient therapeutic effects on brain tumors due to the complex environment of the brain. It is worth noting that ultrasound combined with the cavitation effect of microbubbles can assist BBB opening and enhance brain delivery of nanomedicines. This ultrasound-assisted brain delivery (UABD) technology with related nanomedicines (UABD nanomedicines) can safely open the BBB, facilitate the entry of drugs into the brain, and enhance the therapeutic effect on brain tumors. UABD nanomedicines, as the main component of UABD technology, have great potential in clinical application and have been an important area of interest in the field of brain tumor therapy. However, research on UABD nanomedicines is still in its early stages despite the fact that they have been associated with many disciplines, including material science, brain science, ultrasound, biology, and medicine. Some aspects of UABD theory and technology remain unclear, especially the mechanisms of BBB opening, relationship between materials of nanomedicines and UABD technology, cavitation and UABD nanomedicines design theories. This review introduces the research status of UABD nanomedicines, investigates their properties and applications of brain tumor therapy, discusses the advantages and drawbacks of UABD nanomedicines for the treatment of brain tumors, and offers their prospects. We hope to encourage researchers from various fields to participate in this area and collaborate on developing UABD nanomedicines into powerful tools for brain tumor therapy.

Dual ligand-capped gold nanoclusters for the smart detection of specific reactive oxygen species.

Quantitative detection of different types of reactive oxygen species (ROS) is vital for understanding the crucial roles of them in biological processes. However, few researches achieved the detection of multiple types of ROS with one probe until now. Given this, we designed and prepared fluorescent gold nanoclusters capped by dual ligand bovine serum albumin and lysozyme (BSA-LYS-AuNCs), which could detect 3 specific types of ROS based on its different fluorescent responses to H2O2, •OH and ClO-, respectively. The limit of detection (LOD) of H2O2, •OH, and ClO- was as low as 0.82 µM, 0.45 µM, and 0.62 µM. Moreover, as an important ROS type, ClO- was detected with high sensitivity and low LOD by BSA-LYS-AuNCs. It was also proved that the crosslinking of protein mainly contributed to the unique fluorescent characteristics of the probe exposing to ClO-. Furthermore, the fluorescent probe achieved the smart detection of hROS (including •OH and ClO-) and wROS (the form of H2O2) in the real sample, which could also been applied specifically to the detection of antioxidants, e.g. ascorbic acid. The gold nanoclusters developed have high potential for the smart detection of multiple ROS in the body fluid of organisms.

Derivation of clinical-grade mesenchymal stromal cells from umbilical cord under chemically defined culture condition - platform for future clinical application.

The use of animal serum in culture medium brings safety concerns and batch-to-batch variability, and thus may restrict the clinical use of ex vivo expanded mesenchymal stromal cells (MSCs). Clinically compliant MSCs should be developed in adherence to serum-free, xeno-free and chemically defined medium (S&XFM-CD). In this study, we develop a S&XFM-CD by replacing all serum components with synthetic alternatives for the derivation of clinical-grade umbilical cord-derived MSCs (UCMSCs). The critical aspects including characterization, safety concerns, potency and exogenous factors contamination risk of UCMSCs in S&XFM-CD are compared with serum-containing medium (SCM). UCMSCs in S&XFM-CD retain fibroblastic-like morphology and immunophenotype of MSCs, and exhibit superior clone efficiency, proliferation capacity, and osteogenic and chondrogenic differentiation potential compared with SCM. Moreover, UCMSCs in S&XFM-CD retain similar immunosuppressive potential, and exhibit superior secretion levels of bFGF, PDGF-BB and IGF-1 compared with SCM. In addition, UCMSCs in S&XFM-CD do not undergo transformation, preserve the normal karyotypes and genomic stability, and are less prone to senescence process after long-term in vitro culture, which conforms to the current guidance of international and national evaluation standard. The S&XFM-CD developed here may serve as a GMP-grade production platform of UCMSCs for future clinical application.

Mobilization of Intracellular Copper by Gossypol and Apogossypolone Leads to Reactive Oxygen Species-Mediated Cell Death: Putative Anticancer Mechanism.

There is compelling evidence that serum, tissue and intracellular levels of copper are elevated in all types of cancer. Copper has been suggested as an important co-factor for angiogenesis. It is also a major metal ion present inside the nucleus, bound to DNA bases, particularly guanine. We have earlier proposed that the interaction of phenolic-antioxidants with intracellular copper leads to the generation of reactive oxygen species (ROS) that ultimately serve as DNA cleaving agents. To further validate our hypothesis we show here that the antioxidant gossypol and its semi-synthetic derivative apogossypolone induce copper-mediated apoptosis in breast MDA-MB-231, prostate PC3 and pancreatic BxPC-3 cancer cells, through the generation of ROS. MCF10A breast epithelial cells refractory to the cytotoxic property of these compounds become sensitized to treatment against gossypol, as well as apogossypolone, when pre-incubated with copper. Our present results confirm our earlier findings and strengthen our hypothesis that plant-derived antioxidants mobilize intracellular copper instigating ROS-mediated cellular DNA breakage. As cancer cells exist under significant oxidative stress, this increase in ROS-stress to cytotoxic levels could be a successful anticancer approach.

Intravenous injectable metformin-Cu(II)-EGCG coordination polymer nanoparticles for electrothermally enhanced dual-drug synergistic tumor therapy.

Intravenous injectable metformin-Cu(II)-EGCG infinite coordination polymer nanoparticles (metformin-Cu(II)-EGCG ICP NPs) have been synthesized, and an efficient strategy for synergistic tumor therapy by utilizing these nanoparticles in conjunction with micro-electrothermal needles (MENs) was proposed. These nanoparticles display exceptional uniformity with a diameter of 117.5 ± 53.3 nm, exhibit an extraordinary drug loading capacity of 90% and allow for precise control over the drug ratio within the range of 1 : 1 to 1 : 20 while maintaining excellent thermal stability. Fourier transform infrared spectroscopy, X-ray photoelectron spectroscopy, and X-ray diffraction were employed to determine their chemical structure and coordination state. The combination index (CI) value of the metformin-Cu(II)-EGCG ICP NPs was calculated to be 0.19, surpassing that of the two individual drugs and metformin mixed with EGCG (0.98). Importantly, upon intravenous injection, metformin in nanoparticles demonstrated exceptional stability in the bloodstream, while both drugs were rapidly released within the acidic tumor microenvironment. Animal experiments showcased an impressive tumor inhibition rate of 100% within a mere 20-day time frame after the synergistic therapy with a lower dosage (5.0 mg kg-1 of nanoparticles), coupled with a minimal tumor recurrence rate of only 18.75% over a 60-day observation period. These findings indicate the promising prospects of these nanoparticles in tumor treatment.

Four-component of double-layer infinite coordination polymer nanocomposites for large tumor trimodal therapy via multi high-efficiency synergies.

Multimodal /components tumors synergistic therapy is a crucial approach for enhancing comprehensive efficacy. Our research has identified lots of high efficiency synergies among four suitable components, revealing combinations with remarkably low combination index (CI) values (10-3-10-8). These combinations hold promise for large tumor powerful electrothermal-thermodynamic-multi-chemo trimodal therapy. To implement this approach, we developed four-component of double-layer infinite coordination polymer (ICP) nanocomposites, in which hypoxia-activated AQ4N and thermodynamic agent AIPH coordinated with Cu(Ⅱ) to form initial layer of positively charged ICPs-l NPs, chemotherapeutic agents gossypol-hyaluronic acid (G-HA) and CA4 coordinated with Fe(Ⅲ) to form out layer of negatively charged ICPs-2 NPs, then double-layer infinite coordination polymer nanocomposites (ICPs-1@ICPs-2 CNPs) were fabricated by electrostatic adsorption using ICPs-l NPs and ICPs-2 NPs. Cell experiments have extensively optimized the coordination combinations of the four components and the composition of the two layers. A programmable three-stage therapeutic procedure, assisted by a micro-electrothermal needle (MEN), was developed. Under this procedure the resulting nanocomposites demonstrate the powerful trimodal comprehensive therapeutic outcomes for large tumors using lower components dosage, achieving a tumor inhibition rate nearly reaching 100 % and no recurrence for 60 days. This study offers remarkable potential for tumor multimodal /components synergistic therapy in future.

Umbilical cord mesenchymal stromal cells in serum-free defined medium display an improved safety profile.

BACKGROUND: Safety evaluations in preclinical studies are needed to confirm before translating a cell-based product into clinical application. We previously developed a serum-free, xeno-free, and chemically defined media (S&XFM-CD) for the derivation of clinical-grade umbilical cord-derived MSCs (UCMSCs), and demonstrated that intraperitoneal administration of UCMSCs in S&XFM-CD (UCMSCS&XFM-CD) exhibited better therapeutic effects than UCMSCs in serum-containing media (SCM, UCMSCSCM). However, a comprehensive investigation of the safety of intraperitoneal UCMSCS&XFM-CD treatment should be performed before clinical applications. METHODS: In this study, the toxicity, immunogenicity and biodistribution of intraperitoneally transplanted UCMSCS&XFM-CD were compared with UCMSCSCM in rats via general vital signs, blood routine, blood biochemistry, subsets of T cells, serum cytokines, pathology of vital organs, antibody production and the expression of human-specific gene. The tumorigenicity and tumor-promoting effect of UCMSCS&XFM-CD were compared with UCMSCSCM in nude mice. RESULTS: We confirmed that intraperitoneally transplanted UCMSCS&XFM-CD or UCMSCSCM did not cause significant changes in body weight, temperature, systolic blood pressure, diastolic blood pressure, heart rate, blood routine, T lymphocyte subsets, and serum cytokines, and had no obvious histopathology change on experimental rats. UCMSCS&XFM-CD did not produce antibodies, while UCMSCSCM had very high chance of antibody production to bovine serum albumin (80%) and apolipoprotein B-100 (60%). Furthermore, intraperitoneally injected UCMSCS&XFM-CD were less likely to be blocked by the lungs and migrated more easily to the kidneys and colon tissue than UCMSCSCM. In addition, UCMSCS&XFM-CD or UCMSCSCM showed no obvious tumorigenic activity. Finally, UCMSCS&XFM-CD extended the time of tumor formation of KM12SM cells, and decreased tumor incidence than that of UCMSCSCM. CONCLUSIONS: Taken together, our data indicate that UCMSCS&XFM-CD display an improved safety performance and are encouraged to use in future clinical trials.

Doxorubicin-Fe(III)-Gossypol Infinite Coordination Polymer@PDA:CuO2 Composite Nanoparticles for Cost-Effective Programmed Photothermal-Chemodynamic-Coordinated Dual Drug Chemotherapy Trimodal Synergistic Tumor Therapy.

To achieve the maximum therapeutic effects and minimize adverse effects of trimodal synergistic tumor therapies, a cost-effective programmed photothermal (PTT)-chemodynamic (CDT)-coordinated dual drug chemotherapy (CT) trimodal synergistic therapy strategy in chronological order is proposed. According to the status or volumes of the tumors, the intensity and time of each therapeutic modality are optimized, and three modalities are combined programmatically and work in chronological order. The optimal synergistic therapy begins with high-intensity PTT for 10 min to ablate larger tumors, followed by medium-intensity CDT for several hours to eliminate medium-sized tumors, and then low-intensity coordinated dual drugs CT lasts over 48 h to clear smaller residual tumors. Composite nanoparticles, made of Fe-coordinated polydopamine mixed with copper peroxide as the cores and their surface dotted with lots of doxorubicin-Fe(III)-gossypol infinite coordination polymers (ICPs), have been developed to implement the strategy. These composite nanoparticles show excellent synergistic effects with the minimum dose of therapeutic agents and result in nearly 100% tumor inhibition for mice bearing PC-3 tumors and no observed recurrence within 60 days of treatment. The ratios of the different therapeutic agents in the composite nanoparticles can be adjusted to accommodate different types of tumors with this cost-effective programmed trimodal therapy strategy.

Emerging Anesthetic Nanomedicines: Current State and Challenges.

Anesthetics, which include both local and general varieties, are a unique class of drugs widely utilized in clinical surgery to alleviate pain and promote relaxation in patients. Although numerous anesthetics and their traditional formulations are available in the market, only a select few exhibit excellent anesthetic properties that meet clinical requirements. The main challenges are the potential toxic and adverse effects of anesthetics, as well as the presence of the blood-brain barrier (BBB), which makes it difficult for most general anesthetics to effectively penetrate to the brain. Loading anesthetics onto nanocarriers as anesthetic nanomedicines might address these challenges and improve anesthesia effectiveness, reduce toxic and adverse effects, while significantly enhance the efficiency of general anesthetics passing through the BBB. Consequently, anesthetic nanomedicines play a crucial role in the field of anesthesia. Despite their significance, research on anesthetic nanomedicines is still in its infancy, especially when compared to other types of nanomedicines in terms of depth and breadth. Although local anesthetic nanomedicines have received considerable attention and essentially meet clinical needs, there are few reported instances of nanomedicines for general anesthetics. Given the extensive usage of anesthetics and the many of them need for improved performance, emerging anesthetic nanomedicines face both unparalleled opportunities and considerable challenges in terms of theory and technology. Thus, a comprehensive summary with systematic analyses of anesthetic nanomedicines is urgently required. This review provides a comprehensive summary of the classification, properties, and research status of anesthetic nanomedicines, along with an exploration of their opportunities and challenges. In addition, future research directions and development prospects are discussed. It is hoped that researchers from diverse disciplines will collaborate to study anesthetic nanomedicines and develop them as a valuable anesthetic dosage form for clinical surgery.

IR780-doped cobalt ferrite nanoparticles@poly(ethylene glycol) microgels as dual-enzyme immobilized micro-systems: Preparations, photothermal-responsive dual-enzyme release, and highly efficient recycling.

To solve the problems of separating dual enzymes from the carriers of dual-enzyme immobilized micro-systems and greatly increase the carriers' recycling times, photothermal-responsive micro-systems of IR780-doped cobalt ferrite nanoparticles@poly(ethylene glycol) microgels (CFNPs-IR780@MGs) are prepared. A novel two-step recycling strategy is proposed based on the CFNPs-IR780@MGs. First, the dual enzymes and the carriers are separated from the reaction system as a whole via magnetic separation. Second, the dual enzymes and the carriers are separated through photothermal-responsive dual-enzyme release so that the carriers can be reused. Results show that CFNPs-IR780@MGs is 281.4 ± 9.6 nm with a shell of 58.2 nm, and the low critical solution temperature is 42 °C, and the photothermal conversion efficiency increases from 14.04% to 58.41% by doping 1.6% of IR780 into the CFNPs-IR780 clusters. The dual-enzyme immobilized micro-systems and the carriers are recycled 12 and 72 times, respectively, and the enzyme activity remains above 70%. The micro-systems can realize whole recycling of the dual enzymes and carriers and further recycling of the carriers, thus providing a simple and convenient recycling method for dual-enzyme immobilized micro-systems. The findings reveal the micro-systems' important application potential in biological detection and industrial production.

Ratiometric Fluorescent Detection of Ultrasound-Regulated ATP Release: An Ultrasound-Resistant Cu,N-Doped Carbon Nanosphere.

Focused ultrasound, as a protocol of cancer therapy, might induce extracellular adenosine triphosphate (ATP) release, which could enhance cancer immunotherapy and be monitored as a therapeutic marker. To achieve an ATP-detecting probe resistant to ultrasound irradiation, we constructed a Cu/N-doped carbon nanosphere (CNS), which has two fluorescence (FL) emissions at 438 and 578 nm to detect ultrasound-regulated ATP release. The addition of ATP to Cu/N-doped CNS was conducted to recover the FL intensity at 438 nm, where ATP enhanced the FL intensity probably via intramolecular charge transfer (ICT) primarily and hydrogen-bond-induced emission (HBIE) secondarily. The ratiometric probe was sensitive to detect micro ATP (0.2-0.6 µM) with the limit of detection (LOD) of 0.068 µM. The detection of ultrasound-regulated ATP release by Cu,N-CNS/RhB showed that ATP release was enhanced by the long-pulsed ultrasound irradiation at 1.1 MHz (+37%, p < 0.01) and reduced by the short-pulsed ultrasound irradiation at 5 MHz (-78%, p < 0.001). Moreover, no significant difference in ATP release was detected between the control group and the dual-frequency ultrasound irradiation group (+4%). It is consistent with the results of ATP detection by the ATP-kit. Besides, all-ATP detection was developed to prove that the CNS had ultrasound-resistant properties, which means it could bear the irradiation of focused ultrasound in different patterns and detect all-ATP in real time. In the study, the ultrasound-resistant probe has the advantages of simple preparation, high specificity, low limit of detection, good biocompatibility, and cell imaging ability. It has great potential to act as a multifunctional ultrasound theranostic agent for simultaneous ultrasound therapy, ATP detection, and monitoring.

Molecular Clogging Organogels with Excellent Solvent Maintenance, Adjustable Modulus, and Advanced Mechanics for Impact Protection.

Inspired by mechanically interlocking supramolecular materials, exploiting the size difference between the bulky solvent and the cross-linked network mesh, a molecular clogging (MC) effect is developed to effectively inhibit solvent migration in organogels. A bulky solvent (branched citrate ester, BCE) with a molecular size above 1.4 nm is designed and synthesized. Series of MC-Gels are prepared by in situ polymerization of crosslinked polyurea with BCE as the gel solvent. The MC-Gels are colorless, transparent, and highly homogeneous, show significantly improved stability than gels prepared with small molecule solvents. As solvent migration is strongly inhibited by molecular clogging, the solvent content of the gels can be precisely controlled, resulting in a series of MC-Gels with continuously adjustable mechanics. In particular, the modulus of MC-Gel can be regulated from 1.3 GPa to 30 kPa, with a variation of 43 000 times. The molecular clogging effect also provides MC-Gels with unique high damping (maximum damping factor of 1.9), impact resistant mechanics (high impact toughness up to 40.68 MJ m-3 ). By applying shatter protection to items including eggs and ceramic armor plates, the potential of MC-Gels as high strength, high damping soft materials for a wide range of applications is well demonstrated.

Methylene diphosphonate-conjugated adriamycin liposomes: preparation, characteristics, and targeted therapy for osteosarcomas in vitro and in vivo.

Methylenediphosphonate (MDP)-conjugated adriamycin liposomes (MDP-LADMs) were prepared using mild dynamic dialysis equilibrium method, and their targeted therapeutic effects against osteosarcomas and metastatic SOSP-M lung nodules were evaluated in vivo. The drug loading and encapsulation efficiency of the MDP-LADMs were measured via high-performance liquid chromatography, and their size and morphology of the MDP-LADMs were determined using transmission electron microscopy and a particle size analyzer, respectively. Cells apoptosis were evaluated by flow cytometry and caspase-3 activity. The targeted therapeutic effects of MDP-LADMs against UMR106 and SOSP-M osteosarcoma cells were evaluated using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) method. Tumor growth and animal survival rates were evaluated after UMR106 osteosarcomas were established in Sprague-Dawley rats and SOSP-M pulmonary metastatic osteosarcoma model were established in nude mice, respectively. The results show that the average diameter of the MDP-LADMs was 152 ± 14 nm, and their ADM encapsulation efficiency was 91.7% with respect to a 250 µg/ml of loading efficiency. The conjugation efficiency between technetium-MDP and LADMs was 87.6%. Infrared spectra results of the samples dissolved in deuterated water confirmed that the methylenediphosphonate (MDP) was conjugated with LADMs through hydrogen bonding. The toxicity assay revealed a median lethal dose of 26.78 mg/kg for MDP-LADMs, which was significantly higher than doses observed for free ADM of 9.64 mg/kg (P < 0.05) and LADMs of 15.02 mg/kg(P < 0.05). Tumor growth and animal survival in the MDP-LADMs group were significantly higher than those in the ADM-only, MDP-only (P < 0.01) and LADMs groups (P < 0.05). These findings indicate that MDP-LADMs have higher therapeutic efficacy against osteosarcomas, demonstrate lower toxicity and their clearly targets osteosarcomas more clearly than the stand-alone systems, making them as a promising novel targeted therapy for the treatment of osteosarcoma.

Laser-induced photoexcited audible sound effect based on reticular 2-bromo-2-methylpropionic acid modified Fe3O4 nanoparticle aggregates.

Reticular 2-bromo-2-methylpropionic acid (BMPA) modified Fe3O4 nanoparticle aggregates with novel acoustic properties, namely the photoexcited audible sound (PEAS) effect, were prepared by a laser-induced irradiation method. Their morphology was observed by Lorentz transmission electron microscopy. Their chemical structure, crystal composition, and magnetic properties were analyzed using infrared spectroscopy, X-ray diffraction, and a magnetic property measurement instrument, respectively. It is found that the nanoparticle aggregates appeared reticular, with the size of the BMPA modified Fe3O4 nanoparticles being 5.5 ± 0.4 nm. The saturation magnetization values of the BMPA modified Fe3O4 nanoparticles and associated aggregates were 59.99 and 63.51 emu g-1, respectively. The reticular BMPA modified nanoparticle aggregates can produce strong PEAS signals under very weak laser irradiation with great stability and repeatability. The emitted PEAS signals possessed strong specificity, suitable decay time and a large amount of information under a very weak laser power and can be detected by the human ear without any special detection equipment. Subsequently, a heat transfer model was constructed for the simulation of the possible mechanism of the PEAS effect using COMSOL software. The simulation results showed that the aggregates have a fast heat transfer rate with the temperature increasing to 480 K in only 0.25 s and 600 K in 5 s, respectively, meeting the requirements of the vapor explosion mechanism. Therefore, we realized that the possible mechanism of the PEAS effect of the reticular BMPA modified Fe3O4 nanoparticle aggregates is laser-induced fast heat transfer and vapor explosion in situ, resulting in the observed audible sound phenomenon. This novel PEAS effect has potential for application in materials science, biomedical engineering and other fields.

Accurate and Real-Time Detection Method for the Exothermic Behavior of Enzymatic Nano-Microregions Using Temperature-Sensitive Amino-AgInS2 Quantum Dots.

The thermal behavior of enzymes in nanoscale is of great significance to life phenomena. This nonequilibrium state real-time thermal behavior of enzymes at nanoscale cannot be accurately detected by existing methods. Herein, a novel method is developed for the detection of this thermal behavior. The enzyme-quantum dot (QD) conjugates can be obtained by chemically grafting temperature-sensitive amino-AgInS2 QDs to the enzyme, where the QDs act as nanothermometers with a sensitivity of -2.82% °C-1 . Detecting the photoluminescence intensity changes of the enzyme-QD conjugates, the real-time thermal behavior of enzymes can be obtained. The enzyme-QD conjugates show a temperature difference as high as 6 °C above ambient temperature in nano-microregions with good reproducibility (maximum error of 4%) during catalysis, while solution temperature hardly changed. This method has a temperature resolution of ≈0.5 °C with a detection limit of 0.02 mg mL-1 of enzyme, and spatially ensured that the amino-AgInS2 QDs are quantitatively bound to the enzyme; thus, it can accurately detect the exothermic behavior of the enzyme and can be extended to other organisms' detection. This method has high sensitivity, good stability, and reliability, indicating its great potential application in investigating the thermal behavior of organisms in nanoscale and related life phenomena.

High Drug-Loading Nanomedicines for Tumor Chemo-Photo Combination Therapy: Advances and Perspectives.

The combination of phototherapy and chemotherapy (chemo−photo combination therapy) is an excellent attempt for tumor treatment. The key requirement of this technology is the high drug-loading nanomedicines, which can load either chemotherapy drugs or phototherapy agents at the same nanomedicines and simultaneously deliver them to tumors, and play a multimode therapeutic role for tumor treatment. These nanomedicines have high drug-loading efficiency (>30%) and good tumor combination therapeutic effect with important clinical application potential. Although there are many reports of high drug-loading nanomedicines for tumor therapy at present, systematic analyses on those nanomedicines remain lacking and a comprehensive review is urgently needed. In this review, we systematically analyze the current status of developed high drug-loading nanomedicines for tumor chemo−photo combination therapy and summarize their types, methods, drug-loading properties, in vitro and in vivo applications. The shortcomings of the existing high drug-loading nanomedicines for tumor chemo−photo combination therapy and the possible prospective development direction are also discussed. We hope to attract more attention for researchers in different academic fields, provide new insights into the research of tumor therapy and drug delivery system and develop these nanomedicines as the useful tool for tumor chemo−photo combination therapy in the future.

Adipose-Derived Stem Cells From Patients With Ulcerative Colitis Exhibit Impaired Immunosuppressive Function.

Adipose-derived stem cells (ADSCs) are able to modulate the immune response and are used for treating ulcerative colitis (UC). However, it is possible that ADSCs from patients with inflammatory or autoimmune disorders may show defective immunosuppression. We investigated the use of ADSCs from UC patients for autologous cell treatment, specifically, ADSCs from healthy donors (H-ADSCs) and UC patients (P-ADSCs) in terms of various functions, including differentiation, proliferation, secretion, and immunosuppression. The efficacy of P-ADSCs for treating UC was examined in mouse models of acute or chronic colitis. Both H-ADSCs and P-ADSCs were similar in cell morphology, size, adipogenic differentiation capabilities, and cell surface markers. We found that P-ADSCs had lower proliferative capacity, cloning ability, and osteogenic and chondrogenic differentiation potential than H-ADSCs. P-ADSCs exhibited a diminished capacity to inhibit peripheral blood mononuclear cell proliferation, suppress CD25 and CD69 marker expression, decrease the production of inflammation-associated cytokines interferon-γ and tumor necrosis factor-α, and reduce their cytotoxic effect on A549 cells. When primed with inflammatory cytokines, P-ADSCs secreted lower levels of prostaglandin E2, indoleamine 2, 3-dioxygenase, and tumor necrosis factor-α-induced protein 6, which mediated their reduced immunopotency. Moreover, P-ADSCs exhibited weaker therapeutic effects than H-ADSCs, determined by disease activity, histology, myeloperoxidase activity, and body weight. These findings indicate that the immunosuppressive properties of ASCs are affected by donor metabolic characteristics. This study shows, for the first time, the presence of defective ADSC immunosuppression in UC, indicating that autologous transplantation of ADSCs may be inappropriate for patients with UC.

Molecular simulation, characteristics and mechanism of thermal-responsive acetylated amylose V-type helical complexes.

To explore the thermal-responsive characteristics of acetylated amylose-guest V-type helical complexes (AAGHCs) and their potential use as thermal-responsive drug carriers, different types of AAGHCs were built, in which acetylated amylose was used as a host, and iodine, propofol, or hexane was utilized as the guest molecule. Their thermal-responsive characteristics were investigated through molecular dynamic (MD) simulation and corresponding experiments. MD simulation showed that the thermal-responsive helix-unfolding and guest-release behavior in AAGHCs, and the complete unfolding of AAGHC could be divided into brewing, triggering and collapsing periods. Energy analysis revealed that the Lana-Jones potential is an important binding energy that bridges host and guest molecules and enhances the stability of the helix. The various types or number of guests showed different binding energies. The stronger the binding energy, higher is the temperature required to trigger the unfolding of the helix and the releasing of guests. FT-IR and X-ray diffraction analyses confirmed the structures of AAGHCs. The change in hydrated size, and UV-VIS absorption of AAGHCs at high temperatures both confirmed the thermal-responsiveness of AAGHCs. The fluorescence fluctuation of loaded 7-hydroxycoumarin reflected the same thermal-responsive process and mechanism as MD simulation. This study provides meaningful theoretical guidance for the design of thermal-responsive drug carriers based on acetylated amylose-guest V-type helical complexes.

A Highly Efficient One-for-All Nanodroplet for Ultrasound Imaging-Guided and Cavitation-Enhanced Photothermal Therapy.

BACKGROUND: Photothermal therapy (PTT) has attracted considerable attention for cancer treatment as it is highly controllable and minimally invasive. Various multifunctional nanosystems have been fabricated in an "all-in-one" form to guide and enhance PTT by integrating imaging and therapeutic functions. However, the complex fabrication of nanosystems and their high cost limit its clinical translation. MATERIALS AND METHODS: Herein, a high efficient "one-for-all" nanodroplet with a simple composition but owning multiple capabilities was developed to achieve ultrasound (US) imaging-guided and cavitation-enhanced PTT. Perfluoropentane (PFP) nanodroplet with a polypyrrole (PPy) shell (PFP@PPy nanodroplet) was synthesized via ultrasonic emulsification and in situ oxidative polymerization. After characterization of the morphology, its photothermal effect, phase transition performance, as well as its capabilities of enhancing US imaging and acoustic cavitation were examined. Moreover, the antitumor efficacy of the combined therapy with PTT and acoustic cavitation via the PFP@PPy nanodroplets was studied both in vitro and in vivo. RESULTS: The nanodroplets exhibited good stability, high biocompatibility, broad optical absorption over the visible and near-infrared (NIR) range, excellent photothermal conversion with an efficiency of 60.1% and activatable liquid-gas phase transition performance. Upon NIR laser and US irradiation, the phase transition of PFP cores into microbubbles significantly enhanced US imaging and acoustic cavitation both in vitro and in vivo. More importantly, the acoustic cavitation enhanced significantly the antitumor efficacy of PTT as compared to PTT alone thanks to the cavitation-mediated cell destruction, which demonstrated a substantial increase in cell detachment, 81.1% cell death in vitro and 99.5% tumor inhibition in vivo. CONCLUSION: The PFP@PPy nanodroplet as a "one-for-all" theranostic agent achieved highly efficient US imaging-guided and cavitation-enhanced cancer therapy, and has considerable potential to provide cancer theranostics in the future.