Difficulty Obtaining Daily Necessities and Difficulty Obtaining SCI Services During the COVID-19 Pandemic Among People With Spinal Cord Injury.

OBJECTIVE: To describe the self-reported difficulties during the COVID-19 pandemic on the lives of persons with traumatic spinal cord injury (SCI), and to identify the factors measured prior the pandemic that predict the number of difficulties obtaining daily necessities and difficulties obtaining SCI services during the pandemic. DESIGN: Cohort study. SETTING: A state SCI outcomes follow-up database in the southeastern United States. PARTICIPANTS: 297 participants (N=297) met the following eligibility criteria: (1) ≥18 years of age, (2) traumatic SCI, (3) minimum of 1-year post-injury, and (4) having completed a longitudinal study questionnaire immediately prior to the pandemic (between 12/1/2019 and 03/11/2020). INTERVENTIONS: N/A. MAIN OUTCOME MEASURE(S): The outcome measures were the self-reported number of difficulties obtaining daily necessities (difficulties to get food, medication, and routine medical/dental care) and difficulties obtaining SCI services during the pandemic (difficulties to get treatment for SCI-related problems, to maintain regular SCI equipment, and to get SCI supplies). RESULTS: Among 297 eligible participants, 247 (83%) have completed the follow-up during the pandemic between December 2020 and December 2021. There were 22% participants having at least 1 difficulty obtaining daily necessities and 19% participants having at least 1 difficulty obtaining SCI services. Younger, ambulatory participants, cervical 1-4 injury level, lower household income, more health conditions, and no routine health care access prior to the pandemic were associated with greater number of difficulties obtaining daily necessities. Women, non-ambulatory participants, marital relation, having need for physical assistance, more health conditions, and no routine health care access prior to the pandemic related to greater number of difficulties obtaining SCI services. CONCLUSIONS: People with SCI have experienced living difficulties during the COVID-19 pandemic. Of particular importance, no routine health care access and more health conditions are related to more difficulties obtaining both daily necessities and SCI services after controlling the socio-demographics and injury characteristics.

Genetic evidence strengthens the bidirectional connection between gut microbiota and periodontitis: insights from a two-sample Mendelian randomization study.

BACKGROUND: Recent research has established the correlation between gut microbiota and periodontitis via oral-gut axis. Intestinal dysbiosis may play a pivotal bridging role in extra-oral inflammatory comorbidities caused by periodontitis. However, it is unclear whether the link is merely correlative or orchestrated by causative mechanistic interactions. This two-sample Mendelian randomization (MR) study was performed to evaluate the potential bidirectional causal relationships between gut microbiota and periodontitis. MATERIALS AND METHODS: A two-sample MR analysis was performed using summary statistics from genome-wide association studies (GWAS) for gut microbiota (n = 18,340) and periodontitis (cases = 12,251; controls = 22,845). The inverse-variance weighted (IVW) method was used for the primary analysis, and we employed sensitivity analyses to assess the robustness of the main results. The PhenoScanner database was then searched for pleiotropy SNPs associated with potential confounders. In order to identify the possibly influential SNPs, we further conducted the leave-one-out analysis. Finally, a reverse MR analysis was performed to evaluate the possibility of links between periodontitis and genetically predicted gut microbiota alternation. RESULTS: 2,699 single nucleotide polymorphisms (SNPs) associated with 196 microbiota genera were selected as instrumental variables (IVs). IVW method suggested that order Enterobacteriales (OR: 1.35, 95% CI 1.10-1.66), family Bacteroidales S24.7group (OR: 1.22, 95% CI 1.05-1.41), genus Lachnospiraceae UCG008 (OR: 1.16, 95% CI 1.03-1.31), genus Prevotella 7 (OR: 1.11, 95% CI 1.01-1.23), and order Pasteurellales (OR: 1.12, 95% CI 1.00-1.26) may be associated with a higher risk of periodontitis, while genus Ruminiclostridium 6 may be linked to a lower risk (OR: 0.82, 95% CI 0.70-0.95). The sensitivity and heterogeneity analyses yielded no indication of horizontal pleiotropy or heterogeneity. Only the association between order Enterobacteriales and the likelihood of periodontitis remained consistent across all alternative MR approaches. In the reverse MR analysis, four microbiota genera were genetically predicted to be down-regulated in periodontitis, whereas two were predicted to be up-regulated. CONCLUSIONS: The present MR analysis demonstrated the potential bidirectional causal relationships between gut microbiota and periodontitis. Our research provided fresh insights for the prevention and management of periodontitis. Future research is required to support the finding of our current study.

Composite Hydrogel for the Targeted Capture and Photothermal Killing of Bacteria toward Facilitating Wound Healing.

Pathogenic infections pose a significant risk to public health and are regarded as one of the most difficult clinical treatment obstacles. A reliable and safe photothermal antibacterial platform is a promising technique for the treatment of bacterial infections. Given the damage that high temperatures cause in normal tissues and cells, a multifunctional hydrogel driven by photothermal energy is created by trapping bacteria to reduce heat transfer loss and conduct low-temperature photothermal sterilization efficiently. The 3-aminobenzene boronic acid (ABA)-modified graphene oxide is combined with carboxymethyl chitosan (CMCS) and cellulose nanocrystalline (CNC) networks to create the ABA-GO/CNC/CMCS composite hydrogel (composite gel). The obtained composite gel displays a uniform three-dimensional network structure, which can be rapidly heated to 48 °C under infrared light irradiation and is beneficial for killing wound infection bacteria and promoting wound healing. The results of animal experiments show that the composite gel significantly reduces inflammation by killing >99.99% of bacteria under near-infrared light irradiation. The result also demonstrates that it increases the granulation tissue thickness and collagen distribution and promotes wound healing. After treatment for 14 days, compared with the remaining 27.73% of the remaining wound area in the control group, the wound area in the composite gel with NIR group is only 0.91%. It significantly accelerates the wound healing process of Staphylococcus aureus infection and shows great potential for clinical application.

Gingival mesenchymal stem cell-derived exosomes are immunosuppressive in preventing collagen-induced arthritis.

Due to the unsatisfied effects of clinical drugs used in rheumatoid arthritis (RA), investigators shifted their focus on the biotherapy. Although human gingival mesenchymal stem cells (GMSC) have the potential to be used in treating RA, GMSC-based therapy has some inevitable side effects such as immunogenicity and tumorigenicity. As one of the most important paracrine mediators, GMSC-derived exosomes (GMSC-Exo) exhibit therapeutic effects via immunomodulation in a variety of disease models, bypassing potential shortcomings of the direct use of MSCs. Furthermore, exosomes are not sensitive to freezing and thawing, and can be readily available for use. GMSC-Exo has been reported to promote tissue regeneration and wound healing, but have not been reported to be effective against autoimmune diseases. We herein compare the immunomodulatory functions of GMSC-Exo and GMSC in collagen-induced arthritis (CIA) model and in vitro CD4+ T-cell co-culture model. The results show that GMSC-Exo has the same or stronger effects compared with GMSC in inhibiting IL-17A and promoting IL-10, reducing incidences and bone erosion of arthritis, via inhibiting IL-17RA-Act1-TRAF6-NF-κB signal pathway. Our results suggest that GMSC-Exo has many advantages in treating CIA, and may offer a promising new cell-free therapy strategy for RA and other autoimmune diseases.

Efficient Cancer Regression by a Thermosensitive Liposome for Photoacoustic Imaging-Guided Photothermal/Chemo Combinatorial Therapy.

The capacity to specifically destroy cancer cells while avoiding normal tissue is urgently desirable in cancer treatment. Herein, a photothermal-trigger-released system serves as a photoacoustic imaging agent constructed by entrapping diketopyrrolopyrrole-based conjugated polymers and curcumin in a poly(ethylene glycol) (PEG)-protected thermoresponsive liposomal phospholipid bilayer. This lipid nanostructure can improve the bioavailability of hydrophobic agents for photothermal treatment with high efficiency and deliver the anticancer drug curcumin to the tumor site actuated by near-infrared (NIR) irradiation. A significantly enhanced combined therapeutic effect to HepG2 tumor-bearing mice was acquired in contrast to the result of single therapy alone. These liposomes with the capability of photoacoustic imaging, greater EPR-induced accumulation in tumor sites, and hyperthermia ablation for photothermal chemotherapy show potential for photoacoustic imaging-guided photothermal/chemo combined therapeutic applications.

A Two-Stage Dissociation System for Multilayer Imaging of Cancer Biomarker-Synergic Networks in Single Cells.

The monitoring of cancer biomarkers is crucial to the early detection of cancer. However, a limiting factor in biomarker analysis is the ability to obtain the multilayered information of various biomarker molecules located at different parts of cells from the plasma membrane to the cytoplasm. A two-stage dissociation nanoparticle system based on multifunctionalized polydopamine-coated gold nanoparticles (Au@PDA NPs) is reported, which allows for the two-stage imaging of cancer biomarkers in single cells. We demonstrate the feasibility of this strategy on sialic acids (SAs), p53 protein, and microRNA-21 (miRNA-21) in MCF-7 breast cancer cells by two custom-built probes. Furthermore, the multicolor fluorescence information extracted is used for the monitoring of biomarker expression changes under different drug combinations, which allows us to investigate the complex interactions between various cancer biomarkers and to describe the cancer biomarker-synergic networks in single cells.

Turning Ineffective Transplatin into a Highly Potent Anticancer Drug via a Prodrug Strategy for Drug Delivery and Inhibiting Cisplatin Drug Resistance.

Clinically ineffective transplatin is highly potent against cancer cells when transformed into a transplatin(IV) prodrug nanoparticle. Herein, a hydrophobic transplatin(IV) was synthesized by H2O2-oxidization of transplatin and attachment of two hydrophobic aliphatic chains. Transplatin(IV) was subsequently encapsulated by a biodegradable amphiphilic copolymer, MPEG-PLA, forming a well-defined spherical micelles (M(TransPt)). Transplatin(IV) was protected efficiently and could be released under a simulated cancerous intracellular condition. Compared to the cisplatin and transplatin, M(TransPt) showed the highest Pt uptake and a clathrin-dependent endocytosis pathway. Most importantly, M(TransPt) displayed a nanomolar IC50 on A2780 cells and a great potency on cisplatin resistant A2780DDP cell line. Overall, this nanoplatform for delivering trans-geometry platinum(IV) drug exhibits excellent characteristics for enhancing efficacy and overcoming cisplatin drug resistance, and holds a strong promise for clinical use in the near future.

A Long-Term Study Comparing the Quality of Life and Psychological Status of Patients with Highly Suspicious Thyroid Nodules ≤1 cm Undergoing Active Surveillance with Those Undergoing Immediate Surgery.

Background: Limited information is available on the long-term impact of active surveillance (AS) and immediate surgery (IS) on the quality of life (QoL) and psychological status of patients with highly suspicious subcentimeter thyroid nodules. Methods: A prospective study was conducted on 752 patients showing highly suspicious subcentimeter thyroid nodules, among whom 584 chose AS and 168 chose IS. All patients underwent at least two assessments regarding their QoL and psychological status, using three questionnaires: Thyroid Cancer-Specific Quality of Life (THYCA-QoL), Hospital Anxiety and Depression Scale (HADS), and European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Core Questionnaire (QLQ-C30). Propensity-score matching (PSM) at a ratio of 3:1 was utilized on patients in the AS and IS groups to mitigate selection bias (504 patients in the AS group and 168 in the IS group). Subsequently, the mixed linear model was used to analyze the QoL data. Results: The median time from the initial evaluation to the last follow-up in the AS and IS groups was 24.0 and 14.2 months, respectively. The AS group showed superior QoL outcomes compared to the IS group, mainly manifested in voice (p < 0.001), sympathetic (p = 0.008), throat/mouth (p < 0.001), and problems with scar (p < 0.001) domains, as per the THYCA-QoL questionnaire. Further, the EORTC QLQ-C30 questionnaire highlighted better outcomes in physical function (p = 0.029), role function (p < 0.001), social function (p < 0.001), global health status (p < 0.001), fatigue (p = 0.012), pain (p = 0.028), appetite loss (p = 0.017), and financial difficulties (p < 0.001). Compared to the initial assessment (1 week after surgery), the IS group showed progressive improvements in QoL, especially in voice (p = 0.024), throat/mouth (p < 0.001), physical function (p = 0.004), social function (p = 0.014), nausea and vomiting (p < 0.001), pain (p = 0.006), and appetite loss (p = 0.048) domains as per both questionnaires. Conclusion: Patients with highly suspicious subcentimeter thyroid nodules who choose IS tend to experience a poorer long-term QoL compared to those who choose AS. Although the situation may improve over time, certain issues might persist, making AS a favorable option for these patients.

Biodegradable stereocomplex micelles based on dextran-block-polylactide as efficient drug deliveries.

Biodegradable stereocomplex micelles (SCMs) based on amphiphilic dextran-block-polylactide (Dex-b-PLA) were designed and used for efficient intracellular drug deliveries. The Dex-b-PLA copolymers were successfully synthesized by click reaction. The structures of the resultant copolymers were verified by (1)H NMR and FT-IR spectra. The formation of stable micelles through self-assembly driven by the stereocomplexation between enantiomeric l- and d-PLA blocks was characterized by transmission electron microscopy (TEM), dynamic laser scattering (DLS), and fluorescence techniques. It was interesting to observe that the SCMs showed lower critical micelle concentration values (CMCs) because of the stereocomplex interaction between PLLA and PDLA. Differential scanning calorimetry (DSC) and X-ray diffraction (XRD) analysis provided information on the thermal and crystal properties of the copolymers and SCMs. The improved stability of SCMs should be attractive for intracellular drug delivery. Thus, a model anticancer drug doxorubicin (DOX) was loaded into micelles, and the in vitro drug release in was also studied. The release kinetics of DOX showed DOX-loaded SCMs exhibited slower DOX release. Confocal laser scanning microscopy (CLSM) and flow cytometry studies also showed that the DOX-loaded SCMs exhibited a slower drug release behavior. Meanwhile, the MTT assay demonstrated that DOX-loaded SCMs show lower cellular proliferation inhibition against HepG2. In sum, the micelles through self-assembly driven by stereocomplex interaction would have great potential to be used as stable delivery vehicles for pharmaceutical and biomedical applications.

Angelica sinensis polysaccharide nanoparticles as novel non-viral carriers for gene delivery to mesenchymal stem cells.

This study centers on the use of a nanoparticle based on the polysaccharide from Angelica sinensis (ASP) as an efficient and safe non-viral gene vector. After modification with branched low molecular weight polyethylenimine (1200 Da), the cationized ASP (cASP) was combined with the plasmid encoding transforming growth factor-beta 1 (TGF-ß1) to form a spherical nano-scaled particle (i.e., cASP-pTGF-ß1 nanoparticle). This nanoparticle was applied to transfect rat bone marrow mesenchymal stem cells and human umbilical cord mesenchymal stem cells. As a result, nanoparticles (cASP/pDNA weight ratio 10:1) had the greatest transfection efficiency in both cells, which was significantly higher than those of Lipofectamine2000 and PEI (25 kDa). This was in agreement with the findings of the semi-quantitative RT-PCR and live cell imaging. These nanoparticles were also less toxic than Lipofectamine2000 and PEI (25 kDa). Therefore, cASP could be a potential candidate for a novel non-viral gene vector. FROM THE CLINICAL EDITOR: These authors demonstrate the use of a nanoparticle-based efficient and safe non-viral gene vector delivery system via a spherical nanoparticle based on a polysaccharide from Angelica sinensis, with parameters superior to Lipofectamine2000.

Biofilm-induced corrosion inhibition of Q235 carbon steel by anaerobic Bacillus cereus inoculum in simulated cooling water.

In this study, the corrosion behavior of Q235 carbon steel (CS) under a Bacillus cereus (B. cereus) inoculum in simulated cooling water was evaluated. The weight loss study proved B. cereus inoculum possessed anticorrosion efficiencies of 92.84% and 73.88% for 3-day and 14-day rotation tests, respectively. The electrochemical measurements indicated that the added B. cereus inoculum increased the charge transfer resistance and reduced corrosion current density. B. cereus cells with strong biofilm-forming capacity were able to adhere onto the Q235 CS surface to form compact biofilms and cause biomineralization. Surface characterization analysis demonstrated that the presence of the B. cereus inoculum reduced the amount of Fe2O3 and simultaneously increased the amount of CaCO3 in corrosion products. The corrosion inhibition mechanisms of the B. cereus inoculum involve forming biofilm, generating a biomineralized layer, and consuming dissolved oxygen. Thus, B. cereus inoculum provides a biological strategy for industrial cooling water anticorrosion application.

Active surveillance versus immediate surgery: A comparison of clinical and quality of life outcomes among patients with highly suspicious thyroid nodules 1 cm or smaller in China.

INTRODUCTION: Active surveillance (AS) is considered an alternative to immediate surgery (IS) for low-risk papillary thyroid microcarcinoma (PTMC) patients. However, it is difficult to decide between AS and IS due to limited evidence regarding risks and benefits for patients in China. METHODS: This study prospectively enrolled 485 patients with highly suspicious thyroid nodules

Scanning Accuracy of 10 Intraoral Scanners for Single-crown and Three-unit Fixed Denture Preparations: An In Vitro Study.

OBJECTIVE: To evaluate the accuracy of 10 intraoral scanners for single-crown and three-unit preparation models. METHODS: A maxillary partially edentulous model was fabricated. A dental cast scanner was used to obtain standard tessellation language (STL) data. Ten intraoral scanners, namely Trios 2 (TR2; 3Shape, Copenhagen, Denmark), True Definition (TD; 3M, Saint Paul, MN, USA), CEREC AC Omnicam (OM; Dentsply Sirona, Charlotte, NC, USA), Organical Scan Oral (OS; R+K, Berlin, Germany), PlanScan (PS; Planmeca, Helsinki, Finland), DWIOP (DW; Dental Wings, Montreal, Canada), Xianlin (XL; Hangzhou Xianlin, Hangzhou, China), DL-100 (DL; Guangzhou Longcheng, Guangzhou, China), Trios 3 (TR3; 3Shape) and i500 (MD; MEDIT, Seoul, South Korea) were used to obtain stereolithography data as test groups. Trueness, precision and surface accuracy were evaluated by deviation analysis using 3D image processing software. One tooth with a three-unit preparation for each test group was registered with the reference scan data, and the absolute distance from another tooth was calculated as the absolute accuracy. The data were analysed using a Mann-Whitney U test and Dunn-Bonferroni test (α = 0.05). RESULTS: The best trueness, precision and surface accuracy of scanning single crown preparation were recorded with TD (trueness 2.9 µm and precision 1.9 µm) and XL (surface accuracy 20.3 ± 2.9 µm). The best trueness, precision, surface accuracy and absolute accuracy of three-unit preparations were recorded with TD (2.6 µm), XL (1.9 µm), OM (27.1 ± 5.2 µm) and TR3 (79.2 ± 19.6 µm), respectively. There was no statistically significant difference in trueness between single- and multiple-unit preparations for any of the intraoral scanners (P > 0.05). A statistically significant difference in the surface accuracy between single and multiple preparations was found for TR2, TD, OM, DW, XL, DL and MD (P < 0.05). CONCLUSION: The trueness and precision of intraoral scanners for scanning three-unit preparations were nearly the same as those for single-crown preparations; however, with the exception of OS, PS and TR3, the surface accuracy of single-crown preparations was significantly better than that for three-unit preparations.

Tunable Crosslinking, Reversible Phase Transition, and 3D Printing of Hyaluronic Acid Hydrogels via Dynamic Coordination of Innate Carboxyl Groups and Metallic Ions.

This article reports tunable crosslinking, reversible phase transition, and three-dimensional printing (3DP) of hyaluronic acid (HyA) hydrogels via dynamic coordination of Fe3+ ions with their innate carboxyl groups for the first time. The concentrations of Fe3+ and H+ ions and the reaction time determine the tunable ratios of mono-, bi-, and tridentate coordination, leading to the low-to-high crosslinking densities and reversible solid-liquid phase transition of HyA hydrogels. At the monodentate-dominant coordination, the liquid hydrogels have low crosslinking densities (HyA_L). At the mixed coordination of mono-, bi-, and tridentate bonding, the solid hydrogels have medium crosslinking densities (HyA_M). At the tridentate-dominant coordination, the solid hydrogels have high crosslinking densities (HyA_H). The reversible solid-liquid phase transitions among HyA_L, HyA_M, and HyA_H were achieved via controlling the concentrations of Fe3+ and H+ ions and reaction time. When the crosslinking densities are between HyA_L and HyA_M, the hydrogels become 3D printable (HyA_P). HyA_P hydrogels were 3D-printed successfully using cold-stage or direct writing methods, and the 3D constructs achieved better structural stability using the latter method. In the direct exposure culture with bone marrow-derived mesenchymal stem cells, the 3D-printed HyA_H (HyA_H_3D) and HyA_H hydrogels showed higher average cell adhesion densities than the HyA_M, HyA_P, and HyA_L hydrogel groups under both direct and indirect contact conditions. For all hydrogel groups, cell adhesion densities under direct contact conditions were statistically lower than the same groups under indirect contact conditions. In this article, we elucidated the mechanisms of dynamic coordination and the relationships among the key parameters in controlling the tunable crosslinking, reversible phase transition, and 3DP of HyA hydrogels without blending with other polymers or adding functional groups. This approach can be potentially adapted to crosslink and 3D print other polymeric hydrogels with carboxyl groups, which is promising for a wide range of applications.

Detection of cell-surface sialic acids and photodynamic eradication of cancer cells using dye-modified polydopamine-coated gold nanobipyramids.

A nanoprobe based on polydopamine-coated gold nanobipyramids surface modified with molecules of a phenylboronic acid-substituted distyryl boron dipyrromethene has been fabricated and characterised using various physical and spectroscopic methods. It serves as an ultrasensitive sensor for sialic acids on the surface of cancer cells based on its dual surface-enhanced Raman scattering and fluorescence response. This biomarker can also trigger the photodynamic activity of these nanobipyramids, effectively eradicating the cancer cells mainly through apoptosis as shown by various bioassays.

Zwitterionic Conjugated Polymer as the Single Component for Photoacoustic-Imaging-Guided Dual-Modal Near-Infrared Phototherapy.

Systems consisting of different functional components that synergistically increase the antitumor efficiency of different cancer therapies are in great demand. Here, we report the use of nanoparticles (NPs) composed of a zwitterionic conjugated polymer, generating reactive oxygen species (ROS) and heat. These NPs are more effective in antitumor than single photodynamic therapy (PDT) or photothermal therapy (PTT) and have an optimal absorbance ranging from 700 to 850 nm. Light in this range is capable of reaching tumors by penetrating deep into tissues. The simultaneous PDT and PTT using a single near-infrared (NIR) light can be monitored via photoacoustic imaging (PAI). Treatment of tumor-bearing nude mice with combined PDT and PTT following tail vein injection of NPs resulted in complete tumor remission. No tumor relapse was observed during a 20 day treatment. These zwitterionic conjugated polymeric NPs with the capability of generating ROS and heat show great potential for PAI-guided photodynamic/photothermal dual-modal therapy.

A Nanocomposite Vehicle Based on Metal-Organic Framework Nanoparticle Incorporated Biodegradable Microspheres for Enhanced Oral Insulin Delivery.

Oral insulin delivery has revolutionized diabetes treatment, but challenges including degradation in the gastrointestinal environment and low permeation across the intestinal epithelium remain. Herein, to overcome these barriers, we developed a novel biodegradable nanocomposite microsphere embedded with metal-organic framework (MOF) nanoparticles. An iron-based MOF nanoparticle (NP) (MIL-100) was first synthesized as a carrier with an insulin loading capacity of 35%. The insulin-loaded MIL-100 nanoparticles modified with sodium dodecyl sulfate (Ins@MIL100/SDS) promoted insulin permeation across Caco-2 monolayer models in vitro. To improve resistance to the gastric acid environment, Ins@MIL100/SDS nanoparticles were embedded into a biodegradable microsphere to construct the nanocomposite delivery system (Ins@MIL100/SDS@MS). The microspheres effectively protected the MOF NPs from rapid degradation under acidic conditions and could release insulin-loaded MOF NPs in the simulated intestinal fluid. After the oral administration of Ins@MIL100/SDS@MS into BALB/c nude mice, increased intestinal absorption of the insulin was detected compared to the oral administration of free insulin or Ins@MIL100/SDS. Furthermore, significantly enhanced plasma insulin levels were obtained for over 6 h after oral administration of Ins@MIL100/SDS@MS into diabetic rats, leading to a remarkably enhanced effect in lowering blood glucose level with a relative pharmacological availability of 7.8%. Thus, the MOF-nanoparticle-incorporated microsphere may provide a new strategy for effective oral protein delivery.

Enhanced Lysosomal Escape of pH-Responsive Polyethylenimine-Betaine Functionalized Carbon Nanotube for the Codelivery of Survivin Small Interfering RNA and Doxorubicin.

The combination of gene therapy and chemotherapy has recently received considerable attention for cancer treatment. However, low transfection efficiency and poor endosomal escape of genes from nanocarriers strongly limit the success of the clinical use of small interfering RNA (siRNA). In this study, a novel pH-responsive, surface-modified single-walled carbon nanotube (SWCNT) was designed for the codelivery of doxorubicin (DOX) and survivin siRNA. Polyethylenimine (PEI) was covalently conjugated with betaine, and the resulting PEI-betaine (PB) was further synthesized with the oxidized SWCNT to form SWCNT-PB (SPB), which exhibits an excellent pH-responsive lysosomal escape of siRNA. SPB was modified with the targeting and penetrating peptide BR2 (SPBB), thereby achieving considerably higher uptake of siRNA than SWCNT-PEI (SP) or SPB. Furthermore, SPBB-siRNA presented substantially lower survivin expression and higher apoptotic index than Lipofectamine 2000. DOX and survivin siRNA were adsorbed onto SPB to form DOX-SPBB-siRNA, and siRNA/DOX was released into the cytoplasm and nuclei of adenocarcinomic human alveolar basal epithelial (A549) cells without lysosomal retention. Compared with SPBB-siRNA or DOX-SPBB treatment alone, DOX-SPBB-siRNA significantly reduced tumor volume in A549 cell-bearing nude mice, demonstrating the synergistic effects of DOX and survivin siRNA. Pathological analysis also indicated the potential therapeutic effects of DOX-SPBB-siRNA on tumors without distinct damages to normal tissues. In conclusion, the novel functionalized SWCNT loaded with DOX and survivin siRNA was successfully synthesized, and the nanocomplex exhibited effective antitumor effects both in vitro and in vivo, thereby providing an alternative strategy for the codelivery of antitumor drugs and genes.

Delivery siRNA with a novel gene vector for glioma therapy by targeting Gli1.

BACKGROUND: Gene therapy has recently shown considerable clinical benefit in cancer therapy during the past few years, and the application of this choice in cancer treatments is increasing continually. Gli1 is an ideal candidate target for cancer gene therapy and is important for tumorigenesis. METHODS: In this study, we developed a novel gene delivery system with a self-assembly method by using a 1,2-dioleoyl-3-trimethylammonium-propane and methoxy poly (ethylene glycol)-poly(lactide) copolymer (DMP), with zeta potential of 32.7 mV and measuring 35.6 nm. The effect of this delivery system was tested in vitro and in vivo. RESULTS: DMP showed good performance in delivering siRNA to glioma cells in vitro with high transfection performance (98%). Moreover, DMP-Gli1si shows a satisfactory anti-glioma effect via induction of cell apoptosis and cell growth inhibition in vitro. Furthermore, for subcutaneous tumor-bearing mice, treatment with the DMP-Gli1si complex significantly inhibited tumor growth by inhibiting Gli1 protein expression, promoting apoptosis, and reducing proliferation. CONCLUSION: The complex of Gli1 siRNA and DMP may potentially play an important role as a new drug in the clinical treatment of gliomas.

Enhanced dissolution and oral bioavailability of valsartan solid dispersions prepared by a freeze-drying technique using hydrophilic polymers.

This study aimed to improve the dissolution rate and oral bioavailability of valsartan (VAL), a poorly soluble drug using solid dispersions (SDs). The SDs were prepared by a freeze-drying technique with polyethylene glycol 6000 (PEG6000) and hydroxypropylmethylcellulose (HPMC 100KV) as hydrophilic polymers, sodium hydroxide (NaOH) as an alkalizer, and poloxamer 188 as a surfactant without using any organic solvents. In vitro dissolution rate and physicochemical properties of the SDs were characterized using the USP paddle method, differential scanning calorimetry (DSC), X-ray diffractometry (XRD) and Fourier transform-infrared (FT-IR) spectroscopy, respectively. In addition, the oral bioavailability of SDs in rats was evaluated by using VAL (pure drug) as a reference. The dissolution rates of the SDs were significantly improved at pH 1.2 and pH 6.8 compared to those of the pure drug. The results from DSC, XRD showed that VAL was molecularly dispersed in the SDs as an amorphous form. The FT-IR results suggested that intermolecular hydrogen bonding had formed between VAL and its carriers. The SDs exhibited significantly higher values of AUC 0-24 h and Cmax in comparison with the pure drug. In conclusion, hydrophilic polymer-based SDs prepared by a freeze-drying technique can be a promising method to enhance dissolution rate and oral bioavailability of VAL.