Alpha-Lipoic Acid Attenuates Apoptosis and Ferroptosis in Cisplatin-Induced Ototoxicity via the Reduction of Intracellular Lipid Droplets.

Alpha-lipoic acid (α-LA) is a potent antioxidant that can prevent apoptosis associated with cisplatin-induced ototoxicity through ROS. Ferroptosis is defined as an iron-dependent cell death pathway that has recently been highlighted and is associated with the accumulation of intracellular lipid droplets (LDs) due to an inflammatory process. Herein, we investigated the impact of α-LA on ferroptosis and analyzed the characteristics of LDs in auditory hair cells treated with cisplatin using high-resolution 3D quantitative-phase imaging with reconstruction of the refractive index (RI) distribution. HEI-OC1 cells were treated with 500 µM α-LA for 24 h and then with 15 µM cisplatin for 48 h. With 3D optical diffraction tomography (3D-ODT), the RI values of treated cells were analyzed. Regions with high RI values were considered to be LDs and labelled to measure the count, mass, and volume of LDs. The expression of LC3-B, P62, GPX4, 4-hydroxynonenal (4-HNE), and xCT was evaluated by Western blotting. HEI-OC1 cells damaged by cisplatin showed lipid peroxidation, depletion of xCT, and abnormal accumulation of 4-HNE. Additionally, the count, mass, and volume of LDs increased in the cells. Cells treated with α-LA had inhibited expression of 4-HNE, while the expression of xCT and GPX4 was recovered, which restored LDs to a level that was similar to that in the control group. Our research on LDs with 3D-ODT offers biological evidence of ferroptosis and provides insights on additional approaches for investigating the molecular pathways.

Interactions of Nanoparticles with Macrophages and Feasibility of Drug Delivery for Asthma.

Understanding the interaction between nanoparticles and immune cells is essential for the evaluation of nanotoxicity and development of nanomedicines. However, to date, there is little data on the membrane microstructure and biochemical changes in nanoparticle-loaded immune cells. In this study, we observed the microstructure of nanoparticle-loaded macrophages and changes in lipid droplets using holotomography analysis. Quantitatively analyzing the refractive index distribution of nanoparticle-loaded macrophages, we identified the interactions between nanoparticles and macrophages. The results showed that, when nanoparticles were phagocytized by macrophages, the number of lipid droplets and cell volume increased. The volume and mass of the lipid droplets slightly increased, owing to the absorption of nanoparticles. Meanwhile, the number of lipid droplets increased more conspicuously than the other factors. Furthermore, alveolar macrophages are involved in the development and progression of asthma. Studies have shown that macrophages play an essential role in the maintenance of asthma-related inflammation and tissue damage, suggesting that macrophage cells may be applied to asthma target delivery strategies. Therefore, we investigated the target delivery efficiency of gold nanoparticle-loaded macrophages at the biodistribution level, using an ovalbumin-induced asthma mouse model. Normal and severe asthma models were selected to determine the difference in the level of inflammation in the lung. Consequently, macrophages had increased mobility in models of severe asthma, compared to those of normal asthma disease. In this regard, the detection of observable differences in nanoparticle-loaded macrophages may be of primary interest, as an essential endpoint analysis for investigating nanomedical applications and immunotheragnostic strategies.

Effect of Intermittent Hypoxia on Metabolic Syndrome and Insulin Resistance in the General Male Population.

Background and objectives: Obstructive sleep apnea (OSA) is closely associated with insulin resistance (IR) and is an independent risk factor for incident type 2 diabetes mellitus (T2DM). Most studies evaluate the correlation between OSA and IR in only obese or T2DM patients. Therefore, we tried to investigate the effect of OSA on metabolic syndrome and IR in the general healthy male population. Materials and Methods: 184 subjects who visited a preventive health examination program were recruited for this study. All subjects received overnight polysomnography by a portable device (Watch-PAT 200). We examined several metabolic parameters and a homeostasis model of assessment for insulin resistance index (HOMA-IR). The subjects were divided into three groups by AHI (Apnea-hyponea index): normal group (AHI < 5), mild OSA group (5 ≤ AHI < 15), and moderate-severe OSA group (AHI ≥ 15). They were also divided into two groups according to minimum oxygen saturation: low group, Min-SpO2 < 88%; and high group, Min-SpO2 ≥ 88%. Results: Parameters of metabolic syndrome, including waist circumference, systolic and diastolic blood pressure, triglyceride, and high-density lipoprotein cholesterol showed significant differences among the AHI groups. Furthermore, HOMA-IR showed significant differences among the AHI groups. Those parameters, including metabolic syndrome and HOMA-IR, also showed differences between Min-SpO2 groups. Conclusions: In summary, this study helps confirm that AHI is associated with HOMA-IR in the general male population. Furthermore, the severity of AHI correlated with the parameters of metabolic syndrome. Therefore, AHI might be an indicator for evaluating both T2DM and metabolic syndrome, even in the general male population.

Oral Gavage Delivery of PR8 Antigen with ß-Glucan-Conjugated GRGDS Carrier to Enhance M-Cell Targeting Ability and Induce Immunity.

Oral gavage is known as one of most convenient routes for therapeutic administration in comparison with other available routes such as intravenous, intra muscular, suppository, etc. An oral vaccine delivery system has additional potential as it may provide a convenient way to prevent infectious diseases by introducing optimum immunization in mucus. Although oral vaccine delivery has attracted tremendous interest in vaccine delivery research, various limitations have prevented its rate of progress up to the level that was initially expected. However, the major problems of oral vaccine delivery are vaccine instability and lack of absorbability, resulting from degradation of the sophisticated antigens in the acidic medium in the stomach. In order to obtain adequate microfold-cell (M-cell) targeting and uptake, the therapeutic material is required to pass through the stomach and reach the small intestine without degradation. In this project, we have introduced a conjugate of ß-glucan and Glycine-Arginine-Glycine-Aspartic acid-Serine (GRGDS) that is effective for simultaneous protection of the antigen (PR8) and M-cell targeting. According to the experimental results, the cationic ß-glucan-GRGDS conjugate can encapsulate a certain amount of anionic PR8 through electrostatic interaction, which forms nanoparticles with a range of diameter of 200-250 nm. Also, the PR8 incorporated nanoparticles showed high cell viability and stability in diverse environments. Finally, excellent M-cell targeting ability was verified in an in vitro M-cell model. Most importantly, the in vivo test obviously demonstrated the superiority of this system, which significantly increases antibody concentration in serum, intestine, and mucus as measured 21 days after immunization.

Convolutional neural network model for automatic recognition and classification of pancreatic cancer cell based on analysis of lipid droplet on unlabeled sample by 3D optical diffraction tomography.

INTRODUCTION: Pancreatic cancer cells generally accumulate large numbers of lipid droplets (LDs), which regulate lipid storage. To promote rapid diagnosis, an automatic pancreatic cancer cell recognition system based on a deep convolutional neural network was proposed in this study using quantitative images of LDs from stain-free cytologic samples by optical diffraction tomography. METHODS: We retrieved 3D refractive index tomograms and reconstructed 37 optical images of one cell. From the four cell lines, the obtained fields were separated into training and test datasets with 10,397 and 3,478 images, respectively. Furthermore, we adopted several machine learning techniques based on a single image-based prediction model to improve the performance of the computer-aided diagnostic system. RESULTS: Pancreatic cancer cells had a significantly lower total cell volume and dry mass than did normal pancreatic cells and were accompanied by greater numbers of lipid droplets (LDs). When evaluating multitask learning techniques utilizing the EfficientNet-b3 model through confusion matrices, the overall 2-category accuracy for cancer classification reached 96.7 %. Simultaneously, the overall 4-category accuracy for individual cell line classification achieved a high accuracy of 96.2 %. Furthermore, when we added the core techniques one by one, the overall performance of the proposed technique significantly improved, reaching an area under the curve (AUC) of 0.997 and an accuracy of 97.06 %. Finally, the AUC reached 0.998 through the ablation study with the score fusion technique. DISCUSSION: Our novel training strategy has significant potential for automating and promoting rapid recognition of pancreatic cancer cells. In the near future, deep learning-embedded medical devices will substitute laborious manual cytopathologic examinations for sustainable economic potential.

Serum Zonulin Is a Biomarker for Severe Asthma.

Zonulin is a regulator of epithelial and endothelial barrier function. It regulates intestinal permeability through disrupting tight junctions. Defective epithelial barrier function is a hallmark of airway inflammation in asthma. This study aimed to investigate the role of zonulin in the pathogenesis of severe asthma. We enrolled 56 adult patients with asthma (29 severe asthma and 27 mild-to-moderate asthma) and 33 normal controls. The clinical data, sera, and lung tissues of the patients were provided by the Cohort for Reality and Evolution of adult Asthma in Korea (COREA) and the Biobank of Soonchunhyang University Bucheon Hospital, South Korea. Serum zonulin levels were estimated using an enzyme-linked immunosorbent assay, and zonulin expression in the bronchial tissue was evaluated by immunohistochemical staining. The serum zonulin levels were significantly higher in patients with severe asthma (51.98 ± 19.66 ng/mL) than in those with mild-to-moderate asthma and normal controls (26.35 ± 13.70 vs. 17.26 ± 10.29 ng/mL, P < 0.001). They significantly correlated with percent predicted forced expiratory volume in one second (%FEV1) (r = -0.35, P = 0.009). The zonulin expression in the bronchial epithelium was greater in patients with severe asthma. A serum zonulin cutoff value to distinguish between severe and mild-to-moderate asthmatics was 38.83 ng/mL. Zonulin may play an important role in the pathogenesis of severe asthma, and serum zonulin could be a potential biomarker for severe asthma.

Craniofacial Phenotype in Obstructive Sleep Apnea and Its Impact on Positive Airway Pressure (PAP) Adherence.

Positive airway pressure (PAP) is an important treatment tool for patients with moderate and severe obstructive sleep apnea (OSA), and adherence to PAP significantly affects treatment outcomes. Disease severity, adverse effects, and psychosocial factors are known to predict medication adherence. Cephalometric parameters have been reported to positively correlate with upper airway collapse. However, research on the correlation between these cephalometric parameters and PAP adherence remains insufficient. This study aimed to identify this relationship. This study included 185 patients with OSA who were prescribed PAP. Polysomnography (PSG) was performed to diagnose OSA, and paranasal sinus computed tomography (PNS CT) was performed to check for comorbidities of the upper airway. In addition, cephalometric parameters such as the hyoid-posterior nasal spine (H-PNS), posterior nasal spine-mandibular plane (PNS-MP), and hyoid-mandibular plane (H-MP) were measured in the midsagittal and axial CT views. Adherence was evaluated 3-12 months after the PAP prescription. A total of 136 patients were PAP-adherent, and 49 were nonadherent. There were more males in the adherent group and a higher average height in the adherent group. The PSG results showed that the apnea-hypopnea index (AHI), respiratory disturbance index (RDI), oxygen desaturation index (ODI), arousal index (AI), rapid eye movement (REM) AHI, and supine AHI were significantly higher, and the lowest oxygen saturation was lower in the adherent group. In the analysis of covariance (ANCOVA) model adjusted for sex and height, among the cephalometric parameters, H-MP was significantly longer in the adherent group (p = 0.027), and H-PNS showed a longer tendency (p = 0.074). In the logistic regression analysis model, the odds ratio (OR) and 95% confidence intervals (95% CI) of adherence and severe OSA in the third tertile compared to the first tertile of H-MP were 2.93 (1.25-6.86) and 4.00 (1.87-8.56). In the case of H-PNS, they were 2.58 (1.14-5.81) and 4.86 (2.24-10.54), respectively. This study concluded that an inferiorly placed hyoid bone in adult patients is associated with PAP adherence and disease severity.

The Protective Effects of Human Embryonic Stem Cell-Derived Mesenchymal Stem Cells in Noise-Induced Hearing Loss of Rats.

A few prior animal studies have suggested the transplantation or protective effects of mesenchymal stem cells (MSCs) in noise-induced hearing loss. This study intended to evaluate the fates of administered MSCs in the inner ears and the otoprotective effects of MSCs in the noise-induced hearing loss of rats. Human embryonic stem cell-derived MSCs (ES-MSCs) were systematically administered via the tail vein in adult rats. Eight-week-old Sprague-Dawley rats were randomly allocated to the control (n = 8), ES-MSC (n = 4), noise (n = 8), and ES-MSC+noise (n = 10) groups. In ES-MSC and ES-MSC+noise rats, 5 × 105 ES-MSCs were injected via the tail vein. In noise and ES-MSC+noise rats, broadband noise with 115 dB SPL was exposed for 3 h daily for 5 days. The hearing levels were measured using auditory brainstem response (ABR) at 4, 8, 16, and 32 kHz. Cochlear histology was examined using H&E staining and cochlear whole mount immunofluorescence. The presence of human DNA was examined using Sry PCR, and the presence of human cytoplasmic protein was examined using STEM121 immunofluorescence staining. The protein expression levels of heat shock protein 70 (HSP70), apoptosis-inducing factor (AIF), poly (ADP-ribose) (PAR), PAR polymerase (PARP), caspase 3, and cleaved caspase 3 were estimated. The ES-MSC rats did not show changes in ABR thresholds following the administration of ES-MSCs. The ES-MSC+ noise rats demonstrated lower ABR thresholds at 4, 8, and 16 kHz than the noise rats. Cochlear spiral ganglial cells and outer hair cells were more preserved in the ES-MSC+ noise rats than in the noise rats. The Sry PCR bands were highly detected in lung tissue and less in cochlear tissue of ES-MSC+noise rats. Only a few STEM121-positivities were observed in the spiral ganglial cell area of ES-MSC and ES-MSC+noise rats. The protein levels of AIF, PAR, PARP, caspase 3, and cleaved caspase 3 were lower in the ES-MSC+noise rats than in the noise rats. The systemic injection of ES-MSCs preserved hearing levels and attenuated parthanatos and apoptosis in rats with noise-induced hearing loss. In addition, a tiny number of transplanted ES-MSCs were observed in the spiral ganglial areas.

Microbiome of Unilateral Chronic Rhinosinusitis: A Controlled Paired Analysis.

The sinonasal microbiota in human upper airway may play an important role in chronic rhinosinusitis (CRS). Thus, this study aimed to investigate the human upper airway microbiome in patients with unilateral CRS, and compare the sinonasal microbiome of the unilateral diseased site with that of a contralateral healthy site. Thirty samples, 15 each from the diseased and healthy sites, were collected from the middle meatus and/or anterior ethmoid region of 15 patients with unilateral CRS during endoscopic sinus surgery. DNA extraction and bacterial microbiome analysis via 16S rRNA gene sequencing were then performed. Corynebacterium showed the highest relative abundance, followed by Staphylococcus in samples from both the diseased and healthy sites. Further, the relative abundances of Staphylococcus and Pseudomonas were significantly lower in samples from diseased sites than in those from healthy sites. Conversely, anaerobes, including Fusobacterium, Bacteroides, and Propionibacterium, were abundantly present in samples from both sites, more so in samples from diseased sites. However, the sites showed no significant difference with respect to richness or diversity (p > 0.05). Our results indicate that CRS might be a polymicrobial infection, and also suggest that Corynebacterium and Staphylococcus may exist as commensals on the sinus mucosal surface in the upper respiratory tract.

Cross-Sectional Analysis of the Association between Periodontitis and Cardiovascular Disease Using the Korean Genome and Epidemiology Study Data.

This cross-sectional study aimed to evaluate the association between periodontitis and cardiovascular disease (CVD) by reviewing and discussing the role of the oral microbiome in periodontitis and CVD. This prospective cohort study used epidemiological data from the Korean Genome and Epidemiology Study from 2004 to 2016. We selected 9973 patients with periodontitis and 125,304 controls (non-periodontitis) from 173,209 participants and analyzed their medical histories to determine the relationship between cerebral stroke/ischemic heart disease and periodontitis. The participants were questioned about any previous history of hypertension, diabetes mellitus, hyperlipidemia, cerebral stroke (hemorrhagic or ischemic), ischemic heart disease (angina or myocardial infarction), and periodontitis. Their body mass index, smoking habit, alcohol intake, nutritional intake, and income were recorded. The Chi-square test, independent t-test, and two-tailed analyses were used for statistical analysis. The adjusted OR (aOR) of periodontitis for stroke was 1.35 (95% confidence interval (CI) = 1.16-1.57, p < 0.001). The aOR of periodontitis for ischemic heart disease was 1.34 (95% CI = 1.22-1.48, p < 0.001). We concluded that periodontitis was associated with CVD and may be a risk factor for CVD. However, further studies are required to determine the association between periodontal treatment and CVD.

Comparison of the human microbiome in adults and children with chronic rhinosinusitis.

We hypothesized that differences in the microbiome could be a cause of the substantial differences in the symptoms of and treatment options for adult and pediatric patients with chronic rhinosinusitis (CRS). First, we characterized the differences in the nasal microbiomes of pediatric and adult CRS patients. Swabs were obtained from 19 patients with chronic rhinosinusitis (9 children and 10 adults). The bacterial 16S rRNA gene was pyrosequenced to compare the microbiota of the middle meatus. No significant differences were found in species richness and alpha-diversity indices between the two groups. However, in the comparison of diversity between groups using the unweighted pair group method with arithmetic mean (UPGMA) clustering of microbiome taxonomic profiles, we observed a relatively clear separation between the adult and pediatric groups. Actinobacteria had a significantly higher relative abundance in the adult group than in the pediatric group at the phylum level. At the genus level, Corynebacterium showed significantly higher relative abundance in the adult group than in the pediatric group. This is a comparative study between the microbiomes of adult and pediatric CRS patients. We expect this study to be the first step in understanding the pathogenesis of CRS in adults and children using microbiome analysis.

Biomimetic Gold Nanoshell-Loaded Macrophage for Photothermal Biomedicine.

The purpose of this study was to investigate the effect of photothermal treatment (PTT) with gold nanoshell (ANS) using a macrophage-mediated delivery system in a head and neck squamous cell carcinoma (HNSCC) cell line. To achieve this, ANS-loaded rat macrophages (ANS-MAs) were prepared via the coculture method with ANS. The human HNSCC (FaDu cell) and macrophage (rat macrophage; NR8383 cell) hybrid spheroid models were generated by the centrifugation method to determine the possibility of using ANS-MAs as a cancer therapy. These ANS-MAs were set into the tumor and macrophage hybrid spheroid model to measure PTT efficacy. Kinetic analysis of the spheroid growth pattern revealed that this PTT process caused a decreasing pattern in the volume of the hybrid model containing ANS-MAs (p < 0.001). Comparison with empty macrophages showed harmony between ANS and laser irradiation for the generation of PTT. An annexin V/dead cell marker assay indicated that the PTT-treated hybrid model induced increasing apoptosis and dead cells. Further studies on the toxicity of ANS-MAs are needed to reveal whether it can be considered biocompatible. In summary, the ANS was prepared with a macrophage as the delivery method and protective carrier. The ANS was successfully localized to the macrophages, and their photoabsorption property was stationary. This strategy showed significant growth inhibition of the tumor and macrophage spheroid model under NIR laser irradiation. In vivo toxicology results suggest that ANS-MA is a promising candidate for a biocompatible strategy to overcome the limitations of fabricated nanomaterials. This ANS-MA delivery and PTT strategy may potentially lead to improvements in the quality of life of patients with HNSCC by providing a biocompatible, minimally invasive modality for cancer treatment.

Automatic detection of tympanic membrane and middle ear infection from oto-endoscopic images via convolutional neural networks.

Convolutional neural networks (CNNs), a popular type of deep neural network, have been actively applied to image recognition, object detection, object localization, semantic segmentation, and object instance segmentation. Accordingly, the applicability of deep learning to the analysis of medical images has increased. This paper presents a novel application of state-of-the-art CNN models, such as DenseNet, to the automatic detection of the tympanic membrane (TM) and middle ear (ME) infection. We collected 2,484 oto-endoscopic images (OEIs) and classified them into one of three categories: normal, chronic otitis media (COM) with TM perforation, and otitis media with effusion (OME). Our results indicate that CNN models have significant potential for the automatic recognition of TM and ME infections, demonstrating a competitive accuracy of 95% in classifying TM and middle ear effusion (MEE) from OEIs. In addition to accuracy measurement, our approach achieves nearly perfect measures of 0.99 in terms of the average area under the receiver operating characteristics curve (AUROC). All these results indicate robust performance when recognizing TM and ME effusions in OEIs. Visualization through a class activation mapping (CAM) heatmap demonstrates that our proposed model performs prediction based on the correct region of OEIs. All these outcomes ensure the reliability of our method; hence, the study can aid otolaryngologists and primary care physicians in real-world scenarios.

Oral siRNA delivery using dual transporting systems to efficiently treat colorectal liver metastasis.

Oral siRNA delivery is an ideal way to translate siRNA therapeutic effects in the clinic due to its ability to be administered in convenient and multiple dosages. However, an effective oral delivery system requires overcoming both a hostile gastrointestinal (GI) environment and non-specific targeting. Here, an HTsRP-NC system is a new oral siRNA delivery system consisting of a siRNA/protamine (sRP) nano-complex protected by a multi-functional hyaluronic acid-taurocholic acid (HA-TCA) conjugate. The HTsRP-NC promotes cell penetration and enhances endosomal escape in cancer cells. Moreover, protection of the sRP by HA-TCA from the hostile GI environment helps the AKT siRNA complex to reach the liver through the utilization of a TCA-mediated enterohepatic bile acid recycling system. AKT siRNA was released by 90% in presence of hyaluronidase in the tumor cells which indicate the potential use of HTsRP-NCs for siRNA delivery to treat tumor. After HA receptor (CD44)-mediated cellular uptake of the HTsRP-NC by the liver cancer cells, functional expression of AKT siRNA leads to the suppression of metastatic liver cancer growth in a colorectal liver metastasis (CLM) murine model. Tumor nodules were reduced by more than 1 mm size compared to control group and tumor cells were suppressed by 50% after HTsRP-NCs treatment with AKT siRNA. Overall, oral administration of the HTsRP-NC supports its potential in therapeutic applications for the effective treatment of CLM.

Oral Vaccine Delivery for Intestinal Immunity-Biological Basis, Barriers, Delivery System, and M Cell Targeting.

Most currently available commercial vaccines are delivered by systemic injection. However, needle-free oral vaccine delivery is currently of great interest for several reasons, including the ability to elicit mucosal immune responses, ease of administration, and the relatively improved safety. This review summarizes the biological basis, various physiological and immunological barriers, current delivery systems with delivery criteria, and suggestions for strategies to enhance the delivery of oral vaccines. In oral vaccine delivery, basic requirements are the protection of antigens from the GI environment, targeting of M cells and activation of the innate immune response. Approaches to address these requirements aim to provide new vaccines and delivery systems that mimic the pathogen's properties, which are capable of eliciting a protective mucosal immune response and a systemic immune response and that make an impact on current oral vaccine development.

Antibody-mediated oral delivery of therapeutic DNA for type 2 diabetes mellitus.

BACKGROUND: Diabetes mellitus (DM) is a chronic progressive metabolic disease that involves uncontrolled elevation of blood glucose levels. Among various therapeutic approaches, GLP-1 prevents type 2 diabetes mellitus (T2DM) patients from experiencing hyperglycemic episodes. However, the short half-life (< 5 min) and rapid clearance of GLP-1 often limits its therapeutic use. Here, we developed an oral GLP-1 gene delivery system to achieve an extended antidiabetic effect. METHODS: Human IgG1 (hIgG1)-Fc-Arg/pDNA complexes were prepared by an electrostatic complexation of the expression plasmid with various ratios of the positively modified Fc fragments of an antibody (hIgG1-Fc-Arg) having a targeting ability to FcRn receptor. The shape and size of the complexes were examined by atomic force and field emission electron microscope. The stability of the complexes was tested in simulated gastrointestinal pH and physiological serum condition. Cellular uptake, transport, and toxicity of the complexes were tested in the Caco-2 cells. Biodistribution and antidiabetic effect of the complexes were observed in either Balb/c mice or Lepdb/db mice. RESULTS: A 50/1 ratio of the hIgG1-Fc-Arg/pDNA produced a complex structure having approximately 40 ~ 60 nm size and also demonstrated protection of pDNA in the complex from the physiological pH and serum conditions. Cellular uptake and transport of the complex were demonstrated in Caco-2 cells having FcRn receptor expression and forming the monolayer-polarized structure. The cellular toxicity of both delivery vehicle and the complex revealed their minimal toxicity comparable with nontoxicity of a commercial transfection reagent. Biodistribution of the complex showed the detectable distribution of the complex in the most parts of gastrointestinal tract due to ubiquitous expression of the FcRn receptors. An in vivo type 2 diabetes treatment study of oral administration of hIgG1-Fc-9Arg/pGLP-1 complexes showed absorption and expression in GI tract of either Balb/c mice or Lepdb/db mice. CONCLUSION: In this study, we developed an oral GLP-1 gene delivery system on the platform of cationic hIgG1-Fc-9Arg. Prolonged t1/2, less immunoactivity, and better bioactivities of hIgG-Fc-9Arg/pGLP-1 complexes appeared to be a promising approach to achieve potent treatment of type 2 diabetes treatment.

Oral siRNA Delivery to Treat Colorectal Liver Metastases.

Convenient multiple dosing makes oral administration an ideal route for delivery of therapeutic siRNA. However, hostile GI environments and nonspecific biological trafficking prevent achieving appropriate bioavailability of siRNA. Here, an orally administered AuNP-siRNA-glycol chitosan-taurocholic acid nanoparticle (AR-GT NPs) was developed to selectively deliver Akt2 siRNA and treat colorectal liver metastases (CLM). AR-GT NPs are dual padlocked nonviral vectors in which the initially formed AuNP-siRNA (AR) conjugates are further encompassed by bifunctional glycol chitosan-taurocholic acid (GT) conjugates. Covering the surface of AR with GT protected the Akt2 siRNA from GI degradation, facilitated active transport through enterocytes, and enhanced selective accumulation in CLM. Our studies in CLM animal models resulted in the reduction in Akt2 production, followed by initiation of apoptosis in cancer cells after oral administration of Akt2 siRNA-loaded AR-GT. This therapeutic siRNA delivery system may be a promising approach in treating liver-associated diseases.

Oral delivery of a therapeutic gene encoding glucagon-like peptide 1 to treat high fat diet-induced diabetes.

The number of people suffering from insulin-independent type 2 diabetes mellitus (T2DM) is ever increasing on a yearly basis. Current anti-diabetic medications often result in adverse weight gain and hypoglycemic episodes. Hypoglycemia can be avoided with glucagon-like peptide (GLP)-1 receptor agonists, which are expensive and require daily injections that may result immune activation. This study demonstrates the use of non-viral vector based oral delivery of GLP-1 gene through enterohepatic recycling pathways of bile acids. Oral administration of the plasmid DNA (pDNA) encoding GLP-1 decreased diabetic glucose levels to the normoglycemic range with significant weight reduction in a high-fat diet (HFD) induced diabetic mouse model and a genetically engineered T2DM rat model. This novel oral GLP1 delivery system is an attractive alternative to treat late-stage T2DM conditions that require repeated insulin injection and can potentially minimize the occurrence of hypoglycemic anomalies.

Ternary graphene quantum dot-polydopamine-Mn3O4 nanoparticles for optical imaging guided photodynamic therapy and T1-weighted magnetic resonance imaging.

Imaging-guided therapy, which bridges treatment and diagnosis, plays an important role in overcoming the limitations of classical cancer therapy. To provide a more exact location of the tumor and to reduce side effects to normal tissues, a multifunctional probe was designed to serve as both an imaging agent and a therapeutic agent. Ternary hybrid nanoparticles comprised of visible red-responsive graphene, the T1-weighted magnetic resonance imaging (MRI) agent Mn3O4 and a mussel-inspired linker polydopamine. The conjugation of graphene to Mn3O4 through polydopamine enhanced the water solubility of Mn3O4, enabling an efficient uptake by cancer cells as well as tumor accumulation when the nanoparticles were intravenously administered into mice. These nanoparticles, when localized at a tumor site, exhibited low cytotoxicity in the dark, while light irradiation of the cancer cells transfected with the nanoparticles resulted in significant phototherapeutic effects, apparently by generating toxic reactive oxygen species. These nanoparticles also allowed excellent T1-weighted MR imaging in a human lung cancer xenograft model and were successfully used for combined visible red-imaging-guided photodynamic therapy and T1-weighted MRI.