N-trimethyl Chitosan Research Articles

Core–shell upconversion nanoparticles with suitable surface modification to overcome endothelial barrier

Upconversion nanoparticles (UCNPs), capable of converting near-infrared (NIR) light into high-energy emission, hold significant promise for bioimaging applications. However, the presence of tissue barriers poses a challenge to the effective delivery of nanoparticles (NPs) to target organs. In this study, we demonstrate the core–shell UCNPs modified with cationic biopolymer, i.e., N, N-trimethyl chitosan (TMC), can overcome endothelial barriers. The core–shell UCNP is composed of NaGdF4: Yb3+,Tm3+ (16.7 ± 2.7 nm) as core materials and silica (SiO2) shell. The average particle size of UCNPs@SiO2 is estimated at 26.1 ± 3.7 nm. X-ray diffraction (XRD), transmission electron microscopy (TEM) and element mapping shows the formation of hexagonal crystal structure of β-NaGdF4 and elements doping. The surface of UCNPs@SiO2 has been modified with poly(ethylene glycol) (PEG) to enhance water dispersibility and colloidal stability, and further modified with TMC with the zeta potential increasing from -2.1 ± 0.96 mV to 26.9 ± 12.6 mV. No significant toxic effect is imposed to HUVECs when the cells are treated with core–shell UCNPs with surface modification up to 250 µg/mL. The transport ability of the core–shell UCNPs has been evaluated by using the in vitro endothelial barrier model. Transepithelial electrical resistance (TEER) and immunofluorescence staining of tight junction proteins have been employed to verify the integrity of the in vitro endothelial barrier model. The results indicate that the transport percentage of the UCNPs@SiO2 with PEG and TMC through the model is up to 4.56%, which is twice higher than that of the UCNPs@SiO2 with PEG but without TMC and six times that of the UCNPs@SiO2.

Fabrication of Bio-Based Composite Materials forAntimicrobial Cotton Fabric With Microbial Anti-Adhesive Activity.

The development of multifunctional cotton fabrics that are stain-resistant, antimicrobial, and easy to clean has sparked scientific interest as well as practical usefulness, owing to its medical and healthcare applications. The purpose of this study was to fabricate self-cleaning and antimicrobial cotton for final use by soaking the cotton fabric in nonfluorinated hybrid formulations based on quaternary chitosan-silane using the sol-gel process. The fluorine-free cotton fabric demonstrated high self-cleaning behavior and outstanding bacterial killing efficacy against E. coli and S. aureus bacteria, without altering the desired textile properties of cotton fabric. Remarkably, cotton textiles using the hybrid formulations HTACC-VTES (N-(2-hydroxy)propyl-3-trimethylammonium chitosan chloride-vinyltriethoxy silane) and TMCC-VTES (N, N, N-trimethyl chitosan chloride-vinyltriethoxy silane) demonstrated promising water contact angles of 147° and 142° respectively, indicating a move toward superhydrophobicity. In FTIR spectra, both treated cotton textiles had an absorption peak at 1208 cm-1 (SiOC bending), indicating a stronger interaction between silane binding agents and the cotton substrate. The treated cotton fabric with desirable features retains its stability and endurance after 12 cycles of washing for antibacterial tests and 15 cycles for wettability tests. The manufactured cotton fabric has several potential applications, such as in personal hygiene items and medical applications.

Colonic targeting insulin-loaded trimethyl chitosan nanoparticles coated pectin for oral delivery: In vitro and In vivo studies

Colon-targeted delivery offers several benefits for oral protein delivery, such as low proteolytic enzyme activity, a natural pH environment, and extended residence time, which improve the bioavailability of the encapsulated protein. Therefore, we hypothesize that developing a novel colonic nanocarrier system, featuring modified chitosan that is soluble at physiological pH and coated with a colon-degradable polymer, will provide an effective delivery system for oral insulin. This study aims to synthesize insulin-loaded pectin-trimethyl chitosan nanoparticles (Ins-P-TMC-NPs) as an oral insulin delivery system and to evaluate its efficacy both in vitro and in vivo. N-trimethyl chitosan (TMC), synthesized via a methylation method, was used to prepare insulin-TMC nanoparticles coated with pectin via the ionic gelation method. The nanoparticles were characterized for their physicochemical properties, cumulative release profile, and surface morphology. The in vitro biological cytotoxicity and cellular uptake of the nanoparticles were evaluated against HT-29 cells. The in vivo blood glucose-lowering effect and histological toxicity were assessed in diabetic male Sprague–Dawley rats. The results showed that Ins-P-TMC-NPs were spherical, with an average size of 379.40 ± 40.26 nm, a polydispersity index of 24.10 ± 1.03 %, a zeta potential of +17.20 ± 0.52 mV, and a loading efficiency of 83.21 ± 1.23 %. Compared to uncoated TMC nanoparticles, Ins-P-TMC-NPs reduced insulin loss in simulated gastrointestinal fluid by approximately 67.23 ± 0.97 % and provided controlled insulin release in simulated colonic fluid. In vitro bioactivity studies revealed that Ins-P-TMC-NPs were non-toxic, with cell viability of 91.12 ± 0.91 % after 24 h of treatment, and exhibited high cellular uptake in the HT-29 cell line with a fluorescence intensity of 37.80 ± 2.40 after 4 h of incubation. Furthermore, the in vivo study demonstrated a sustained reduction in blood glucose levels after oral administration of Ins-P-TMC-NPs, peaking after 8 h with a blood glucose reduction of 87 ± 1.03 %. Histological sections showed no signs of toxicity when compared to those of healthy rats. Overall, the developed colon-targeted oral insulin delivery system exhibits strong potential as a candidate for effective oral insulin administration.

Lysosomal Activation Mediated by Endocytosis in J774 Cell Culture Treated with N-Trimethyl Chitosan Nanoparticles.

Safety and effectiveness are the cornerstone objectives of nanomedicine in developing nanotherapies. It is crucial to understand the biological interactions between nanoparticles and immune cells. This study focuses on the manufacture by the microfluidic technique of N-trimethyl chitosan/protein nanocarriers and their interaction with J774 cells to elucidate the cellular processes involved in absorption and their impact on the immune system, mainly through endocytosis, activation of lysosomes and intracellular degradation. TEM of the manufactured nanoparticles showed spherical morphology with an average diameter ranging from 36 ± 16 nm to 179 ± 92 nm, depending on the concentration of the cargo protein (0, 12, 55 μg/mL). FTIR showed the crosslinking between N-trimethyl chitosan and the sodium tripolyphosphate and the α-helix binding loss of BSA. TGA revealed an increase in the thermal stability of N-trimethyl chitosan/protein nanoparticles compared with the powder. The encapsulation of the cargo protein used was demonstrated using XPS. Their potential to improve cell permeability and use as nanocarriers in future vaccine formulations was demonstrated. The toxicity of the nanoparticles in HaCaT and J774 cells was studied, as well as the importance of evaluating the differentiation status of J774 cells. Thus, possible endocytosis pathways and their impact on the immune response were discussed. This allowed us to conclude that N-trimethyl chitosan nanoparticles show potential as carriers for the immune system. Still, more studies are required to understand their effectiveness and possible use in therapies.

N-trimethyl chitosan and tripalmitin loaded solid lipid nanoparticles of tofacitinib citrate: Characterization and in-vivo anti-inflammatory assessment

N-trimethyl chitosan and tripalmitin loaded solid lipid nanoparticles of tofacitinib citrate: Characterization and in-vivo anti-inflammatory assessment

Induction of humoral and cell-mediated immunity in mice by chitosan-curdlan composite nanoparticles administered intranasally and subcutaneously

Infectious diseases seriously threaten human life. The need for novel delivery systems and adjuvants suitable to be used in clinic for antigens remains a challenge. Among various attempts that have been made to provide optimum immune responses for protein antigens with poor immunogenicity, polymeric nanoparticles offer great opportunities. In this study, carboxymethyl curdlan (CMC) as a polyanionic polymer and chitosan chloride (CC) and N-trimethyl chitosan (TMC) as polycationic polymers were synthesised in-house and composite nanoparticles (CC-CMC-BSA and TMC-CMC-BSA) loaded with bovine serum albumin (BSA) as a model antigen were prepared via polyelectrolyte complexation and reported here for the first time. Nanoparticles with an average size ranging from 153 nm to 615 nm, positive surface charge (from +24 mV to +55 mV) and encapsulation efficiency as high as 90% were obtained depending on the concentration of polymers in the formulation. The nanoparticles showed good physical stability for three months and low toxicity in Calu-3 and A549 cells. Furthermore, SDS integrity of antigen was maintained. In vivo studies in mice indicated that nasal and subcutaneous administration of composite nanoparticles could provide long-term humoral and cellular immunity as determined by serum antibody titres (IgG, IgG1, IgG2a) and cytokine (IL-2, IL-4, IL-6, IL-10 and IFN-γ) levels. Elevated sIgA levels after nasal administration of the nanoparticles showed that mucosal immunity was successfully stimulated. These findings suggest that chitosan-curdlan composite nanoparticles show optimum properties to be used as nanovaccine for nasal immunisation of protein antigens.

Chitosan, Chitosan/IgG-Loaded, and N-Trimethyl Chitosan Chloride Nanoparticles as Potential Adjuvant and Carrier-Delivery Systems.

This work proposes a feasible, reproducible, and low-cost modified method to manufacture chitosan, chitosan/IgG-protein-loaded, and trimethylated chitosan nanoparticles, using microfluidics combined with the microemulsion technique, which differs from the traditional batch process of chitosan-based nanoparticles. The synthesis process consists of generating microreactors of chitosan-based polymer in a poly-dimethylsiloxane ψ-shaped microfluidic device and then crosslinking with sodium tripolyphosphate outside the cell. Transmission electron microscopy demonstrates an improvement in size control and distribution of the solid-shape chitosan nanoparticles (~80 nm) compared to the batch synthesis. Regarding chitosan/IgG-protein-loaded nanoparticles, these presented a core-shell morphology having a diameter of close to 15 nm. Raman and X-ray photoelectron spectroscopies confirmed the ionic crosslinking between the amino groups of chitosan and the phosphate groups of sodium tripolyphosphate in the fabricated samples and the total encapsulation of IgG protein during the fabrication of chitosan/IgG-loaded nanoparticles. Then, an ionic crosslinking and nucleation-diffusion process of chitosan-sodium tripolyphosphate was carried out during the nanoparticle formation, with and without IgG protein loading. The use of N-trimethyl chloride chitosan nanoparticles in vitro on human-keratinocyte-derived cell line HaCaT did not show side effects independently of its concentration from 1 to 10 μg/mL. Therefore, the proposed materials could be used as potential carrier-delivery systems.

N-Trimethylated chitosan coating white adipose tissue vascular-targeting oral nano-system for the enhanced anti-obesity effects of celastrol

Oral nanoparticles (NPs) are more suitable for obesity control compared to NPs administered intravenously, as their convenience increases patient compliance. Herein, we developed an oral nano-system to improve the anti-obesity efficacy of celastrol (Cel). The observed enhanced efficacy was mediated by zein core NPs decorated with adipose-homing peptides that were coated with N-trimethylated chitosan. The optimized Cel/AHP-NPs@TMC exhibited spherical morphology by TEM, as well as narrow size distribution (221.76 ± 6.73 nm) and adequate stability in a gastrointestinal environment. Based on the combined delivery advantages of AHP-NPs@TMC – i.e., improved cellular internalization within Caco-2 cells and enhanced white adipose tissue (WAT) vascular targeting – Cel/AHP-NPs@TMC significantly reduced the body weight, blood lipid levels, adipose inflammation, and WAT distribution in diet-induced obese mice without side-effects. In short, this study provides clear evidence that TMC-based oral NPs can effectively improve celastrol for obesity treatment.

A bivalent form of nanoparticle-based dengue vaccine stimulated responses that potently eliminate both DENV-2 particles and DENV-2-infected cells.

Dengue is the most prevalent mosquito-borne viral disease and continues to be a global public health concern. Although a licensed dengue vaccine is available, its efficacy and safety profile are not satisfactory. Hence, there remains a need for a safe and effective dengue vaccine. We are currently developing a bivalent dengue vaccine candidate. This vaccine candidate is composed of a C-terminus truncated non-structural protein 1 (NS11-279) and envelope domain III (EDIII) of DENV-2 encapsidated in the nanocarriers, N, N, N-trimethyl chitosan nanoparticles (TMC NPs). The immunogenicity of this bivalent vaccine candidate was investigated in the present study using BALB/c mice. In this work, we demonstrate that NS1+EDIII TMC NP-immunized mice strongly elicited antigen-specific antibody responses (anti-NS1 and anti-EDIII IgG) and T-cell responses (NS1- and EDIII-specific-CD4+ and CD8+ T cells). Importantly, the antibody response induced by NS1+EDIII TMC NPs provided antiviral activities against DENV-2, including serotype-specific neutralization and antibody-mediated complement-dependent cytotoxicity. Moreover, the significant upregulation of Th1- and Th2-associated cytokines, as well as the increased levels of antigen-specific IgG2a and IgG1, indicated a balanced Th1/Th2 response. Collectively, our findings suggest that NS1+EDIII TMC NPs induced protective responses that can not only neutralize infectious DENV-2 but also eliminate DENV-2-infected cells.

Synthesis of biodegradable antimicrobial pH-sensitive silver nanocomposites reliant on chitosan and carrageenan derivatives for 5-fluorouracil drug delivery toward HCT116 cancer cells

The current research relies on a one-pot green biosynthesis of silver nanoparticles (SNPs) with various ratios of silver (Ag) in the existence of N, N, N-trimethyl chitosan chloride (TMC) and carboxymethyl kappa-carrageenan (CMKC), to investigate the effectiveness of the synthesized silver nanocomposites (SNCs) as pH sensitive biodegradable carrier for orally intestinal delivery of 5-fluorouracil (5-FU) drug. FTIR, XRD, TEM and FE-SEM/EDX methods were utilized to demonstrate the structure of the prepared polyelectrolyte complex PEC (TMC/CMKC) and SNCs (TMC/CMKC/Ag). The results showed that the 5-FU encapsulation effectiveness inside all of the prepared SNCs samples was improved by increasing the concentration of Ag, reaching 92.16 ± 0.57 % with 3 % Ag. In vitro release behavior of 5-FU loaded SNC 3 % (TMC/CMKC/Ag 3 %), displayed slow and sustained release reaching 96.3 ± 0.81 % up to 24 h into pH 7.4 medium. The successful release of 5-FU from the loaded SNC 3 % was confirmed through occurrence of strong cytotoxicity, with an IC50 value of 31.15 μg/ml, and high % of apoptotic cells (30.66 %) within the treated HCT116 cells. Besides, SNC 3 % showed good biodegradability and antimicrobial properties against different bacterial strains. Overall, SNC 3 % can be suggested as an effective system for both controlled drug delivery and antibacterial action.

Antimicrobial Efficiency of Chitosan and Its Methylated Derivative against Lentilactobacillus parabuchneri Biofilms.

Antimicrobial materials are considered potential alternatives to prevent the development of biofilm-associated contaminations. Concerns regarding synthetic preservatives necessitate the development of innovative and safe natural antimicrobials. In the present study, we discuss the in situ infrared attenuated total reflection spectroscopy (IR-ATR) investigations of the selective antimicrobial efficiency of chitosan in controlling the growth of Lentilactobacillus parabuchneri biofilms. The protonated charges of chitosan were additionally amplified by structural modification via methylation, yielding quaternized derivative TMC (i.e., N, N, N-trimethyl chitosan). To evaluate antimicrobial effectiveness against L. parab. biofilms, IR-ATR spectroscopy provided information on molecular mechanisms and insights into chemical changes during real-time biofilm inhibition studies. The integrated fiberoptic oxygen microsensors enabled monitoring oxygen (O2) concentration gradients within biofilms, thereby confirming the metabolic oxygen depletion dropping from 4.5 to 0.7 mg L-1. IR studies revealed strong electrostatic interactions between chitosan/its water-soluble derivative and bacteria, indicating that a few hours were sufficient to affect biofilm disruption. The significant decrease in the IR bands is related to the characteristic spectral information of amide I, II, III, nucleic acid, and extracellular polymeric matrix (EPS) produced by L. parabuchneri biofilms. Cell clusters of biofilms, microcolonies, and destabilization of the EPS matrix after the addition of biopolymers were visualized using optical microscopy. In addition, scanning electron microscopy (SEM) of biofilms grown on polystyrene and stainless-steel surfaces was used to examine morphological changes, indicating the disintegration of the biofilm matrix into individual cells. Quantification of the total biofilm formation correlated with the CV assay results, indicating cell death and lysis. The electrostatic interactions between chitosan and the bacterial cell wall typically occur between protonated amino groups and negatively charged phospholipids, which promote permeabilization. Biofilm growth inhibition was assessed by a viability assay for a period of 72 h and in the range of low MIC values (varying 0.01-2%). These results support the potential of chitosan and TMC for bacterial growth prevention of the foodborne contaminant L. parabuchneri in the dairy industry and for further implementation in food packaging.

Nasal Administration of M2e/CpG-ODN Encapsulated in N-Trimethyl Chitosan (TMC) Significantly Increases Specific Immune Responses in a Mouse Model.

The nasal passage is the primary entry point for many infectious agents. Therefore, nasal vaccines that can overcome the limitations associated with antigen uptake are likely to play an important role in protecting these infectious agents. Thus, adjuvants and antigen-carrying systems that can induce a suitable mucosal and systemic immune response against their accompanying antigens are highly important. In this study, synthetic oligodeoxynucleotides containing CpG motifs (CpG-ODN) accompanied by the recombinant ectodomain of influenza M2 protein were encapsulated in N-trimethyl chitosan (TMC) nanoparticles. After the preparation of TMC nanoparticles, the morphological characteristics and loading efficiency and in vitro antigen release, as well as their ability to induce efficient immune responses against M2e in intranasal inoculation in the mouse model, were studied. Based on the size and zeta potential of the nanoparticles prepared in this study, it was determined that they were all nanosized, and their positive zeta potential ranged from 25 to 28 mV, while their polydispersity index was between 0.1 to 0.2, indicating a narrow range of particle sizes. A significant increase in serum levels of the total M2e-specific IgG antibody and BALF anti-M2e IgA was observed in mice intranasally immunized with M2e/CpG-ODN/TMC as opposed to those that were intranasally immunized with M2e/TMC, M2e/CpG-ODN, free M2e, and CpG-ODN/TMC. There was also a significant change in the IgG2a/IgG1 ratio in favour of IgG2a seems that CpG-ODN is responsible for directing the immune system towards Th1. Our findings show that CpG-ODN can significantly enhance the mucosal and systemic humoral immune response against M2e when encapsulated in a suitable carrier such as TMC for intranasal administration. In conclusion, when combined with a suitable carrier, CpG-ODN can be considered an effective adjuvant for mucosal administration.

Effects of Charged Polyelectrolytes on Amyloid Fibril Formation of a Tau Fragment.

The microtubule-associated protein tau is involved in more than 20 different neurological disorders characterized by aberrant intracellular aggregation of tau in the brain. Here, we investigated the aggregation of a novel 20-residue model peptide, tau298-317, which is derived from the key microtubule binding domain of the full sequence tau. Our results show that tau298-317 highly mimics the physical and aggregation properties of tau. Under normal physiological conditions, the peptide maintains a disordered random coil without aggregation. The presence of polyanionic heparin (Hep) significantly promotes the aggregation of this peptide to form amyloid fibrils. The Hep-induced aggregation is sensitive to the ionic strength of the solution and the introduction of the negatively charged phosphate group on a serine (Ser305) residue in the sequence, suggesting an important role of electrostatic interactions in the mechanism of Hep-mediated aggregation. In addition, two positively charged polysaccharides, chitosan (CHT) and its quaternary derivative N-trimethyl chitosan (TMC), were found to effectively inhibit Hep-induced aggregation of tau298-317 in a concentration-dependent manner. Attractive electrostatic interactions between the positively charged moieties in CHT/TMC and the negatively charged residues of Hep play a critical role in inhibiting Hep-peptide interactions and suppressing peptide aggregation. Our results suggest that positively charged polyelectrolytes with optimized charged groups and charge distribution patterns can serve as effective molecular candidates to block tau-Hep interactions and prevent aggregation of tau induced by Hep and other polyanions.

Mice immunized with trimethyl chitosan nanoparticles containing DENV-2 envelope domain III elicit neutralizing antibodies with undetectable antibody-dependent enhancement activity.

Dengue is a disease that poses a significant global public health concern. Although a tetravalent live-attenuated dengue vaccine has been licensed, its efficacy is still debated due to evidence of vaccine breakthrough infection. To avoid this issue, dengue vaccines should stimulate a high degree of serotype-specific response. Thus, envelope domain III (EDIII), which contains serotype-specific neutralizing epitopes, is an attractive target for dengue vaccine development. In this study, we investigated how EDIII encapsidated in N, N, N-trimethyl chitosan chloride nanoparticles (TMC NPs) stimulates a serotype-specific response and whether this response exerts a potential in vitro breakthrough infection. The immune response to DENV-2 elicited by EDIII TMC NP-immunized mice was monitored. We demonstrated that immunization with EDIII TMC NPs resulted in a high level of anti-EDIII antibody production. These antibodies included IgG, IgG1, and IgG2a subtypes. Importantly, antibodies from the immunized mice exerted efficient neutralizing activity with undetectable antibody dependent enhancement (ADE) activity. We also found that EDIII TMC NPs activated functional EDIII-specific CD4+ and CD8+ T cell responses. In conclusion, EDIII TMC NPs stimulated humoral immunity with a strong neutralizing antibody response, as well as a cellular immune response against DENV-2.

N-trimethyl chitosan coated targeting nanoparticles improve the oral bioavailability and antioxidant activity of vitexin

Vitexin is a flavonoid which exerted many protective activities. However, the low bioavailability discounts the in vivo effects of vitexin. This study designed vitexin loaded bilayer nanoparticles by the assembly of soybean peptides and the coating of goblet cell targeting peptide CSKSSDYQC (CSK) coupled N-trimethyl chitosan (TMC), to improve the bioavailability of vitexin. The results showed that the bilayer nanoparticles could protect vitexin from being released in stomach and promote sustained release in intestine. Ex vivo experiments confirmed that nanoparticles promoted absorption of vitexin through tight junctions. Further in vivo studies suggested that the embedding of vitexin by nanoparticles increased the bioavailability and antioxidant activity of vitexin. Our results indicated that the nanoparticles could not only promote the absorption of vitexin, but also improve its in vivo antioxidant activity. Therefore, the reported nanoparticles could be effective delivery platforms to improve the bioavailability of vitexin.

Effects of N-trimethyl chitosan-recombinant tissue factor pathway inhibitor complex on avulsion flap with roll compaction in rat

Effects of N-trimethyl chitosan-recombinant tissue factor pathway inhibitor complex on avulsion flap with roll compaction in rat

N-trimethyl chitosan coated nano-complexes enhance the oral bioavailability and chemotherapeutic effects of gemcitabine

N-trimethyl chitosan (TMC) is a multifunctional polymer that can be used in various nanoparticle forms in the pharmaceutical, nutraceutical and biomedical fields. In this study, TMC was used as a mucoadhesive adjuvant to enhance the oral bioavailability and hence antitumour effects of gemcitabine formulated into nanocomplexes composed of poly(lactic-co-glycolic acid) nanoparticles (PLGA NPs) conjugated with d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS). A central composite design was applied to achieve the optimal formulation. Cellular uptake and drug transportation studies revealed the nanocomplexes permeate over the intestinal cells via adsorptive-mediated and caveolae-mediated endocytosis. Pharmacokinetic studies demonstrated the oral drug bioavailability of the nanocomplexes was increased 5.1-fold compared with drug solution. In pharmacodynamic studies, the formulation reduced tumour size 3.1-fold compared with the drug solution. The data demonstrates that TMC modified nanocomplexes can enhance gemcitabine oral bioavailability and promote the anticancer efficacy.

Nanoparticle-mediated intravesical delivery of conditioned medium derived from mesenchymal stem cells for interstitial cystitis/bladder pain syndrome treatment

Interstitial cystitis/bladder pain syndrome (IC/BPS) is a critical disease characterized by debilitating pelvic pain associated with lower urinary tract symptoms. Effective therapeutic strategies remain challenging due to their elusive pathogenesis. Mesenchymal stem cell (MSC) therapy offers a promising therapeutic approach for IC/BPS treatment. Yet, the ethical arguments and tumorigenic risks from cell therapy by stem cells restrict the clinical application. Herein, we developed a nanoparticle that encapsulates the conditioned medium (CM) from stem cells and coated with cationic N-trimethyl chitosan chloride (TMC) on the surface to improve the penetration of epithelial barrier in intravesical therapy for IC/BPS. The TMC coating enhanced the accumulation of CM-loaded nanoparticles in the urothelium and subsequently improved the therapeutic efficacy on the mechanical threshold and micturition function through facilitating the effect of anti-inflammation and BDNF/TrkB signaling, which provides a great potential application on the transmucosal delivery platform for intravesical therapy of IC/BPS.

Enhanced antitumor efficacy of glutathione-responsive chitosan based nanoparticles through co-delivery of chemotherapeutics, genes, and immune agents

To achieve the co-delivery of chemotherapeutic drugs, genes, and immune agents in a single nanoparticulate system, p-mercaptobenzoic acid-grafted N, N, N-trimethyl chitosan nanoparticles (MT NPs) were successfully synthesized. Paclitaxel (PTX) was encapsulated into the hydrophobic core of the MT NPs, and meanwhile, survivin shRNA-expressing plasmid (iSur-pDNA) and recombinant human interleukin-2 (rhIL-2) were loaded onto the hydrophilic shell of the MT NPs. Owing to the redox-sensitiveness of MT NPs, a rapid release of PTX was triggered by the high concentration of glutathione. The synergistic effects of PTX (1.5 mg/kg), iSur-pDNA (1.875 mg/kg), and rhIL-2 (6 × 105 IU/kg) at a low dose endowed the MT/PTX/pDNA/rhIL-2 NPs with enhanced antitumor efficacies and improved tumor-induced immunosuppression. These results demonstrated that the co-delivery of PTX, iSur-pDNA, and rhIL-2 by the amphiphilic chitosan based NPs with redox-sensitiveness could be a promising strategy in the treatment of tumors.

An orally available PD-1/PD-L1 blocking peptide OPBP-1-loaded trimethyl chitosan hydrogel for cancer immunotherapy

Blockade of the immune checkpoint PD-1/PD-L1 with monoclonal antibodies demonstrated unprecedented clinical efficacies in many cancers. But the orally available low molecular weight inhibitors remain infancy. Compared to small molecules, peptide exhibits better selectivity and fewer side effects, but poor half-life and a big challenge to be orally administrated. Here, we developed a proteolysis-resistant D peptide OPBP-1 (Oral PD-L1 Binding Peptide 1) which could selectively bind PD-L1, significantly block PD-1/PD-L1 interaction and enhance IFN-γ (interferon γ) secretion from CD8+ T cells in human PBMCs (Peripheral blood mononuclear cells). OPBP-1 could significantly inhibit tumor growth in murine colorectal CT26 and melanoma B16-OVA models at a relatively low dose of 0.5 mg/kg, with enhancing the infiltration and function of CD8+ T cells. More interestingly, oral delivery of OPBP-1 loaded TMC (N, N, N-trimethyl chitosan) hydrogel (OPBP-1@TMC) showed promising OPBP-1 oral bioavailability (52.8%) and prolonged half-life (14.55 h) in rats, and also significantly inhibited tumor growth in CT26 model. In conclusion, we discovered and optimized a PD-1/PD-L1 blocking peptide OPBP-1, and subsequently loaded into a TMC based hydrogel oral delivery system, in order to maximally elevate the oral bioavailability of the peptide drug and effectively inhibit tumor growth. These results opened up a new prospect for oral drug development in cancer immunotherapy.