O-carboxymethyl Chitosan Nanoparticles Research Articles

Gold nanorod-chitosan based nanocomposites for photothermal and chemoembolization therapy of breast cancer

Gold nanorods (AuNR) have received significant attention in tumor thermo-chemotherapy. However, insufficient thermal availability limits the in vivo highly efficient applications of AuNR in photothermal therapy. In this study, we have fabricated N-isopropylacrylamide grafted O-carboxymethyl chitosan nanoparticles (NCMC NPs) with thermo-responsive properties for co-encapsulating AuNR and doxorubicin (DOX), forming AuNR@NCMC/DOX nanocomposites (NCs). As a result of the thermo- and photothermal-responsiveness, AuNR@NCMC/DOX NCs exhibited irreversible aggregation at high temperature and under near-infrared (NIR) irradiation with an increase of size to 3 μm. When AuNR@NCMC/DOX NCs reached tumor sites following intravenous administration, they were located in the tumor vessels under NIR irradiation due to an embolization effect. This response enhanced tumor targeting, on-demand release, and the thermal performance of AuNR@NCMC/DOX NCs. We have observed higher tumor accumulation of DOX and AuNR with subsequent stronger inhibition of tumor growth than that achieved without NIR irradiation. The development of AuNR-based NCs with multiple smart responsivenesses at tumors can provide a promising paradigm for solid tumor treatment via the cooperative effects of photothermal therapy and chemoembolization.

Nano-pesticide carrier O-Carboxymethyl chitosan is indigestible in Apis cerana cerana and affects intestinal flora

O-Carboxymethyl chitosan nanoparticles (O-CMC-NPs), which are organic pesticide carriers, have excellent application potential. Exploring the effects of O-CMC-NPs on non-target organisms, such as Apis cerana cerana, is critical for their effective application; however, such studies are limited. This study investigated the stress response of A. cerana Fabricius after O-CMC-NPs ingestion. The administration of high O-CMC-NP concentrations enhanced the activities of antioxidant and detoxifying enzymes in A. cerana, with the activity of glutathione-S-transferase increasing by 54.43 %–64.33 % after one day. The transit of O-CMC-NPs into the A. cerana midgut resulted in their deposition and adherence to the intestinal wall, as they cluster and precipitate in acidic conditions. The population of Gillianella bacteria in the middle intestine was remarkably reduced after 6 d of administration of high O-CMC-NP concentrations. Contrastingly, the abundance of Bifidobacteria and Lactobacillus in the rectum significantly increased. These results indicate that the intake of high concentrations of O-CMC-NPs causes a stress response in A. cerana and affects the relative abundance of crucial intestinal flora, which may pose a potential risk to the colony. This implies that even nanomaterials with favorable biocompatibility should be applied reasonably within a specific range to avoid adverse effects on the environment and non-target organisms in the context of large-scale research and promotion of nanomaterials.

Chitosan derivative composite nanoparticles as adjuvants enhance the cellular immune response via activation of the cGAS-STING pathway

Chitosan and its derivatives are widely used in vaccine adjuvants and delivery systems. Vaccine antigens encapsulated in or conjugated onto N-2-hydroxypropyl trimethyl ammonium chloride chitosan/N,O-carboxymethyl chitosan nanoparticles (N-2-HACC/CMCS NPs) induce strong cellular, humoral, and mucosal immune responses, but the mechanism of action is not fully understood. Therefore, the purpose of this study was to explore the molecular mechanism of composite NPs by upregulating the cGAS-STING signalling pathway to enhance the cellular immune response. We showed that the N-2-HACC/CMCS NPs could be taken up by RAW264.7 cells and produced high levels of IL-6, IL-12p40, and TNF-α. The N-2-HACC/CMCS NPs activated BMDCs, promoted Th1 responses, and enhanced the expression of cGAS, TBK1, IRF3, and STING, as further demonstrated by qRT–PCR and western blotting. Moreover, the NP-induced expression of I-IFNs, IL-1β, IL-6, IL-10 and TNF-α in macrophages was closely related to cGAS-STING. These findings provide a reference for chitosan derivative nanomaterials as vaccine adjuvants and delivery systems and demonstrate that N-2-HACC/CMCS NPs can engage the STING-cGAS pathway to trigger the innate immune response.

Design, optimization, and in-vivo performance of glipizide-loaded O-carboxymethyl chitosan nanoparticles in insulin resistant/type 2 diabetic rat model

Developing an oral nano-based delivery system for diabetes combines the desirable patient compliance of oral delivery with the tunable physicochemical features of nano-systems. Glipizide (GPZ) is a second-generation sulfonylurea drug used for treating type-2 diabetes (T2D). GPZ suffers from poor solubility and a short half-life (2–4 h). GPZ was loaded into O-Carboxymethyl chitosan (O-CMC) nanoparticles (NPs) to obtain a prolonged antidiabetic effect and monitor their effects on different T2D-related biomarkers. Optimized GPZ-O-CMC-NPs showed a particle size of 216 ± 2.5 nm, a zeta potential of −14.2 ± 2.1 mV, and an entrapment efficiency of 80.7 ± 0.8%. Fourier transform-infrared (FTIR) spectroscopy, Differential scanning calorimetry (DSC), and Transmission electron microscopy (TEM) were performed. GPZ-O-CMC-NPs had a superior and prolonged release profile than that of marketed and pure GPZ. Treatment with GPZ-O-CMC-NPs had a more significant impact (P < 0.05) on serum glucose, insulin, lipid profile (3–4 folds), oxidative stress markers (2–3 folds), and inflammatory cytokines (2.5–3.5 folds) than marketed or pure GPZ. These findings corroborate the potential benefits of GPZ-O-CMC-NPs for treating T2D.

Enhanced Immune Responses to Mucosa by Functionalized Chitosan-Based Composite Nanoparticles as a Vaccine Adjuvant for Intranasal Delivery.

Nasal administration for vaccine delivery is a novel non-invasive vaccine administration approach that can induce local or systemic immune responses and overcome the disadvantages caused by traditional injectable administration. However, mucosal vaccine and adjuvant delivery systems with sustained-release ability and enhanced immune effects at mucosal sites have still been highly demanded. In this work, N-2-hydroxypropyl trimethyl ammonium chloride chitosan/N,O-carboxymethyl chitosan nanoparticles (N-2-HACC/CMCS NPs) with excellent mucosal absorption, high drug loading capacity, and enhanced immune responses were prepared by the ionic cross-linking method. To evaluate the potential capacity of the N-2-HACC/CMCS NPs as a vaccine adjuvant and the molecular mechanism for the induction of enhanced mucosal and systemic immune responses, bovine serum albumin (BSA) was employed as a general model antigen and loaded into the N-2-HACC/CMCS NPs to prepare a BSA-loaded N-2-HACC/CMCS adjuvant vaccine (N-2-HACC/CMCS/BSA NPs). It was well demonstrated that the N-2-HACC/CMCS/BSA NPs with great biostability and mucosal absorption could effectively promote the proliferation of lymphocytes and the secretion of related pro-inflammatory factors, resulting in the stimulation of specific mucosal and systemic immune responses. This study revealed that the chitosan-based nano-delivery system can act as the mucosal vaccine adjuvant and possesses great promise in viral infectious diseases and immunization therapy.

Immune enhancement of N-2-Hydroxypropyl trimethyl ammonium chloride chitosan/carboxymethyl chitosan nanoparticles vaccine

The immunogenicity and toxicity of N-2-Hydroxypropyl trimethyl ammonium chloride chitosan/N, O-carboxymethyl chitosan nanoparticles (N-2-HACC/CMCS NPs) as a universal vaccine adjuvant/delivery system remains unclear. The present study indicated that the positively charged N-2-HACC/CMCS NPs showed a regular spherical morphology, with a particle size of 219 ± 13.72 nm, zeta potential of 37.28 ± 4.58 mV, had hemocompatibility and biodegradation. Acute toxicity, repeated dose toxicity, abnormal toxicity, muscle stimulation, whole body allergic reaction evaluation in vitro, and cytotoxicity in vivo confirmed N-2-HACC/CMCS NPs is safe and non-toxic. N-2-HACC/OVA/CMCS NPs were prepared to evaluate the immunogenicity, which showed a particle size of 248.1 ± 15.53 nm, zeta potential of 17.24 ± 1.28 mV, encapsulation efficiency of 92.43 ± 0.96 %, and loading capacity of 42.97 ± 0.07 %. Oral or intramuscular route with the N-2-HACC/OVA/CMCS NPs in mice not only induced higher IgG, IgG1, IgG2a, and sIgA antibody titers, but also significantly produced higher levels of IL-6, IL-4, IFN-γ, and TNF-α, demonstrating that the N-2-HACC/OVA/CMCS NPs enhance humoral, cellular, and mucosal immune responses. Our results not only support the N-2-HACC/CMCS NPs to be a safe and potential universal nano adjuvant/delivery system in vaccine development, especially mucosal vaccines, but also rich the database knowledge of adjuvant/delivery systems, and provide new direction to introduce more licensed adjuvants.

Smart flame retardant coating containing carboxymethyl chitosan nanoparticles decorated graphene for obtaining multifunctional textiles

A revolutionary and straightforward technique with a dual functionality was manipulated for preparing graphene sheets (O-GRP) decorated with O-carboxymethyl chitosan nanoparticles (CMChNPs). Graphene was successfully exfoliated and decorated with CMChNPs through a simple ultrasonication tool. The developed graphene sheets were then utilized as the green binder for coating the surface of textile with the Ppy-Ag nanocomposite. A new vapor polymerization was used to synthesize the nanocomposite of polypyrrole-Ag on the graphene-modified fabric for acquiring ternary modified textiles (CT/O-GRP-Ppy-Ag). The structure and surface morphology of CMCh, O-GRP, and the various coated textiles have been carefully approved using various spectroscopic and microscopic analysis. The thermal stability, mechanical properties besides their electrical resistance, antimicrobial, and flame retardancy behaviors for the coated fabrics were investigated. The as-fabricated textile composites attained an inferior electrical resistance as 0.05 kΩ than that for the virgin textile (2770 kΩ) as an indication for the high conductive fabrics. The inhibition diameter zone for modified textiles was recorded as 24, and 28 mm for the E.coli, and S. aureus bacterial strains, respectively. Moreover, the rate of burning and LOI values for CT/O-GRP200-Ppy-Ag were significantly improved to 30.9 mm/min, and 22.8%, respectively compared to uncoated textile (149.3 mm/min, 17.8%), and the blank CT/O-GRP200 (79.2 mm/min, 19.9%) confirming the enhanced retardation against the fire growth.

Improved Neuroprotective Effects of Gallic Acid-Loaded Chitosan Nanoparticles Against Ischemic Stroke.

Ischemic stroke is a typical cerebrovascular illness with high morbidity and mortality worldwide. Nevertheless, strategies for the prevention and treatment of cerebral ischemia/reperfusion injury (CIRI) are limited. Gallic acid (GA) is a plant polyphenol that has been used against CIRI. However, the pharmacokinetic (PK) properties of GA, such as its low absorption, poor bioavailability, and quick elimination, have negative effects on its application. To strengthen its effectiveness, a delivery system of GA-loaded o-carboxymethyl chitosan nanoparticles (GA-NPs) was synthesized in our study. In PKs study, GA-NPs apparently increases the area under the curve of plasma concentration-time and prolonged half-life of GA. Then, we measured the in vitro and in vivo effects of the GA-NPs in the oxygen glucose deprivation model and the middle cerebral artery occlusion model. The results from our pharmacodynamic studies, including assessment of neurological deficit, cerebral infarction, levels of inflammation, and oxidative stress, showed that GA-NPs possess better neuroprotection compared with GA. In conclusion, GA-NPs may be used as an efficacious delivery vehicle for GA in the treatment of CIRI.

Delivery of pemetrexed by magnetic nanoparticles: design, characterization, in vitro and in vivo assessment

Drug-loaded magnetic nanoparticles have been developed because of the advantages of specific drug targeting in cancer treatment. Pemetrexed (PEM) is a multi-targeting antifolate agent that is effective for the treatment of many cancers, for example, non-small cell lung cancer. Here, PEM loaded magnetic O-carboxymethyl chitosan (O-CMC) nanoparticles were prepared to deliver PEM on tumor tissue with an external magnetic field. The modification of chitosan to O-CMC was confirmed by FTIR analysis. Nanoparticle synthesis was performed via ionic gelation method. The diameter of magnetic O-CMC nanoparticles (MCMC) was found to be 130.1 ± 22.96 nm. After PEM loading, diameter was found to be 123.9 ± 11.42 nm. The drug release of PEM loaded MCMC (PMCMC) was slower in physiological medium than in acidic medium. A549-luc-C8 and CRL5807 cell lines were used for MTT test which showed that IC50 values of nanoparticles were lower than PEM. The antitumor efficiency of PMCMC in xenograft tumor model was examined with in vivo imaging system (IVIS) and caliper and with hematological analyses. In vivo studies revealed that PMCMC had targeted antitumor activity in A549-luc-C8-tumor-bearing mice compared to PEM. As a result, it was suggested that PMCMC have great potential for the treatment of non-small cell lung cancer.

Apoptosis of A549 cells by small interfering RNA targeting survivin delivery using poly-β-amino ester/guanidinylated O-carboxymethyl chitosan nanoparticles

Gene-based therapeutics has emerged as a promising approach for human cancer therapy. Among a variety of non-viral vectors, polymer vectors are particularly attractive due to their safety and multivalent groups on their surface. This study focuses on guanidinylated O-carboxymethyl chitosan (GOCMCS) along with poly-β-amino ester(PBAE) for siRNA delivery. Binding efficiency of PBAE/siRNA/GOCMCS nanoparticles were characterized by gel electrophoresis. The siRNA-loaded nanoparticles were found to be stable in the presence of RNase A, serum and BALF respectively. Fine particle fraction (FPF) which was determined by a two-stage impinger (TSI) was 57.8% ± 2.6%. The particle size and zeta potential of the nanoparticles were 153.8 ± 12.54 nm and + 12.2 ± 4.94 mV. In vitro cell transfection studies were carried out with A549 cells. The cellular uptake was significantly increased. When the cells were incubated with siSurvivin-loaded nanoparticles, it could induce 26.83% ± 0.59% apoptosis of A549 cells and the gene silencing level of survivin expression in A549 cells were 30.93% ± 2.27%. The results suggested that PBAE/GOCMCS nanoparticle was a very promising gene delivery carrier.

LFC131 peptide-conjugated polymeric nanoparticles for the effective delivery of docetaxel in CXCR4 overexpressed lung cancer cells

CXCR4 is a chemokine receptor which is over expressed in multiple cancers including lung cancers. LFC131 peptide (d-Tyr-Arg-Arg-2-Nal-Gly), an inhibitor of CXCR4-ligand binding, is a low molecular weight CXCR4 antagonist. In this study, we developed novel LFC131 peptide surface conjugated O-carboxymethyl chitosan nanoparticles (O-CMC NP) to target CXCR4 over expressed A549 lung cancer cells. CXCR4-targeted drug delivery system was characterized for its binding, uptake, targeting specificity, and in vitro antitumour effect. Our main goal was to increase the intracellular concentration of docetaxel (DTX) in the cancer cells via a targeted approach. We have reported a nanosized particle with spherical shape and showed a high loading capacity. The CMC NP showed a controlled release pattern and presence of LFC131 did not influence the release of DTX. The fluorescence analysis showed an enhanced cell uptake for targeted NP via CXCR4-LFC131 biological interactions. The receptor-mediated cellular internalization was further confirmed confocal microscopy. The cytotoxicity assays showed enhanced cancer cell death by targeted NPs due to the selective delivery of DTX. Consistent with the cellular uptake analysis, targeted NPs induced a greater caspase-3 activity in A549 cancer cells. LFC/CMC NP exhibited a remarkable cell apoptosis by inducing apoptotic and necrotic cell death. Together, targeted LFC/CMC NP significantly enhanced cancer cell death than compared to non-targeted and free drugs. This kind of targeted nanoplatform which is based on polymeric nanocarriers could further facilitate a treatment protocol for CXCR4 overexpressing A549 lung cancer cells.

In vitro and in vivo biological evaluation of O-carboxymethyl chitosan encapsulated metformin nanoparticles for pancreatic cancer therapy.

In vitro anticancer effect and in vivo biodistribution and biocompatibility of metformin encapsulated O-Carboxymethyl chitosan nanoparticles were evaluated for its application as pancreatic cancer therapy. In vitro studies such as cell migration assay, clonogenic assay, cell cycle analysis and qRT-PCR analysis were done in pancreatic cancer cells (MiaPaCa-2) treated with O-CMC-metformin NPs for evaluating its anticancer potential. In vivo biodistribution studies were carried out by NIR imaging of O-CMC-metformin NPs after tagging it with ICG. In vivo biocompatibility of the NPs was assessed by histopathology analysisof organs from mice administered with the NPs. In vitro cell migration assay showed marginal effect of NPs on migration property of pancreatic cancer cells (MiaPaCa-2). In vitro clonogenic assay established that the O-CMC-metformin NPs reduced colony formation ability of the cancer cells. While cell cycle analysis showed that the O-CMC-metformin NPs had only minor effect on progression of cell cycle in the cancer cells. qRT-PCR analysis exhibited reduced mRNA expression of p21, vanin 1 and MMP9 in pancreatic cancer cells treated with the nanoparticles. In vivo NIR imaging study showed normal biodistribution pattern of the intravenously injected O-CMC-metformin NPs suggesting normal clearance rate of nanoparticles and no adverse toxicity to the organs. The biocompatible O-CMC-metformin NPs with anticancer potential and capability for normal biodistribution can be beneficial for the treatment of pancreatic cancer.

O-Carboxymethyl Chitosan Nanoparticles for Controlled Release of Non-Steroidal Anti-Inflammatory Drugs

O-Carboxymethyl Chitosan Nanoparticles for Controlled Release of Non-Steroidal Anti-Inflammatory Drugs

Amidase encapsulated O-carboxymethyl chitosan nanoparticles for vaccine delivery

This work reports the development of amidase encapsulated O-carboxymethyl chitosan nanoparticles (Ami-O-CMC NPs) of 300±50nm size by ionic cross-linking method. The prepared Ami-O-CMC NPs had an encapsulation efficiency of 55.39%. Haemolysis assay and cytotoxicity studies proved the hemocompatibility and cytocompatibility of the prepared NPs. The sustained release of Ami from the NPs is expected to prolong its immunogenicity and in turn lead to development of better protective immunity against Staphylococcus aureus infections.

Cetuximab conjugated O-carboxymethyl chitosan nanoparticles for targeting EGFR overexpressing cancer cells

Nanoparticle mediated delivery of antineoplastic agents, functionalized with monoclonal antibodies has achieved extraordinary potential in cancer therapy. The objective of this study was to develop a drug delivery system comprising O-carboxymethyl chitosan (O-CMC) nanoparticles, surface-conjugated with Cetuximab (Cet) for targeted delivery of paclitaxel (PTXL) to Epidermal Growth Factor Receptor (EGFR) over-expressing cancer cells. Nanoparticles around 180±35nm and negatively charged were prepared through simple ionic gelation technique. The alamar blue assay indicated that these targeted nanoparticles displayed a superior anticancer activity compared to non-targeted nanoparticles. The nanoformulation triggered enhanced cell death (confirmed by flow cytometry) due to its higher cellular uptake. The selective uptake of Cet-PTXL-O-CMC nanoparticles by EGFR +VE cancer cells (A549, A431 and SKBR3) compared to EGFR −VE MIAPaCa-2 cells confirms the active targeting and delivery of PTXL via the targeted nanomedicine. Cet-PTXL-O-CMC nanoparticles can be used a promising candidate for the targeted therapy of EGFR over expressing cancers.

Glycyrrhizin-modified O-carboxymethyl chitosan nanoparticles as drug vehicles targeting hepatocellular carcinoma

Here we describe the O-carboxymethyl chitosan nanoparticles (CMCNP) modified by glycyrrhizin (GL) with various substitution degrees as hepatocellular carcinoma (HCC)-targeted delivery vehicles, which could efficiently deliver paclitaxel (PTX) into HCC. The resultant CMCNP-GL exhibited spherical in shape and high stability in plasma with fixed negative charged (∼−30 mV) and a size range of 100–205 nm. PTX was loaded into CMCNP-GL with a maximal encapsulation efficiency of 83.7% and performed a biphasic release. CMCNP-GL promoted liver cancer SMMC-7721 cell internalization by approximate 10.0-fold as compared to unmodified CMCNP. Within 72 h, the IC50 of PTX/CMCNP-GL, PTX/CMCNP, and PTX injection was 2.7–3.2, 8.1, and 13.5 μg/mL, respectively. Biodistribution experiments revealed that PTX/CMCNP-GL exerted significantly superior targeting to tumor than PTX/CMCNP. The in vivo tumor inhibition ratio of PTX/CMCNP-GL was 87.5%, showing remarkably higher than that of PTX/CMCNP (64.0%) and PTX injection (34.5%). CMCNP-GL with different substitution degrees possessed similar targeting property and therapeutic efficacy. Furthermore, toxicity studies suggested that blank CMCNP-GL had no systemic or hepatic toxicity.

Efficacy of tetracycline encapsulated O-carboxymethyl chitosan nanoparticles against intracellular infections of Staphylococcus aureus

Intracellular bacterial infections are recurrent, persistent and are difficult to treat because of poor penetration and limited availability of antibiotics within macrophages and epithelial cells. We developed biocompatible, 200nm sized tetracycline encapsulated O-carboxymethyl chitosan nanoparticles (Tet-O-CMC Nps) via ionic gelation for its sustained delivery of Tet into cells. S. aureus binds and aggregates with Tet-O-CMC Nps increasing drug concentrations at the infection site. Tet-O-CMC Nps were sixfold more effective in killing intracellular S. aureus compared to Tet alone in HEK-293 and differentiated THP1 macrophage cells proving it to be an efficient nanomedicine to treat intracellular S. aureus infections.

O-Carboxymethyl chitosan nanoparticles for metformin delivery to pancreatic cancer cells

In this work we developed metformin loaded O-carboxymethyl chitosan (O-CMC) nanoparticles (NPs) by ionic-gelation method. The prepared NPs of 240 ± 50 nm size with spherical morphology exhibited a pH sensitive release of metformin in vitro. Cytotoxicity studies showed that the drug-incorporated NPs induced significant toxicity on pancreatic cancer cells (MiaPaCa-2) compared to normal cells (L929). Metformin loaded NPs exhibited nonspecific internalization by normal and pancreatic cancer cells; however metformin released from the NPs induced preferential toxicity on pancreatic cancer cells. Our preliminary studies suggested that such a novel approach could possibly overcome the current limitations of metformin in its clinical application against pancreatic cancer.

Preparation of Folate Conjugated O-Carboxymethyl Chitosan Nanoparticles

Anticancer drugs are always restricted as lacking of tumor cell-selective targeting. In this paper, to achieve double effects of targeting and decreasing the drug toxicity, the folate (FA) -O-carboxymethyl chitosan (O-CMC) and the methotrexate (MTX) encapsulated FA-O-CMC/CaCl2 nanoparticles were prepared. The numbers of FA conjugated to O-CMC, particle size, surface morphology, encapsulation efficiency and loading efficiency of the obtained nanoparticles were characterized. The results showed that the FA-O-CMC possessing targeting ability was achieved. MTX had been successfully loaded into the nanoparticles. The prepared nanoparticles were spherical in morphology with an average size of 322 nm

Synthesis, characterization, cytotoxicity and antibacterial studies of chitosan, O-carboxymethyl and N, O-carboxymethyl chitosan nanoparticles

Chitosan (CS) is a naturally occurring biopolymer. It has important biological properties such as biocompatibility, antifungal and antibacterial activity, wound healing ability, anticancerous property, anticholesteremic properties, and immunoenhancing effect. Recently, CS nanoparticles have been used for biomedical applications. However, due to the limited solubility of CS in water its water-soluble derivatives are preferred for the above said applications. In this work, the nanoparticles of CS and its water-soluble derivatives such as O-carboxymethyl chitosan ( O-CMC) and N,O-carboxymethyl chitosan ( N,O-CMC) was synthesized and characterized. In addition, cytotoxicity and antibacterial activity of the prepared nanoparticles was also evaluated for biomedical applications.