Chitosan Conjugates Research Articles

Docetaxel-Loaded Chitosan-Cholesterol Conjugate-Based Self-Assembled Nanoparticles for Overcoming Multidrug Resistance in Cancer Cells.

Cholesteryl hemisuccinate (CHS)-conjugated chitosan (CS)-based self-assembled nanoparticles (NPs) were developed for enhancing the intracellular uptake of docetaxel in multidrug resistance (MDR)-acquired cancer cells. CHS-CS was successfully synthesized and self-aggregation, particle size, zeta potential, drug entrapment efficiency, and in vitro drug release of docetaxel-loaded CHS-CS NPs were tested. The optimized NPs had a mean hydrodynamic diameter of 303 nm, positive zeta potential of 21.3 mV, and spherical shape. The in vitro release of docetaxel from the optimized CHS-CS NPs in different pH medium (pH 6.0 and 7.4) revealed that the release was improved in a more acidic condition (pH 6.0), representing a tumor cell’s environment. The superior MDR-overcoming effect of docetaxel-loaded CHS-CS NPs, compared with docetaxel solution, was verified in anti-proliferation and cellular accumulation studies in MDR-acquired KBV20C cells. Thus, CHS-CS NPs could be potentially used for overcoming the MDR effect in anticancer drug delivery.

A Combinative Assembly Strategy Inspired Reversibly Borate-Bridged Polymeric Micelles for Lesion-Specific Rapid Release of Anti-Coccidial Drugs

HighlightsA combined assembly strategy from hydrophobicity-driving and reversible borate bridges is proposed for high drug-loading efficiency and superior stability.Intestinal environment-triggered drug delivery system represents an effective treatment for local infection due to the site-specific targeting and shuttling of drugs.The reduced dosage brought by the drug-loading micelles could solve the problem of drug residue in breeding industry.Stimuli-triggered drug delivery systems hold vast promise in local infection treatment for the site-specific targeting and shuttling of drugs. Herein, chitosan conjugates (SPCS) installed with sialic acid (SA) and phenylboronic acid (PBA) were synthesized, of which SA served as targeting ligand for coccidium and reversible-binding bridge for PBA. The enhanced drug-loading capacity of SPCS micelles was attributed to a combination assembly from hydrophobicity-driving and reversible borate bridges. The drug-loaded SPCS micelles shared superior biostability in upper gastrointestinal tract. After reaching the lesions, the borate bridges were snipped by carbohydrates under a higher pH followed by accelerated drug release, while SA exposure on micellar surface facilitated drug cellular internalization to eliminate parasites inside. The drug-micelles revealed an enhanced anti-coccidial capacity with a higher index of 185.72 compared with commercial preparation. The dual-responsive combination of physicochemical assembly could provide an efficient strategy for the exploitation of stable, safe and flexible anti-infectious drug delivery systems.

Molecular docking, synthesis, and characterization of chitosan‐graft‐2‐mercaptobenzoic acid derivative as potential drug carrier

AbstractChitosan is a hydrophilic polymer with prominent mucoadhesive properties. However, it forms weak hydrogen bonds with mucin thus limiting its mucoadhesion and exhibit reduced bioavailability due to its short retention time in the body. The aim of the present study was to synthesize and characterize novel thiolated chitosan with improved functional property. A unique approach of using molecular docking to select ligand to chemically modify chitosan has been employed in the present research. A set of ligands were screened virtually using docking analysis and 2‐mercapto benzoic acid showed the lowest glide score of −4.31 Kcal/Mol thus displayed better binding interaction with chitosan. Based on the docking results, the best‐fit ligand was selected for wet lab synthesis. 2‐Mercapto benzoic acid was covalently attached to chitosan via formation of an amide bond and the reaction was mediated by carbodiimide and N‐hydroxysuccinimide. The synthesized polymer was in turn evaluated for zeta potential, Fourier transformed infrared, differential scanning calorimetry, molecular weight that confirmed conjugation of chitosan with the thiol ligand. The prepared thiomer was further subjected to mucoadhesion studies and displayed better mucoadhesion properties as compared to unmodified chitosan. Thus, the potential of the novel thiomer can be further explored as an excipient for drug delivery system with an emphasis on mucoadhesion.

Extension of postharvest shelf life of strawberries (Fragaria ananassa) using a coating of chitosan-whey protein isolate conjugate.

Chitosan and whey protein isolate (WPI) conjugate films were prepared as a novel matrix for encapsulating and extending the postharvest shelf life of strawberries. Film forming solutions of chitosan, WPI, and chitosan-WPI conjugate were mixed with glycerol, casted for films at 60±2°C and assessed for their colour, water vapour and oxygen transfer rate, textural, functional groups and secondary structure, thermal, crystallinity, and antioxidant properties. Chitosan-WPI conjugate films were applied as an edible coating on strawberries, and studied for storage stability at 5°C and 20°C by assessing physical and biochemical parameters. A considerable reduction in colour indices, weight loss, pH and titratable acidity, reducing sugars, ascorbic acid, total phenolics, DPPH and ABTS assay was noted in the coated strawberries over the control at both the studied temperatures. The control strawberries had a shelf life of 5 and 3days, whereas coating enhanced the shelf life of strawberries to 8 and 5days when stored at 5°C and 20°C, respectively.

Chitosan derived glycolipid nanoparticles for magnetic resonance imaging guided photodynamic therapy of cancer

Currently, the development of polysaccharide, especially chitosan (CS), based drug delivery system to afford magnetic resonance imaging (MRI) guided theranostic cancer therapy remains largely unexplored. Herein, we successfully developed a CS derived polymer (Gd-CS-OA) through chemical conjugation of CS, octadecanoic acid (OA) and gadopentetic acid (GA). After self-assemble into glycolipid nanoparticles to loaded chlorin e6 (Ce6), the resulted Gd-CS-OA/Ce6 was able to realize MRI guided photodynamic therapy (PDT) of cancer. Our results revealed that Gd-CS-OA was able to increase the MRI sensitivity as compared to Gd-DTPA with decent residence time and preferable excretion behavior in vivo. Moreover, the Gd-CS-OA/Ce6 showed negligible hemolysis, satisfactory ROS generation and stability in physiological environments with preferable cellular uptake and enhanced in vitro cytotoxicity (through elevated ROS generation) on 4T1 cells. Most importantly, Gd-CS-OA/Ce6 demonstrated promising in vivo tumor targetability (enhanced penetration and retention effect) and powerful MRI guided tumor ablation through PDT on in situ 4T1 tumor model.

Fabrication of Bioinspired Gallic Acid-Grafted Chitosan/Polysulfone Composite Membranes for Dye Removal via Nanofiltration.

In this work, we have developed a novel and facile method to prepare gallic acid-grafted chitosan/polysulfone (PS) composite membranes for dye removal from aqueous solutions. First, the gallic acid was grafted onto the eco-friendly chitosan through a free-radical grafting copolymerization reaction. Second, the gallic acid-grafted chitosan conjugates were codeposited onto the top surface of PS substrates by electrostatic interactions in order to transform the ultrafiltration membrane to the thin and defect-free nanofiltration membrane. The morphology and chemical composition of the as-prepared composite membranes were fully characterized by various spectroscopy and microscopy techniques. Moreover, after the optimization of preparation parameters, the obtained membrane displayed a high rejection of 97.2% for Congo red with a high permeance of 14.0 L h–1 m–2 bar–1. Furthermore, the composite membranes also exhibited good rejections for other dyes with different molecular weights such as Evan blue (97.3%), Acid red 94 (97.6%), and Alcian blue 8GX (98%) on the basis of size exclusion, accompanied with good permeance of 12.9, 11.9, and 10.9 L h–1 m–2 bar–1, respectively, which shows potential for scale-up industrial applications.

Study of Copernicium Nanoparticles Delivery Process in Human Cancer Cells, Tissues and Tumors Under Gravitationally Accelerating Ions Through the Super Contorted 'Tubular' Polar Areas of Magnetic Fields

Cancer is a major cause of death with more than 10 million annual patients. It is possible that this number reaches 15 million patients per year by 2020. Though chemotherapy has largely been successful in controlling and treating cancer, live tissue damage, systemic toxicity and side effects in this method are among the issues that cannot be overlooked. In order to reduce the negative effects of anticancer drugs on normal tissues, we need to design Nano-sized carriers that can pass the safety barriers and body tissues and reach their target site. In this article, the size and zeta potential of Nano-carriers PLGA–Cs–Paclitaxel were evaluated. Chitosan connection in physical or conjugated forms may lead to a significant increase of polydispersity. According to the study carried out on the concentration of Chitosan and the type of absorption, it was concluded that nanoparticles size increases with higher concentrations of Chitosan. The zeta potential will increase, provided the conjugation of Chitosan is higher than physical adsorption.

Drug-Loaded Photosensitizer-Chitosan Nanoparticles for Combinatorial Chemo- and Photodynamic-Therapy of Cancer.

In this study we have developed biodegradable polymeric nanoparticles (NPs) containing the cytostatic drugs mertansine (MRT) or cabazitaxel (CBZ). The NPs are based on chitosan (CS) conjugate polymers synthesized with different amounts of the photosensitizer tetraphenylchlorin (TPC). These TPC–CS NPs have high loading capacity and strong drug retention due to π–π stacking interactions between the drugs and the aromatic photosensitizer groups of the polymers. CS polymers with 10% of the side chains containing TPC were found to be optimal in terms of drug loading capacity and NP stability. The TPC–CS NPs loaded with MRT or CBZ displayed higher cytotoxicity than the free form of these drugs in the breast cancer cell lines MDA-MB-231 and MDA-MB-468. Furthermore, light-induced photochemical activation of the NPs elicited a strong photodynamic therapy effect on these breast cancer cells. Biodistribution studies in mice showed that most of the TPC–CS NPs accumulated in liver and lungs, but they were also found to be localized in tumors derived from HCT-116 cells. These data suggest that the drug-loaded TPC–CS NPs have a potential in combinatory anticancer therapy and as contrast agents.

Fabrication of Carboxylmethyl Chitosan Nanocarrier via Self-Assembly for Efficient Delivery of Phenylethyl Resorcinol in B16 Cells.

Micro-molecular drugs have special advantages to cope with challenging diseases, however their structure, physical and chemical properties, stability, and pharmacodynamics have more requirements for the way they are delivered into the body. Carrier-based drug delivery systems can circumvent many limited factors of drug delivery and increase their bioavailability. In this context, stable drug nanocarriers of alkaline amino acids (arginine, Arg) modified conjugated linoleic acid-carboxymethyl chitosan (CLA-CMCS) conjugate were developed, which could generate supramolecular micelles to effectively encapsulate the tyrosinase inhibitor phenylethyl resorcinol (PR). The resulting CCA-NPs were spherical nanoparticles with a mean size around 175 nm. The 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) assay and cellular uptake investigation demonstrated that the CCA-NPs were non-cytotoxic and had excellent cell transport ability. In addition, these CCA-NPs were able to effectively deliver PR and inhibited melanin formation to reduce pigmentation by enhancing cellular uptake. In conclusion, our research indicated that nanocarriers based on self-assembly amphiphilic polymers constituted a promising and effective drug delivery system in hyperpigmentation targeting.

Antimicrobial Chitosan Conjugates: Current Synthetic Strategies and Potential Applications.

As a natural polysaccharide, chitosan possesses good biocompatibility, biodegradability and biosafety. Its hydroxyl and amino groups make it an ideal carrier material in the construction of polymer-drug conjugates. In recent years, various synthetic strategies have been used to couple chitosan with active substances to obtain conjugates with diverse structures and unique functions. In particular, chitosan conjugates with antimicrobial activity have shown great application prospects in the fields of medicine, food, and agriculture in recent years. Hence, we will place substantial emphasis on the synthetic approaches for preparing chitosan conjugates and their antimicrobial applications, which are not well summarized. Meanwhile, the challenges, limitations, and prospects of antimicrobial chitosan conjugates are described and discussed.

Multifunctional MIL-Cur@FC as a theranostic agent for magnetic resonance imaging and targeting drug delivery: in vitro and in vivo study

Owing to the importance of multifunctional theranostics as promising systems to overcome key problems of conventional cancer therapy, in this study a multifunctional metal–organic framework-based (MOF) theranostic system was prepared and applied as intelligent theranostic systems in cancer. Iron-based MOF, MIL-88B, in a multi-faceted shape was initially prepared. Curcumin (Cur) was then loaded into the pores of MIL and folic acid–chitosan conjugate (FC) was finally coated on the surface of the carrier to accomplish cancer-specific targeting properties. MTT assay revealed perfect cytocompatibility of the system and selective toxicity against cancerous cells. In vivo MRI images showed high tumour uptake for MIL-Cur@FC and high T1–T2 contrast effect. The growth inhibiting efficiencies of MIL-Cur@FC on M109 tumour bearing Balb/C mice without reducing their body weight showed maximum tumour eradication with no significant toxicities. Due to the outstanding features of the system achieved from in vitro and in vivo studies, we believe that this study will provide a novel approach for developing targeted theranostic agents in cancer diagnosis and treatment.

Antibiofilm efficacy of root-end filling materials against Enterococcus faecalis - An in vitro study

Aim of the Study: This study aims to evaluate the antibiofilm activity of root end materials against Enterococcus faecalis. Materials and Methods: Mineral trioxide aggregate (MTA), MTA plus and Biodentine were conjugated with chitosan gel and tested against the 3-day biofilm of E. faecalis. The incubated plates were stained using crystal violet stain and the optical density of adherent stained biofilm was read at 590 nm using ELISA auto reader. Results: There was a mean clinical reduction in the biofilms of the conjugates as compared to their individual counter parts. There was a statistically significant difference seen between the groups (MTA Plus – Chitosan Conjugate) and (MTA – Chitosan Conjugate) with P = 0.0495. Conclusion: The conjugates did perform better in inhibiting the biofilm activity of E. faecalis. Although all conjugates formed were not statistically significant.

L-Carnitine conjugated chitosan-stearic acid polymeric micelles for improving the oral bioavailability of paclitaxel

A delivery system based on l-carnitine (LC) conjugated chitosan (CS)-stearic acid polymeric micelles has been developed for improving the oral bioavailability of paclitaxel (PTX) through targeting intestinal organic cation/carnitine transporter 2 (OCTN2). Stearic acid grafted chitosan (CS-SA), as micelle skeleton material, was synthesized by 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC)-mediated coupling reaction. The PTX-loaded micelles were prepared by solvent evaporation-hydration method, and the ligand LC was conjugated onto the micelle surface by anchoring its derivative stearoyl group to the lipophilic core of micelle. The modified polymeric micelles showed regular spherical shapes with small particle size of 157.1 ± 5.2 nm and high drug loading capacity of 15.96 ± 0.20 wt%, and the micelle stability in water was supported by low critical micelle concentration of 14.31 ± 0.21 μg/ml. The drug-loaded micelles presented a slow and incomplete in vitro release, and the pharmacokinetic studies indicated the micelle carriers increased the relative bioavailability of PTX to 165.8% against the commercial formulation. The enhancement effect on intestinal absorption was also confirmed by the intracellular uptake of Caco-2 cells. The proposed micelle carrier system manifested a prospective tool for oral drug delivery.

Functionalized polyhedral oligosilsesquioxane (POSS) based composites for bone tissue engineering: synthesis, computational and biological studies.

Functionalized polyhedral oligosilsesquioxanes (POSS) containing an isoxazolidine nucleus have been synthesized by microwave assisted 1,3-dipolar cycloaddition of N-methyl-C-alkoxycarbonyl nitrone 1 with POSS containing olefin moieties. The results of cycloaddition processes were rationalized by computational studies at the DFT level. The covalent conjugation of chitosan with the cycloadduct 3a leads to composite material CS-POSS 7 which was gelified using genipin as cross linking agent. The suitability of the system for bone tissue engineering purposes was evaluated by in vitro drug release studies using ketoprofen as a model drug and cytotoxicity assays performed on human fetal osteoblastic cells. The preliminary biological tests showed the lack of cytotoxicity of the hybrid material and suggest its potential role in bone tissue engineering applications.

Mucoadhesive dexamethasone-glycol chitosan nanoparticles for ophthalmic drug delivery.

Self-assembly of drug-polysacrrides conjugates forming nanostructures provides a simple and promising strategy for the extension of precorneal retention and enhancement of corneal permeability. In the present study, a series of dexamethasone-glycol chitosan (Dex-GCS) conjugates were synthesized and thoroughly characterized by Fourier transform infrared spectroscopy (FTIR), X-ray powder diffraction (XRD) and ultraviolet-visible (UV-Vis) spectroscopy. The resulting Dex-GCS conjugates were able to self-assemble into nanoparticles spontaneously with particle sizes in the range of 277-289nm and a positive charge of approximately +15mV. Roughly spherical nanoparticles were observed by transmission electron microscopy (TEM). The in vitro mucoadhesive properties of Dex-GCS nanoparticles were evaluated by recording the variations in the zeta potential after incubation with different concentrations of mucin. In vitro release studies performed in phosphate-buffered saline (PBS, pH=7.4) indicated progressive Dex release up to 8h, followed by a plateau up to 48h. Dex-GCS nanoparticles caused slight cytotoxicity against L929, HCEC and RAW 264.7 cells after 24h of incubation and displayed a nearly identical anti-inflammatory efficacy to dexamethasone sodium phosphate (Dexp) in lipopolysaccharide (LPS)-activated RAW 264.7 macrophages. More importantly, the proposed Dex-GCS nanoparticles showed good ocular tolerance and provided a relatively longer precorneal duration compared with that of the aqueous solution formulation, which suggested that the self-assembled Dex-GCS nanoparticle might be a promising candidate for ophthalmic drug delivery.

Synergistic Chemical and Photodynamic Antimicrobial Therapy for Enhanced Wound Healing Mediated by Multifunctional Light-Responsive Nanoparticles

Recently, rapid acquisition of antibiotic resistance, increased prevalence of antibiotic-resistant bacterial infections, and slow healing of infected wound have led to vast difficulties in developing innovative antimicrobial agents to obliterate pathogenic bacteria and simultaneously accelerate wound healing. To effectively solve this problem, we designed light-responsive multifunctional nanoparticles with conjugation of quaternary ammonium chitosan and photosensitizer chlorin e6 (Ce6) to merge chemical and photodynamic therapy to efficient antibacteria. The Mg/(-)-epigallocatechin-3-gallate (EGCG) complex rapidly responded to light irradiation under 660 nm with release of magnesium ions, which effectively accelerated wound healing without toxicity to mammalian cells. Notably, positively charged nanoparticles could efficiently adhere to the bacterial surface, and reactive oxygen species (ROS) produced under laser irradiation destroyed the membrane structure of the bacteria, which is irreversible, ultimately leading to bacteria death. Thus, multifunctional nanoparticles with a combination of chemical and photodynamic antimicrobial therapy would offer guidance to rational predicted and designed new effective antimicrobial nanomaterials. Most importantly, it may represent a promising class of antimicrobial strategy for potential clinical translation.

Research on Polyethylene Glycol, Crosslinked Polyethylene Glycol & Polyethylene Glycol Chitosan Conjugate Coating for Biomedical Application

Polyethylene glycol used as coating materials because it resist to protein adsorption and bacterial adhesion. Polyethylene glycol and crosslinked polyethylene glycol & polyethylene glycol chitosan conjugate used for coating glass implants. Fourier transform infrared spectroscopy (FTIR) analysis showed proper crosslinking in crosslinked polyethylene glycol but in polyethylene glycol & chitosan conjugate no reaction takes place. Scanned Electron Microscope (SEM) used for study of surface morphology. Polyethylene glycol & chitosan conjugate have smoother surface than pure polyethylene glycol, polyethylene glycol chitosan conjugate. Differential scanning calorimetry (DSC) analysis used for glass transition temperature study. Crosslinked polyethylene glycol has good mechanical properties. Antimicrobial properties of polyethylene glycol chitosan conjugate are good in comparison to pure polyethylene glycol, crosslinked polyethylene glycol.

Ability of casein hydrolysate-carboxymethyl chitosan conjugates to stabilize a nanoemulsion: Improved freeze-thaw and pH stability

An oil-in-water (O/W) nanoemulsion stabilized by casein hydrolysates (CHs) and carboxymethyl chitosan (OCC) (CHs-OCC) conjugates was prepared and its stability characteristics were evaluated under environmental conditions. The conjugated reaction between CHs and OCC was easier with a maximum degree of glycosylation (DG) of 40.7% and a browning index (BI) of 1.47 were obtained on the 20th day. This result was confirmed by the bathochromic-shift (350–358 nm) of the conjugates determined by intrinsic tryptophan fluorescence spectroscopy and sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE). Transmission electron microscopy (TEM) revealed that the particles of the nanoemulsion prepared with CHs-OCC (0.5–3.0%, w/v) had a smaller size (227–833 nm) and a spherical structure. In addition, due to the strong steric effect provided by the conjugated polysaccharide chains, the CHs-OCC nanoemulsion exhibited the best stability characteristics; the droplet particle size increased from 227 nm (fresh, 2.5%, w/v) to 427 nm (pH 2.0–7.4 at room temperature, 12 h), 488 nm (63 °C/30 min), 389 nm (95 °C/10 min), 236 nm (0–200 mM NaCl), and 255 nm (1–15-d storage, 4 °C). In particular, the CHs-OCC considerably enhanced the freeze-thaw stability of the nanoemulsion: the particle size after 3 freeze-thaw cycles showed a narrow distribution and did not exhibit the bimodal (0.1–1 μm) appearance, compared with casein. CHs-OCC may be suitable as a natural emulsifier in O/W nanoemulsions.

Studies on anti-hepatocarcinoma effect, pharmacokinetics and tissue distribution of carboxymethyl chitosan based norcantharidin conjugates

Aiming to enhance therapeutic efficiency and reduce toxic effect of norcantharidin (NCTD), NCTD-conjugated carboxymethyl chitosan (CMCS) conjugates (CNC) were prepared and evaluated for the treatment of hepatocellular carcinoma. In vitro cellular assays revealed that CNC conjugates possessed potent inhibitory effects on the proliferation and migration of BEL-7402 cells. Besides, CNC could change nuclear morphology of tumor cells. In comparison with free NCTD at equivalent dose, CNC exerted enhanced therapeutic efficiency and diminished systemic toxicity in H22 tumor-bearing mice with a tumor inhibition rate of 56.20%. Further investigation about pharmacokinetics and tissue distribution by high performance liquid chromatography (HPLC) analysis indicated that CNC showed a longer retention time in blood circulation and reduced distribution in heart and kidney tissues, thereby exerting different antitumor efficacy and toxicity compared with free NCTD. Our results suggested that CNC conjugates based on CMCS as polymer carriers might be used as a potential clinical alternative for NCTD in tumor therapy.

PH-responsive stearic acid-O-carboxymethyl chitosan assemblies as carriers delivering small molecular drug for chemotherapy

Recently, chemotherapy is still widely exploited to treat the residual, infiltrative tumor cells after surgical resection. However, many anticancer drugs are limited in clinical application due to their poor water-solubility (hydrophibic) and stability, low bioavailability, and unfavorable pharmacokinetics. Herein, an amphiphilic stearic acid-O-carboxymethyl chitosan (SA-CMC) conjugate was synthesized by amide linkage of SA to the backbone of CMC polymer and then self-assembled into nanoparticles (SA-CMC NPs) with the hydrodynamic particle size of ~100 nm. Subsequently, Paclitaxel (PTX) as a potent and broad-spectrum anticancer drug was loaded into SA-CMC NPs by a probe sonication combined with dialysis method. Owing to the multi-hydrophobic inner cores, the prepared PTX-SA-CMC NPs showed a considerable drug-loading capacity of ~19 wt% and a biphasic release behavior with an accumulative release amount in the range of 70-90% within 72 h. PTX-SA-CMC NPs remarkably enhanced the accumulation at the tumor sites by passive targeting followed by cellular endocytosis. Upon the stimuli of acid, PTX-SA-CMC NPs showed exceptional instability by pH change, thereby triggering the rapid disassembly and accelerated drug release. Consequently, compared with Cremophor EL-based free PTX treatment, PTX-SA-CMC NPs under pH-stimuli accomplished highly efficient apoptosis in cancer cells and effectively suppression of tumors by chemotherapy. Overall, PTX-SA-CMC NPs integrating imaging capacity might be a simple yet feasible PTX nanosystem for tumor-targeted delivery and cancer therapy.