A Brief Review on Hydrophobic Modifications of Glycol Chitosan into Amphiphilic Nanoparticles for Enhanced Drug Delivery

Glycol chitosan (GC) is the chitosan derivative that is capable of forming amphiphilic nanoparticles upon structure modifications at the reactive functional amine group on the polymer sugar backbone. Owing to the hydrophilic feature of GC and hydrophobic moieties that can be added to the GC structure, modifiable nanosystems were constructed to entrap poorly soluble drugs, mostly chemotherapeutic agents and several anti-inflammatory, anaesthetic, immunosuppressant, and antifungal drugs for more efficient delivery of the payload to the target site and improving the intended therapeutic effects. This review highlights the various hydrophobic molecules used in the chemical modification of GC to create amphiphilic nanoparticles for hydrophobic drug delivery, along with the summary of their physicochemical criteria and successful therapeutic enhancement achieved with the application of the drug-loaded amphiphiles. The biodegradable, GC-based nanoparticles particularly having the inner hydrophobic core and outer hydrophilic shell are an efficient system for drug entrapment, protection and targeting to improve the bioavailability and safety of the drug, in particular for cancer treatment purposes. The significant drug delivery enhancements achieved by these various hydrophobically-modified GC nanoparticles may provide the insights for their further use in nanomedicine.

In Vitro Cellular Uptake and Transfection of Oligoarginine-Conjugated Glycol Chitosan/siRNA Nanoparticles

Chitosan and its derivatives have been extensively utilized in gene delivery applications because of their low toxicity and positively charged characteristics. However, their low solubility under physiological conditions often limits their application. Glycol chitosan (GC) is a derivative of chitosan that exhibits excellent solubility in physiological buffer solutions. However, it lacks the positive characteristics of a gene carrier. Thus, we hypothesized that the introduction of oligoarginine peptide to GC could improve the formation of complexes with siRNA, resulting in enhanced uptake by cells and increased transfection efficiency in vitro. A peptide with nine arginine residues and 10 glycine units (R9G10) was successfully conjugated to GC, which was confirmed by infrared spectroscopy, 1H NMR spectroscopy, and elemental analysis. The physicochemical characteristics of R9G10-GC/siRNA complexes were also investigated. The size and surface charge of the R9G10-GC/siRNA nanoparticles depended on the amount of R9G10 coupled to the GC. In addition, the R9G10-GC/siRNA nanoparticles showed improved uptake in HeLa cells and enhanced in vitro transfection efficiency while maintaining low cytotoxicity determined by the MTT assay. Oligoarginine-modified glycol chitosan may be useful as a potential gene carrier in many therapeutic applications.

Thiol-Responsive Gold Nanodot Swarm with Glycol Chitosan for Photothermal Cancer Therapy

Photothermal therapy (PTT) is one of the most promising cancer treatment methods because hyperthermal effects and immunogenic cell death via PTT are destructive to cancer. However, PTT requires photoabsorbers that absorb near-infrared (NIR) light with deeper penetration depth in the body and effectively convert light into heat. Gold nanoparticles have various unique properties which are suitable for photoabsorbers, e.g., controllable optical properties and easy surface modification. We developed gold nanodot swarms (AuNSw) by creating small gold nanoparticles (sGNPs) in the presence of hydrophobically-modified glycol chitosan. The sGNPs assembled with each other through their interaction with amine groups of glycol chitosan. AuNSw absorbed 808-nm laser and increased temperature to 55 °C. In contrast, AuNSw lost its particle structure upon exposure to thiolated molecules and did not convert NIR light into heat. In vitro studies demonstrated the photothermal effect and immunogenic cell death after PTT with AuNSW. After intratumoral injection of AuNSw with laser irradiation, tumor growth of xenograft mouse models was depressed. We found hyperthermal damage and immunogenic cell death in tumor tissues through histological and biochemical analyses. Thiol-responsive AuNSw showed feasibility for PTT, with advanced functionality in the tumor microenvironment.

IMINATION OF CHITOSAN NANOFIBERS IN A HETEROGENEOUS SYSTEM. SYNTHESIS OPTIMIZATION AND IMPACT ON FIBER MORPHOLOGY

The paper aimed to prepare imino-chitosan fibers by the imination reaction in a heterogenous system, targeting the improvement of anti-pathogenic activity. To this end, porous neat chitosan fibers were prepared by electrospinning of the polyethylene glycol/chitosan blend, followed by polyethylene glycol removal. Imination of the neat chitosan fibers was carried out in three liquid phase systems using solvents of different polarity and, consequently, different ability to swell the solid phase chitosan fibers. The successful imination was qualitatively and quantitatively assessed by FTIR and 1H-NMR spectroscopy, and the impact of the liquid phase on the fibers’ morphology was evaluated by SEM, POM and AFM microscopy. Further, the antimicrobial activity of the imino-chitosan fibers was investigated on relevant bacterial and fungal strains. It was concluded that the prior swelling in water of the fibers improved the imination degree, while the use of a less polar solvent, such as toluene, favored the preservation of the fibrous morphology. The imination with an antimicrobial aldehyde endowed the chitosan fibers with the ability to create a physical barrier against pathogens.

3D Printing of Polysaccharide-Based Self-Healing Hydrogel Reinforced with Alginate for Secondary Cross-Linking

Three-dimensional (3D) bioprinting has been attractive for tissue and organ regeneration with the possibility of constructing biologically functional structures useful in many biomedical applications. Autonomous healing of hydrogels composed of oxidized hyaluronate (OHA), glycol chitosan (GC), and adipic acid dihydrazide (ADH) was achieved after damage. Interestingly, the addition of alginate (ALG) to the OHA/GC/ADH self-healing hydrogels was useful for the dual cross-linking system, which enhanced the structural stability of the gels without the loss of their self-healing capability. Various characteristics of OHA/GC/ADH/ALG hydrogels, including viscoelastic properties, cytotoxicity, and 3D printability, were investigated. Additionally, potential applications of 3D bioprinting of OHA/GC/ADH/ALG hydrogels for cartilage regeneration were investigated in vitro. This hydrogel system may have potential for bioprinting of a custom-made scaffold in various tissue engineering applications.

A New Recombinant Fibronectin/Cadherin Protein-Hydrophobically Modified Glycol Chitosan/Paclitaxel Layer-By-Layer Self-Assembly Strategy for the Postoperative Therapy of Osteosarcoma and Correlated Bone Injury

Osteosarcoma is one of the most aggressive cancers which greatly threatens the health of adolescents and surgery is difficult to resect the whole piece of tumor tissue. The residual tumor cells might proliferate at the tumor site and invade into the blood circulation, leading to tumor recurrence and metastasis. Besides, the invasion of tumor cells could also lead to bone injury. We designed a recombinant fibronectin-cadherin fusion protein/hydrophobically modified glycol chitosan-PTX nanoparticles (rFN-CDH/HGC-PTX) layer-by-layer self-assembly polymer based on biphasic calcium phosphate ceramic (BCP) (BCP-PEI-(rFN/CDH-PTX/HGC)n-rFN/CDH). The SEM, FTIR, XPS and contact angle experiments proved the successful synthesis of the polymer. The chemotherapy drug PTX and bone-repairing-related rFN/CDH fusion protein could be stably released within one week and the in vitro experiments exhibited the efficacy of the polymer to kill residual tumor cells and promote the proliferation of osteoblast, confirming that our polymer was a superior material for postoperative osteosarcoma therapy.