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Utility of glycol-chitosan-coated gold nanoparticles (GC-AuNPs) as a photoacoustic contrast agent for cancer cell imaging was demonstrated. Through the synergistic effect of glycol chitosan and gold nanoparticles, GC-AuNPs showed cellular uptake in breast cancer cells and resulted in strong photoacoustic signals in tissue-mimicking cell phantoms. The performance of GC-AuNPs as contrast agents was established with photoacoustic imaging and confirmed with dark-field microscopy. The cell phantoms displayed strong photoacoustic signals if cells were incubated more than 3 h with GC-AuNPs, compared with PEG-AuNPs that showed no photoacoustic signal increase. The enhanced photoacoustic signals originated from the plasmon coupling effect of GC-AuNPs after the cellular uptake in cancer cells. Importantly, photoacoustic imaging of cancer cells was achieved with GC-AuNPs—contrast agents that did not require antibodies or complex surface modification. The endocytosis of GC-AuNPs was also confirmed with dark-field microscopy. The results show that GC-AuNPs have potential as a photoacoustic contrast agent for cellular imaging including tumor tissue imaging.

In this study, we prepared an injectable drug delivery depot system based on a visible light-cured glycol chitosan (GC) hydrogel containing paclitaxel (PTX)-complexed beta-cyclodextrin (β-CD) (GC/CD/PTX) for ovarian cancer (OC) therapy using a tumor-bearing mouse model. The hydrogel depot system had a 23.8 Pa of storage modulus at 100 rad/s after visible light irradiation for 10 s. In addition, GC was swollen as a function of time. However, GC had no degradation with the time change. Eventually, the swollen GC matrix affected the releases of PTX and CD/PTX. GC/PTX and GC/CD/PTX exhibited a controlled release of PTX for 7 days. In addition, GC/CD/PTX had a rapid PTX release for 7 days due to improved water solubility of PTX through CD/PTX complex. In vitro cell viability tests showed that GC/CD/PTX had a lower cell viability percentage than the free PTX solution and GC/PTX. Additionally, GC/CD/PTX resulted in a superior antitumor effect against OC. Consequently, we suggest that the GC/CD system might have clinical potential for OC therapy by improving the water solubility of PTX, as PTX is included into the cavity of β-CD.

ABSTRACT Purpose The application of gold nanoparticles (AuNPs) in biomedical field was limited due to the low stability in the biological condition. Herein, to enhance stability and tumor targeting ability of AuNPs, their surface was modified with biocompatible glycol chitosan (GC) and the in vivo biodistribution of GC coated AuNPs (GC-AuNPs) were studied through computed tomography (CT). Methods Polymer-coated gold nanoparticles were produced using GC as a reducing agent and a stabilizer. Their feasibility in biomedical application was explored through CT in tumor-bearing mice. Results Stability of gold nanoparticles increased in the physiological condition due to the GC coating layer on the surface. Tomographic images of tumor were successfully obtained in the tumor-xenografted animal model when the GC-AuNPs were used as a CT contrast agent. The tumor targeting property of the gold nanoparticles was due to the properties of GC because GC-AuNPs were accumulated in the tumor, while most of heparin-coated nanoparticles were found in the liver and spleen. Conclusions The polymer properties on the surface played an important role in the behavior of gold nanoparticles in the biological condition and the enhanced stability and tumor targeting property of nanoparticles were inherited from GC on the surface.

This study was aimed to develop doxorubicin-loaded quaternary ammonium palmitoyl glycol chitosan (DOX-GCPQ) nanoformulation that could enable DOX delivery and noninvasive monitoring of drug accumulation and biodistribution at tumor site utilizing self-florescent property of doxorubicin. DOX-GCPQ amphiphilic polymeric nanoformulations were prepared and optimized using artificial neural network (ANN) and characterized for surface morphology by atomic force microscopy, particle size with polydispersity index (PDI), and zeta potential by dynamic light scattering. Fourier transformed infrared (FTIR) and X-ray diffractometer studies were performed to examine drug polymer interaction. The ANN-optimized nanoformulation was investigated for in vitro release, cellular, tumor, and tissue uptake. The optimized DOX-GCPQ nanoformulation was anionic spherical micelles with the hydrodynamic particle size of 97.8±1.5 nm, the PDI of <0.3, the zeta potential of 28±2 mV, and the encapsulation efficiency of 80%±1.5%. Nanoformulation demonstrated a sustained release pattern over 48 h, assuming Weibull model. Fluorescence microscopy revealed higher uptake of DOX-GCPQ in human rhabdomyosarcoma (RD) cells as compared to free DOX. In vitro cytotoxicity assay indicated a significant cytotoxicity of DOX-GCPQ against RD cells as compared to DOX and blank GCPQ ( <0.05). DOX-GCPQ exhibited low IC (1.7±0.404 µmol) when compared to that of DOX (3.0±0.968 µmol). In skin tumor xenografts, optical imaging revealed significantly lower DOX-GCPQ in heart and liver ( <0.05) and accumulated mainly in tumor ( <0.05) as compared to other tissues. The features of nanoformulation, ie, small particle size, sustained drug release, and enhanced cellular uptake, potential to target tumor passively coupled with the possibility of monitoring of tumor localization by optical imaging may make DOX-GCPQ an efficient nanotheranostic system.

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.

Bone tissue engineering scaffolds offer the merits of minimal invasion as well as localized and controlled biomolecule release to targeted sites. In this study, we prepared injectable hydrogel systems based on visible light-cured glycol chitosan (GC) hydrogels containing bone morphogenetic protein-2 (BMP-2) and/or transforming growth factor-beta1 (TGF-β1) as scaffolds for bone formation in vitro and in vivo. The hydrogels were characterized by storage modulus, scanning electron microscopy (SEM) and swelling ratio analyses. The developed hydrogel systems showed controlled releases of growth factors in a sustained manner for 30 days. In vitro and in vivo studies revealed that growth factor-loaded GC hydrogels have no cytotoxicity against MC3T3-E1 osteoblast cell line, improved mRNA expressions of alkaline phosphatase (ALP), type I collagen (COL 1) and osteocalcin (OCN), and increased bone volume (BV) and bone mineral density (BMD) in tibia defect sites. Moreover, GC hydrogel containing BMP-2 (10 ng) and TGF-β1 (10 ng) (GC/BMP-2/TGF-β1-10 ng) showed greater bone formation abilities than that containing BMP-2 (5 ng) and TGF-β1 (5 ng) (GC/BMP-2/TGF-β1-5 ng) in vitro and in vivo. Consequently, the injectable GC/BMP-2/TGF-β1-10 ng hydrogel may have clinical potential for dental or orthopedic applications.

Gold nanoclusters (AuNCs) have emerged as promising agents for photothermal cancer therapy due to their unique optical properties and potential for tumour targeting. In this study, we developed clustered, excretable AuNCs using a glycol chitosan derivative (GCPQ) and investigated their physicochemical properties, photothermal effect, and therapeutic efficacy. The AuNCs exhibited tunable surface plasmon resonance peaks dependent on the polymer:AuNP ratio, with optimized clusters showing surface enhanced Raman scattering and photothermal heating. In vivo studies in a mouse tumour model demonstrated significant tumour growth inhibition (334% growth vs 607% growth for untreated animals after 6 days) when combining intratumoural AuNC injection with near-infrared laser irradiation. The results provide proof-of-concept for the potential of these AuNCs in photothermal cancer therapy. Future work should focus on improving tumour targeting, optimizing treatment parameters, and assessing long-term safety to advance this platform toward clinical translation.

Background Glycol chitosan nanoparticles (CNPs) have emerged as an effective drug delivery system for cancer diagnosis and treatment. Although they have great biocompatibility owing to biodegradable chemical structure and low immunogenicity, sufficient information on in vivo toxicity to understand the potential risks depending on the repeated high-dose have not been adequately studied. Herein, we report the results of in vivo toxicity evaluation for CNPs focused on the number and dose of administration in healthy mice to provide a toxicological guideline for a better clinical application of CNPs. Results The CNPs were prepared by conjugating hydrophilic glycol chitosan with hydrophobic 5β-cholanic acid and the amphiphilic glycol chitosan-5β-cholanic acid formed self-assembled nanoparticles with its concentration-dependent homogeneous size distributions (265.36–288.3 nm) in aqueous condition. In cell cultured system, they showed significantly high cellular uptake in breast cancer cells (4T1) and cardiomyocytes (H9C2) than in fibroblasts (L929) and macrophages (Raw264.7) in a dose- and time-dependent manners, resulting in severe necrotic cell death in H9C2 at a clinically relevant highly concentrated condition. In particular, when the high-dose (90 mg/kg) of CNPs were intravenously injected into the healthy mice, considerable amount was non-specifically accumulated in major organs (liver, lung, spleen, kidney and heart) after 6 h of injection and sustainably retained for 72 h. Finally, repeated high-dose of CNPs (90 mg/kg, three times) induced severe cardiotoxicity accompanying inflammatory responses, tissue damages, fibrotic changes and organ dysfunction. Conclusions This study demonstrates that repeated high-dose CNPs induce severe cardiotoxicity in vivo. Through the series of toxicological assessments in the healthy mice, this study provides a toxicological guideline that may expedite the application of CNPs in the clinical settings.

Abstract Photo-chemotherapy is a potent anticancer therapeutic approach. Herein, we designed a gold-capsulated lapatinib nanomedicine for breast cancer treatment. The biodegradable PLGA (poly (lactic-co-glycolic acid)) nanoparticles were surface coated with glycol chitosan followed by adsorption and reduction of gold seeds on the surface to form nanocapsule. These multifunctional nanomaterials exhibited significant absorbance (600–900 nm) in the near-infrared region and had a porous surface that facilitated controlled diffusion of the encapsulated anticancer drug, lapatinib. Further, the gold-coated PLGA lapatinib nanocapsule showed synergistic effect of combined chemo-photothermal therapy with > 80% cytotoxicity. Moreover, these nanomaterials were found to be non-hemolytic and biocompatible. The biodistribution of the nanocapsule in Balb/c mice revealed higher Au content in the liver followed by spleen with no significant change in body weight and abnormal clinical signs. Hence, gold-capsuled polymeric nanomedicine could be a promising therapeutic agent.

We used a hydrogel-mediated dual drug delivery approach, based on an injectable glycol chitosan (GC) hydrogel, doxorubicin hydrochloride (DOX⋅HCl), and a complex of beta-cyclodextrin (β-CD) and paclitaxel (PTX) (GDCP) for breast cancer therapy in vitro and in vivo. The hydrogel was swollen over 3 days and remained so thereafter. After an initial burst period of 7 hours, the two drugs were released in a sustained manner for 7 days. The in vitro cell viability test showed that GDCP had a better anticancer effect than well plate and DOX⋅HCl/PTX (DP). In addition, the in vivo tests, which evaluated the anticancer effect, systemic toxicity, and histology, proved the feasibility of GDCP as a clinical therapy for breast cancer.