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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., (© 2023. The Author(s).)

The objective of the present study is synthesis of glycol chitosan coated selenium nanoparticles (GC-Se NPs) and evaluation of oxidative stress and ginsenoside accumulation in P. ginseng C. A. Meyer. We synthesized (Se NPs and GC-Se NPs) and characterized using various spectroscopic analyses. The highest concentration (20 mg L -1 ) of GC-Se NPs induced moderate ROS (O 2 - and H 2 O 2 ) accumulation and upregulation of PgSOD and PgCAT showing good biocompatibility and less toxicity at the highest concentration. Furthermore, ginsenoside biosynthetic pathway genes (PgHMGR, PgSS, PgSE, PgDDS) also showed significant upregulation upon 20 mg L -1 GC-Se NPs treatment. At 20 mg L -1 GC-Se NPs treatment, ginsenoside accumulated upto 217.47 mg/mL and 169.86 mg/mL mainly due to the increased proportion of Rb1 and Re ginsenosides. Altogether, our results suggested that ecofriendly conjugation of GC with Se NPs could be used as a bio fortifier to enhance the ginsenoside profile and to increase the quality of ginseng roots., (Copyright © 2021. Published by Elsevier Ltd.)

Development of biopolymer-based imaging agents which can access rapidly and provide detailed information about the diseases has received much attention as an alternative to conventional imaging agents. However, development of biopolymer-based nanomaterials for tumor imaging still remains challenging due to their low sensitivity and image resolution. To surmount of these limitations, multimodal imaging agents have been developed, and they were widely utilized for theranostic applications. Herein, iodine containing echogenic glycol chitosan nanoparticles are developed for x-ray computed tomography (CT) and ultrasound (US) imaging of tumor diagnosis. X-ray CT/US dual-modal imaging probe was prepared by following below two steps. First, iodine-contained diatrizoic acid (DTA) was chemically conjugated to the glycol chitosan (GC) for the CT imaging. DTA conjugated GC (GC-DTA NPs) formed stable nanoparticles with an average diameter of 315 nm. Second, perfluoropentane (PFP), a US imaging agent, was physically encapsulated into GC-DTA NPs by O/W emulsion method yielding GC-DTA-PFP nanoparticles (GC-DTA-PFP NPs). The GC-DTA-PFP NPs formed nanoparticles in physiological condition, and they presented the strong x-ray CT, and US signals in phantom test in vitro. Importantly, GC-DTA-PFP NPs were effectively accumulated on the tumor site by enhanced permeation and retention (EPR) effects. Moreover, GC-DTA-PFP NPs showed x-ray CT, and US signals in tumor tissues after intratumoral and intravenous injection, respectively. Therefore, GC-DTA-PFP NPs indicated that x-ray CT/US dual-modal imaging using iodinated echogenic nanoparticles could be provided more comprehensive and accurate diagnostic information to diagnosis of tumor., Competing Interests: Competing Interests: The authors have declared that no competing interest exists.

Recent progress in nanomedicine has shown a strong possibility of targeted therapy for obstinate chronic lung diseases including idiopathic pulmonary fibrosis (IPF). IPF is a fatal lung disease characterized by persistent fibrotic fibroblasts in response to type I collagen-rich extracellular matrix. As a pathological microenvironment is important in understanding the biological behavior of nanoparticles, in vitro cellular uptake of glycol chitosan nanoparticles (CNPs) in human lung fibroblasts was comparatively studied in the presence or absence of type I collagen matrix. Primary human lung fibroblasts from non-IPF and IPF patients (n=6/group) showed significantly increased cellular uptake of CNPs (>33.6-78.1 times) when they were cultured on collagen matrix. To elucidate the underlying mechanism of enhanced cellular delivery of CNPs in lung fibroblasts on collagen, cells were pretreated with chlorpromazine, genistein, and amiloride to inhibit clathrin-mediated endocytosis, caveolae-mediated endocytosis, and macropinocytosis, respectively. Amiloride pretreatment remarkably reduced the cellular uptake of CNPs, suggesting that lung fibroblasts mainly utilize the macropinocytosis-dependent mechanism when interacted with collagen. In addition, the internalization of CNPs was predominantly suppressed by a phosphoinositide 3-kinase (PI3K) inhibitor in IPF fibroblasts, indicating that enhanced PI3K activity associated with late-stage macropinocytosis can be particularly important for the enhanced cellular delivery of CNPs in IPF fibroblasts. Our study strongly supports the concept that a pathological microenvironment which surrounds lung fibroblasts has a significant impact on the intracellular delivery of nanoparticles. Based on the property of enhanced intracellular delivery of CNPs when fibroblasts are made to interact with a collagen-rich matrix, we suggest that CNPs may have great potential as a drug-carrier system for targeting fibrotic lung fibroblasts., Competing Interests: Disclosure The authors report no conflicts of interest in this work.

Enhanced drug-loading and therapeutic efficacies are highly essential properties for nanoparticles as tumor-targeting drug carriers. Herein, we developed the glycol chitosan nanoparticles with hydrotropic oligomers (HO-CNPs) as a new tumor targeting drug delivery system. For enhancing drug-loading efficiency of paclitaxel in drug carriers, hydrotropic 2-(4-(vinylbenzyloxy)-N,N-diethylnicotinamide) (VBODENA-COOH) oligomers, that were used for enhancing the aqueous solubility of paclitaxel, were directly conjugated to glycol chitosan polymers. The amphiphilic conjugates readily formed nanoparticle structure (average size=302 ± 22 nm) in aqueous condition. Water-insoluble paclitaxel (PTX) was readily encapsulated into HO-CNPs with a high drug-loading amount up to 24.2 wt.% (2.4 fold higher than other polymeric nanoparticles) by a simple dialysis method. The PTX encapsulated HO-CNPs (PTX-HO-CNPs; average size=343 ± 12 nm) were very stable in aqueous media up to 50 days. Also, PTX-HO-CNPs presented rapid cellular uptake and lower cytotoxicity in cell culture system, compared to Cremophor EL/ethanol formulation of PTX. In tumor-bearing mice, the extravasation and accumulation of PTX-HO-CNPs in tumor tissue were precisely observed by intravital fluorescence imaging techniques. Furthermore, PTX-HO-CNPs showed the higher therapeutic efficacy, compared to Abraxane®, a commercialized PTX-formulation. These overall results demonstrate its potential as a new nano-sized PTX carrier for cancer treatment., (© 2013.)