a-rapid-screening-workflow-to-identify-potential-combination-therapy

A Rapid Screening Workflow to Identify Potential Combination Therapy for GBM using Patient-Derived Glioma Stem Cells

The glioma stem cells (GSCs) are a small fraction of cancer cells which play essential roles in tumor initiation, angiogenesis, and drug resistance in ...

Nanjing Medical University

The gliomas treatment is challenging due to the limits imposed by blood-brain barrier to the distribution of the drugs in the brain. Therefore, we designed a brain glioma targeting redox-sensitive hyaluronic acid (HA)-ss-curcumin (CUR) micelles. HA was conjugated to CUR through a disulfide bond, which could form micelles independently in aqueous solution. And we further increased the drug loading by loading free CUR. Brain penetration was achieved with Tween 80, whereas glioma-targeting was inclined by CD44-mediated endocytosis. Compared to the disulfide-free group, the redox-sensitive micelles exhibited rapid in vitro drug release under high glutathione conditions, significantly enhanced cell apoptosis and cellular uptake in G422 glioma cells. Redox-sensitive micelles displayed about 4.70-fold higher area under the curve in rats after intravenous injection in comparison to the free CUR and effectively accumulated in the brain. These findings suggest that redox-sensitive micelles could be a promising candidate to achieve brain targeted CUR delivery.

Understanding the cellular uptake and biodistribution of a dual-targeting carrier based on redox-sensitive hyaluronic acid-ss-curcumin micelles for treating brain glioma.

A micelle system based on hyaluronic acid (HA)-octadecylamine (OA) conjugate (HOA) functionalized with N-acetylcysteine (NAC) was constructed to yield NAC modified HOA conjugate (NHOA) for improving oral paclitaxel (PTX) delivery (PTX-NHOA). The average size of spherical PTX-NHOA micelles was 162.7 nm with a zeta potential of -27.6 mv. The encapsulation efficiency (EE) and drug loading (DL) of PTX-NHOA micelles were 92.64% and 6.96%, respectively. Additionally, NHOA micelles exihibited significantly higher cellular uptake in comparison with HOA micelles by caveolin-mediated and clathrin-mediated endocytosis. Higher permeation ability of NHOA micelles (2.75-fold and 1.32-fold, respectively) through cell monolayers of Caco-2/HT29 cells than that of Taxol and HOA micelles were also observed. The intestinal biodistribution result showed that NAC-modified micelles could enhance its adhesion to the intestinal surface and permeate deeply within the intestinal villi. The NHOA micelles were better absorbed in the duodenum, followed by the jejunum and the ileum. In vivo pharmacokinetic studies showed that AUC value of PTX-NHOA micelles was about 5.92-fold and 2.47-fold higher compared to that of Taxol and PTX-HOA micelles, respectively. In a word, NHOA micelles is a promising drug delivery system in improving the oral absorption of insoluble drugs.

The enhancing effect of N-acetylcysteine modified hyaluronic acid-octadecylamine micelles on the oral absorption of paclitaxel.

A major obstacle to the clinical use of curcumin (CUR) is its reduced bioavailability because of the drug's hydrophobic nature, low intestinal absorption, and rapid metabolism. In this study, a novel oral drug delivery system was constructed for improving the stability and enhancing mucoadhesion of CUR in the gastrointestinal (GI) tract. First, CUR was encapsulated in the bovine serum albumin nanoparticles (CUR-BSA-NPs). Then, -acetyl cysteine (NAC)-modified CUR-BSA-NPs (CUR-NBSA-NPs) were obtained. The average particle size and zeta potential of CUR-NBSA-NPs were 251.6 nm and -30.66 mV, respectively; encapsulation efficiency and drug loading were 85.79 and 10.9%, respectively. CUR-NBSA-NPs exhibited a sustained release property and prominently enhanced stability in simulated GI conditions. Additionally, enhanced mucoadhesion of CUR-NBSA-NPs was also observed. An MTT study showed that the CUR-NBSA-NPs were safe for oral administration. Overall, NAC-modified BSA-NPs may potentially serve as an oral vehicle for improving CUR stability in the GI tract and enhancing mucoadhesion.

BSA Nanoparticles Modified with -Acetylcysteine for Improving the Stability and Mucoadhesion of Curcumin in the Gastrointestinal Tract.

Itraconazole (ITZ) can be used for the treatment of cryptococcus neoformans meningitis and aspergillus brain abscess. While, the inherent hydrophobicity of ITZ and the existence of blood brain barrier (BBB) limit its applications as a central nervous system drug. In this study, a novel brain targeting drug delivery system based on bovine serum albumin (BSA) was constructed for enhancing ITZ distribution in brain. Firstly, ITZ was loaded into BSA nanoparticles (ITZ-NPs) with 11.6% of drug loading. Subsequently, the nanoparticles were modified with borneol (BO) and polyethylene glycol (PEG) (PEG/BO-ITZ-NPs). The resulting nanoparticles retained their nanosize (186.3 nm), uniform and spherical morphology, and negative surface charge (-21.03 mV). Cell uptake studies showed that compared with ITZ-NPs, PEG/BO-ITZ-NPs had significantly increased uptake in bEnd.3 cells, and the increase in BO concentration was beneficial for the cellular uptake of NPs. Moreover, PEG/BO-ITZ-NPs displayed an approximately 3.5-fold higher area under the curve in rats and about 2-fold higher brain distribution in mice than that of Sporanox®, i.e. ITZ solubilized by hydroxylpropyl-β-cyclodetrin, after i.v. administration. In a word, BO and PEG dual modified BSA nanoparticles may potentially serve as an ITZ vehicle for brain targeting.

Borneol and poly (ethylene glycol) dual modified BSA nanoparticles as an itraconazole vehicle for brain targeting.

To solve the low oral bioavailability of curcumin (CUR) due to the limits imposed by gastrointestinal (GI) barrier, we constructed a nano delivery system to evaluate the effect of N-acetyl-L-cysteine (NAC) on intestinal absorption and oral bioavailability of CUR. CUR was first encapsulated in bovine serum albumin nanoparticles (CUR-BSA-NPs), and then was further modified by NAC (CUR-NBSA-NPs). In situ single-pass intestinal perfusion assay demonstrated that CUR-NBSA-NPs displayed excellent permeation and absorption rates in GI tract. Additionally, the distribution study in GI tract revealed that more NBSA-NPs were absorbed by intestinal segments compared to the BSA nanoparticles. Plasma concentration-time curves in rats showed that AUC, C and MRT values of CUR after oral administration of CUR-NBSA-NPs were increased to 3.25-, 4.42-, and 1.43-fold compared with that of CUR suspension. In conclusion, NAC promotes oral absorption of CUR, thereby improving its oral bioavailability.

The enhancement of N-acetylcysteine on intestinal absorption and oral bioavailability of hydrophobic curcumin.

Herein, lactoferrin (Lf)/phenylboronic acid (PBA)-functionalized hyaluronic acid nanogels crosslinked with disulfide-bond crosslinker was developed as a reduction-sensitive dual-targeting glioma therapeutic platform for doxorubicin hydrochloride (DOX) delivery (Lf-DOX/PBNG). Spherical Lf-DOX/PBNG with optimized physicochemical properties was obtained, and it could rapidly release the encapsulated DOX under high glutathione concentration. Moreover, enhanced cytotoxicity, superior cellular uptake efficiency, and significantly improved brain permeability of Lf-DOX/PBNG were observed in cytological studies compared with those of DOX solution, DOX-loaded PBA functionalized nanogels (DOX/PBNG), and Lf modified DOX-loaded nanogels (Lf-DOX/NG). The pharmacokinetic study exhibited that the area under the curve of DOX/PBNG, Lf-DOX/NG, and Lf-DOX/PBNG increased by 8.12, 4.20 and 4.32 times compared with that of DOX solution, respectively. The brain accumulation of Lf-DOX/PBNG was verified in biodistribution study to be 12.37 and 4.67 times of DOX solution and DOX/PBNG, respectively. These findings suggest that Lf-DOX/PBNG is an excellent candidate for achieving effective glioma targeting.

Lactoferrin/phenylboronic acid-functionalized hyaluronic acid nanogels loading doxorubicin hydrochloride for targeting glioma.

This study was aimed at improving the water solubility and oral bioavailability of Chl by self-microemulsifying drug delivery system (Chl-SMEDDS).

Article	Year
Understanding the cellular uptake and biodistribution of a dual-targeting carrier based on redox-sensitive hyaluronic acid-ss-curcumin micelles for treating brain glioma. International journal of biological macromolecules\| PubMed ID: 31199976	2019
The enhancing effect of N-acetylcysteine modified hyaluronic acid-octadecylamine micelles on the oral absorption of paclitaxel. International journal of biological macromolecules\| PubMed ID: 31330211	2019
BSA Nanoparticles Modified with -Acetylcysteine for Improving the Stability and Mucoadhesion of Curcumin in the Gastrointestinal Tract. Journal of agricultural and food chemistry\| PubMed ID: 31379162	2019
Borneol and poly (ethylene glycol) dual modified BSA nanoparticles as an itraconazole vehicle for brain targeting. International journal of pharmaceutics\| PubMed ID: 31893546	2020
The enhancement of N-acetylcysteine on intestinal absorption and oral bioavailability of hydrophobic curcumin. European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences\| PubMed ID: 32763460	2020
Lactoferrin/phenylboronic acid-functionalized hyaluronic acid nanogels loading doxorubicin hydrochloride for targeting glioma. Carbohydrate polymers\| PubMed ID: 33278970	2021
Preparation and evaluation of oral self-microemulsifying drug delivery system of Chlorophyll. Drug development and industrial pharmacy\| PubMed ID: 33650446	2021

Ziyi Hu

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