Therapeutic impacts of GNE477loaded H2O2 stimulusresponsive dodecanoic acidphenylborate esterdextran polymeric micelles on osteosarcoma.
Int J Mol Med
; 54(2)2024 08.
Article
en En
| MEDLINE
| ID: mdl-38940336
ABSTRACT
Osteosarcoma (OS) is a highly malignant primary bone neoplasm that is the leading cause of cancerassociated death in young people. GNE477 belongs to the second generation of mTOR inhibitors and possesses promising potential in the treatment of OS but dose tolerance and drug toxicity limit its development and utilization. The present study aimed to prepare a novel H2O2 stimulusresponsive dodecanoic acid (DA)phenylborate esterdextran (DABDEX) polymeric micelle delivery system for GNE477 and evaluate its efficacy. The polymer micelles were characterized by morphology, size and critical micelle concentration. The GNE477 loaded DABDEX (GNE477@DBD) tumortargeting drug delivery system was established and the release of GNE477 was measured. The cellular uptake of GNE477@DBD by three OS cell lines (MG63, U2OS and 143B cells) was analyzed utilizing a fluorescent tracer technique. The hydroxylated DAB was successfully grafted onto dextran at a grafting rate of 3%, suitable for forming amphiphilic micelles. Following exposure to H2O2, the DABDEX micelles ruptured and released the drug rapidly, leading to increased uptake of GNE477@DBD by cells with sustained release of GNE477. The in vitro experiments, including MTT assay, flow cytometry, western blotting and RTqPCR, demonstrated that GNE477@DBD inhibited tumor cell viability, arrested cell cycle in G1 phase, induced apoptosis and blocked the PI3K/Akt/mTOR cascade response. In vivo, through the observation of mice tumor growth and the results of H&E staining, the GNE477@DBD group exhibited more positive therapeutic outcomes than the free drug group with almost no adverse effects on other organs. In conclusion, H2O2responsive DABDEX presents a promising delivery system for hydrophobic antitumor drugs for OS therapy.
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Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Osteosarcoma
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Dextranos
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Peróxido de Hidrógeno
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Ácidos Láuricos
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Micelas
Límite:
Animals
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Humans
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Male
Idioma:
En
Revista:
Int J Mol Med
Asunto de la revista:
BIOLOGIA MOLECULAR
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GENETICA MEDICA
Año:
2024
Tipo del documento:
Article