Ursolic acid nanoprecipitates loaded hydrogels to specifically inhibit O6-methylguanine-DNA methyltransferase (MGMT) in the standard of care of glioblastoma
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Date
2023-06-23
Authors
Saleh, Amr
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Abstract
Glioblastoma (GBM) is the most common brain cancer and it represents nearly half of all central nervous system malignant tumors. The current treatment involves surgery followed by a combination of radiotherapy and chemotherapy. In most cases of GBM, there is a tumor recurrence that is characterized by high chemoresistance. MGMT is a DNA repair enzyme that is responsible for the chemoresistance against temozolomide (TMZ), the clinical standard chemotherapeutic agent used to treat GBM. Recently, it was found that ursolic acid (UA) can inhibit the expression of MGMT. But since UA is a highly lipophilic molecule, a nanomedicine formulation is required to enhance its pharmaceutical properties. To ensure minimal systemic toxicity, we plan to benefit from the surgery procedure to apply a hydrogel formulation loaded with a UA nanoprecipitates (UANP) to locally treat GBM.
In this study, we have shown that UA can be formulated easily with or without adding a helper lipid such as SChol. Adding SChol reduced the size and size distribution and increased the charge at the surface of UANP, enhancing the stability of the particles. UANP with or without SChol was added to the hydrogel formulation, resulting in the same desirable solution-gel transition temperatures. UANP can be efficiently trapped within the gel network, which ensures that the release of UA always follow the dissolution of the hydrogel. The cytotoxicity of our formulations was tested against U-87 MG and T98G GBM cell lines. The results indicated that SChol can help to internalize UA nanoprecipitates causing more cytotoxicity, while the poloxamers in the hydrogel formulations may reduce the internalization and the cytotoxicity in U-87 MG cells. T98G cells were more sensitive and susceptible to more toxicity. Overall, there is a high potential to locally treat GBM using such formulations and this strategy needs to be investigated more, even for other types of cancers.
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Keywords
Glioblastoma (GBM), Ursolic acid nanoprecipitates, Brain tumor treatment