Effect of Nanoparticles of DOX and miR-125b on DNA Damage Repair in Glioma U251 Cells and Underlying Mechanisms

Abstract

Glioma is the most common primary craniocerebral malignant tumor, arising from the canceration of glial cells in the brain and spinal cord. The quality of life and prognosis of patients with this disease are still poor. Doxorubicin (DOX) is one of the most traditional and economical chemotherapeutic drugs for the treatment of glioma, but its toxic effect on normal cells and the resistance of tumor cells to DOX make the application of DOX in the treatment of glioma gradually less effective. To solve this problem, we co-encapsulated DOX and endogenous tumor suppressor miR-125b into nanoparticles (NPs) by nanoprecipitation methods, and passively targeted them into glioma cells. In vitro experiments show that miR-125b and DOX can be effectively encapsulated into nanoparticles with different ratios, and by targeting YES proto-oncogene 1 (YES1), they can affect the adenosine 5′-monophosphate (AMP)-activated protein kinase (AMPK)/p53 pathway and induce brain glioma cell apoptosis. They can also affect the DNA damage repair process and inhibit cell proliferation. The obtained data suggest that co-delivery of DOX and miR-125b could achieve synergistic effects on tumor suppression. Nanosystem-based co-delivery of tumor suppressive miRNAs and chemotherapeutic agents may be a promising combined therapeutic strategy for enhanced anti-tumor therapy.

Synthesis and evaluation of chitosan/miR-125b nanoparticles for targeting Raf-1 and BMPR1b genes in MCF-7 breast cancer cells

“…However, other studies reported that miR-125b-5p had an oncogenic role in breast cancer by promoting survival and conferring resistance to chemotherapy. For example, miR-125b-5p was found to be upregulated in doxorubicin-resistant breast cancer cells and to inhibit the expression of pro-apoptotic genes [10]. MiR-125b-5p was also found to be downregulated in tamoxifen-resistant breast cancer patients and to be inversely correlated with HER2/neu status [27].…”

“…However, the delivery of miR-125b to breast cancer cells faces several challenges, such as low stability, low cellular uptake, and low target speci city [10]. To overcome these challenges, an e cient and safe delivery system for miR-125b is needed.…”

PEG-liposomal doxorubicin as a potential agent for canine metastatic osteosarcoma – in vitro and ex ovo studies

“…Liposomes as drug delivery systems may reduce the negative side effects and increase the therapeutic efficacy. Compared with conventional drugs, liposomes can directly deliver drugs to specific cells or tissues, thereby greatly reducing the adverse effects ( 29 ). In a community-based observational study, Salzberg et al ( 19 ) indicated that PEG-liposomal doxorubicin is a well-tolerated active agent in patients with metastatic breast cancer.…”

Nanomedicine-based combination therapies for overcoming temozolomide resistance in glioblastomas

“…It has been reported that overexpression of miR-125b enhances the sensitivity of the DOX-resistant breast cancer cell line, MCF-7/R, to DOX and exhibits a similar potential in other tumors, including GBM. Wang et al 80 encapsulated DOX and miR-125b into an amphiphilic co-polymer (γ-PGA-co-PLA-DPPE) containing poly [gamma-glutamic acid (γ-PGA)], polylactide (PLA), and 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine (DPPE), and formed co-polymer NPs using a nano-precipitation method. The results showed that miR-125b aggravates cell cycle arrest caused by DNA damage by DOX and activates the AMPK/p53 pathway in U251 cells, thus improving chemosensitivity and promoting tumor cell apoptosis.…”