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Brain-Targeted Codelivery of Bcl-2/Bcl-xl and Mcl-1 Inhibitors by Biomimetic Nanoparticles for Orthotopic
Wenya He, Xiaozhe Li, Marco Morsch1
1Center for Motor Neuron Disease Research, Macquarie Medical School, Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney, New South Wales 2109, Australia.
Abstract:
Glioblastoma (GBM) is among the most treatment-resistant solid tumors and often recurrs after resection. One of the mechanisms through which GBM escapes various treatment modalities is the overexpression of anti-apoptotic Bcl-2 family proteins (e.g., Bcl-2, Bcl-xl, and Mcl-1) in tumor cells. Small-molecule inhibitors such as ABT-263 (ABT), which can promote mitochondrial-mediated cell apoptosis by selectively inhibiting the function of Bcl-2 and Bcl-xl, have been proven to be promising anticancer agents in clinical trials. However, the therapeutic prospects of ABT for GBM treatment are hampered by its limited blood-brain barrier (BBB) penetration, dose-dependent thrombocytopenia, and the drug resistance driven by Mcl-1, which is overexpressed in GBM cells and further upregulated upon treatment with ABT. Herein, we reported that the Mcl-1-specific inhibitor A-1210477 (A12) can act synergistically with ABT to induce potent cell apoptosis in U87 MG cells, drug-resistant U251 cells, and patient-derived GBM cancer stem cells. We further designed a biomimetic nanomedicine, based on the apolipoprotein E (ApoE) peptide-decorated red blood cell membrane and pH-sensitive dextran nanoparticles, for the brain-targeted delivery of ABT and A12. The synergistic anti-GBM effect was retained after encapsulation in the nanomedicine. Additionally, the obtained nanomedicine possessed good biocompatibility, exhibited efficient BBB penetration, and could effectively suppress tumor growth and prolong the survival time of mice bearing orthotopic GBM xenografts without inducing detectable adverse effects.
Insights
This study developed a novel nanomedicine for glioblastoma (GBM) treatment. It combines two inhibitors, ABT and A12, to overcome drug resistance and enhance apoptosis, showing promising results in preclinical models.
Area of Science:
- Oncology
- Nanomedicine
- Pharmacology
Background:
- Glioblastoma (GBM) is a highly treatment-resistant brain tumor.
- Overexpression of anti-apoptotic Bcl-2 proteins contributes to GBM treatment resistance.
- Existing inhibitors like ABT-263 have limitations including poor blood-brain barrier (BBB) penetration and Mcl-1-mediated resistance.
Purpose of the Study:
- To investigate the synergistic effect of ABT-263 (ABT) and Mcl-1 inhibitor A-1210477 (A12) against GBM.
- To design and evaluate a novel brain-targeted nanomedicine for co-delivery of ABT and A12.
Main Methods:
- Synergistic apoptosis induction was tested in GBM cell lines and patient-derived cells.
- A biomimetic nanomedicine using red blood cell membranes and pH-sensitive nanoparticles was engineered for ABT and A12 delivery.
- In vivo efficacy was assessed in orthotopic GBM xenograft mouse models.
Main Results:
- A12 synergized with ABT to induce potent apoptosis in various GBM models.
- The developed nanomedicine demonstrated effective BBB penetration and retained the synergistic anti-GBM effect.
- In vivo studies showed suppressed tumor growth, prolonged survival, and good biocompatibility.
Conclusions:
- Co-inhibition of Bcl-2/Bcl-xl and Mcl-1 offers a promising strategy for GBM treatment.
- The developed brain-targeted nanomedicine effectively delivers synergistic drugs, overcoming BBB limitations and improving therapeutic outcomes for GBM.
