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Tackling Anticancer Drug Resistance and Endosomal Escape in Aggressive Brain Tumors Using Bioelectronics
Akhil Jain1,2, Philippa Wade3, Snow Stolnik4
1Division of Pharmacy and Optometry, School of Health Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Oxford Road, Manchester M13 9PT, U.K.
Abstract:
Resistance mechanisms in brain tumors, such as medulloblastoma and glioblastoma, frequently involve the entrapment of chemotherapeutic agents within endosomes and the extracellular expulsion of drugs. These barriers to effective treatment are exacerbated in nanotechnology-based drug delivery systems, where therapeutic nanoparticles often remain confined within endosomes, thus diminishing their therapeutic efficacy. Addressing this challenge necessitates the development of novel strategies to enhance the efficiency of cancer therapies. This study tests the hypothesis that external electrical stimuli can modulate intracellular trafficking of chemotherapeutic drugs in common malignant brain tumors in children (medulloblastoma) and adults (glioblastoma) by using gold nanoparticles (GNPs). In our experiments, alternating current (AC) stimulation ranging from 1 kHz to 5 MHz and at a strength of 1 V/cm significantly reduced cell viability in drug-resistant medulloblastoma and enhanced delivery of GNPs in glioblastoma. Low-frequency AC resulted in a 50% increase in apoptosis compared to controls and an 8-fold increase in cell death in cisplatin-resistant medulloblastoma cells, accompanied by a substantial reduction in EC50 from 2.5 to 0.3 μM. Similarly, vincristine-resistant cells demonstrated a 4-fold enhancement in drug sensitivity. Furthermore, high-frequency AC facilitated a significant increase from 20 to 75% in the endosomal escape of GNPs in glioblastoma cells. These findings underscore the potential of AC to selectively disrupt cancer cell resistance mechanisms and bolster the efficacy of nanoparticle-based therapies. The results indicate the effectiveness of AC stimulation in circumventing the limitations inherent in current nanotechnology-based drug delivery systems but also illustrates its transformative potential for treating aggressive, drug-resistant brain tumors.
Insights
Alternating current (AC) stimulation enhances chemotherapy delivery and efficacy in brain tumors. This approach overcomes drug resistance and improves nanoparticle delivery, offering new hope for treating aggressive brain cancers.
Area of Science:
- Oncology
- Nanotechnology
- Biophysics
Background:
- Brain tumors like medulloblastoma and glioblastoma exhibit resistance to chemotherapy due to drug entrapment in endosomes and extracellular drug expulsion.
- Nanotechnology-based drug delivery systems face challenges with nanoparticles remaining trapped in endosomes, reducing therapeutic effectiveness.
- Novel strategies are needed to enhance cancer therapy efficiency and overcome drug resistance in brain tumors.
Purpose of the Study:
- To investigate if external electrical stimuli, specifically alternating current (AC), can modulate intracellular drug trafficking in medulloblastoma and glioblastoma.
- To test the hypothesis that AC stimulation can enhance the efficacy of chemotherapeutic drugs and gold nanoparticle (GNP) delivery in brain tumors.
Main Methods:
- Utilized gold nanoparticles (GNPs) for drug delivery in medulloblastoma and glioblastoma models.
- Applied alternating current (AC) stimulation at frequencies from 1 kHz to 5 MHz and an electric field strength of 1 V/cm.
- Assessed cell viability, apoptosis, drug sensitivity (EC50), and endosomal escape of GNPs.
Main Results:
- Low-frequency AC significantly increased apoptosis and cell death in cisplatin-resistant medulloblastoma cells, reducing EC50 and enhancing vincristine sensitivity.
- High-frequency AC significantly increased the endosomal escape of GNPs in glioblastoma cells from 20% to 75%.
- AC stimulation demonstrated a selective disruption of cancer cell resistance mechanisms and improved nanoparticle-based therapy efficacy.
Conclusions:
- Alternating current (AC) stimulation is effective in overcoming limitations of current nanotechnology-based drug delivery systems for brain tumors.
- AC stimulation shows transformative potential for treating aggressive, drug-resistant brain tumors by enhancing chemotherapy and nanoparticle delivery.
- External electrical stimuli represent a promising strategy to improve therapeutic outcomes in challenging brain cancer cases.
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