Photothermal therapy of glioblastoma multiforme using multiwalled carbon nanotubes optimized for diffusion in
Brittany N Eldridge1, Brian W Bernish1, Cale D Fahrenholtz1
1Department of Cancer Biology, Wake Forest School of Medicine, Medical Center Boulevard, Winston Salem, NC, 27157, USA.
Abstract:
Glioblastoma multiforme (GBM) is the most common and most lethal primary brain tumor with a 5 year overall survival rate of approximately 5%. Currently, no therapy is curative and all have significant side effects. Focal thermal ablative therapies are being investigated as a new therapeutic approach. Such therapies can be enhanced using nanotechnology. Carbon nanotube mediated thermal therapy (CNMTT) uses lasers that emit near infrared radiation to excite carbon nanotubes (CNTs) localized to the tumor to generate heat needed for thermal ablation. Clinical translation of CNMTT for GBM will require development of effective strategies to deliver CNTs to tumors, clear structure-activity and structure-toxicity evaluation, and an understanding of the effects of inherent and acquired thermotolerance on the efficacy of treatment. In our studies, we show that a dense coating of phospholipid-poly(ethylene glycol) on multiwalled CNTs (MWCNTS) allows for better diffusion through brain phantoms, while maintaining the ability to achieve ablative temperatures after laser exposure. Phospholipid-poly(ethylene glycol) coated MWCNTs do not induce a heat shock response (HSR) in GBM cell lines. Activation of the HSR in GBM cells via exposure to sub-ablative temperatures or short term treatment with an inhibitor of heat shock protein 90 (17-(dimethylaminoethylamino)-17-demethoxygeldanamycin (17-DMAG)), induces a protective heat shock response that results in thermotolerance and protects against CNMTT. Finally, we evaluate the potential for CNMTT to treat GBM multicellular spheroids. These data provide pre-clinical insight into key parameters needed for translation of CNMTT including nanoparticle delivery, cytotoxicity, and efficacy for treatment of thermotolerant GBM.
Insights
Carbon nanotube mediated thermal therapy (CNMTT) shows promise for glioblastoma treatment. Nanoparticle coating improves delivery and efficacy, but thermotolerance in GBM cells presents a challenge.
Area of Science:
- Oncology
- Nanotechnology
- Biomedical Engineering
Background:
- Glioblastoma multiforme (GBM) is an aggressive brain tumor with poor prognosis.
- Current therapies for GBM are limited and have significant side effects.
- Focal thermal ablative therapies, enhanced by nanotechnology, offer a potential new treatment strategy.
Purpose of the Study:
- To investigate the clinical translation of carbon nanotube mediated thermal therapy (CNMTT) for GBM.
- To evaluate nanoparticle delivery, structure-activity, structure-toxicity, and thermotolerance effects on CNMTT efficacy.
- To provide pre-clinical insights for the development of CNMTT for GBM treatment.
Main Methods:
- Coating multiwalled carbon nanotubes (MWCNTS) with phospholipid-poly(ethylene glycol) for improved brain phantom diffusion.
- Assessing the heat shock response (HSR) in GBM cell lines after MWCNT exposure.
- Inducing thermotolerance in GBM cells using sub-ablative temperatures or HSP90 inhibition (17-DMAG).
- Evaluating CNMTT efficacy on GBM multicellular spheroids.
Main Results:
- Phospholipid-poly(ethylene glycol) coated MWCNTS demonstrated enhanced diffusion and achieved ablative temperatures.
- Coated MWCNTS did not induce HSR in GBM cell lines.
- Induced HSR in GBM cells conferred thermotolerance, reducing CNMTT efficacy.
- CNMTT showed potential for treating GBM multicellular spheroids.
Conclusions:
- Phospholipid-poly(ethylene glycol) coated MWCNTS are a viable platform for CNMTT delivery in GBM.
- Understanding and overcoming GBM cell thermotolerance is crucial for successful CNMTT treatment.
- These findings provide essential pre-clinical data for advancing CNMTT towards clinical application in GBM therapy.
