Photothermal Therapy of Glioblastoma Multiforme Using Multiwalled Carbon Nanotubes Optimized for Diffusion in Extracellular Space

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.

Prostate-specific membrane antigen–directed nanoparticle targeting for extreme nearfield ablation of prostate cancer cells

“…Nevertheless, many of these models, even if they are targeted toward specific tumor mass, may face challenges in confining heat production at the very local levels; studies show that during the photothermal treatments of the cells using the nanoparticles, the temperature of the entire field is raised by a significant amount. [48][49][50][51] This could raise serious concerns about damage upon nearby, non-targeted tissue as the entire field is being affected. Our method tries to overcome this drawback by promoting target-specific attachment of the nanoparticle products to the tumor: This had led to dramatic reduction in overall heat generation of the field (Figure 5), while producing enough thermal energy at proximity to the target to induce sufficient damage on the tumor while minimizing temperature change.…”

Evaluation of multiwalled carbon nanotube cytotoxicity in cultures of human brain microvascular endothelial cells grown on plastic or basement membrane

“…PEG functionalized SWCNTs also did not induce significant morphological alterations in rat hippocampus(Dal Bosco et al, 2015). Similarly, we found that DSPE-PEG coated, acid oxidized MWCNTs were cytotoxic to glioblastoma cells grown in two-dimensional monolayer, but had no observable effect on growth of glioblastoma cells grown as three-dimensional spheroids(Eldridge et al, 2016). However, astrocytes exposed to PEG functionalized SWCNTs may mature and increase glial cell activity(Gottipati et al, 2015).…”

“…CNTs generate tremendous heat upon exposure to near infrared radiation, making them useful for photothermal cancer therapy(Burke et al, 2012; Singh and Torti, 2013). We and others demonstrated the potential to use CNTs for photothermal treatment of glioblastoma, a deadly brain tumor(Eldridge et al, 2016; Santos et al, 2014; Wang et al, 2011). …”

“…For these studies, we focused on the cytotoxicity of MWCNTs. Because MWCNTs are commonly acid treated or coated in surfactants like phospholipid-polyethylene glycol to improve their dispersion in water and to enhance their diffusion through extracellular matrix(Eldridge et al, 2016), we determined the influence of these modifications on MWCNT cytotoxicity. Furthermore, we examined the effect of MWCNTs on the capacity for HBMECs to form microvascular tubes.…”

Carbon Nanomaterials for Breast Cancer Treatment

“…Recently, the properties of carbon nanomaterials and their potential applications in PDT have been analyzed in an attempt to substitute current invasive thermal procedures that remove tumors or cancer cells of breast cancer [70][71][72][73][74][75][76][77][78][79][80][81]. Due to the carbon nanomaterials presence in the PDT, cancer cells accumulate light-sensitive molecules (carbon nanomaterials) which, in the presence of oxygen, absorb the radiation of an infrared camera and turn it into heat.…”