The selective thermal ablation of malignant tissue is an important objective in cancer research and offers a viable alternative treatment option when surgical resection is not possible. Modalities such as radiofrequency ablation (RFA) have been shown to be efficacious for treatment of various malignancies including liver, lung, and prostate tumors.1,2
Cell death is induced by irreversible protein denaturation or membrane damage at temperatures above 40 °C.3,4
While RFA and other thermal ablative strategies such as ultrasound or microwave treatment(5
) offer a less invasive alternative to surgery, these techniques have neither inherent specificity for malignant cells nor any potential to be utilized in a molecularly targeted approach. Thus, the development of novel approaches for the selective sensitization of malignant cells to irradiation is necessary to realize the potential of this methodology.
Various nanoparticles including single-walled carbon nanotubes (SWNTs)6,7
and gold nanoparticles(8
) have been shown to be efficient transducers of near-infrared (nIR) irradiation to generate heat that is sufficient to cause cell death. In the case of SWNTs and multiwalled carbon nanotubes (MWNTs), the mechanism of heat generation involves excitation of optical transitions with relaxation resulting in enhanced vibrational modes in the carbon lattice that cause solution heating.(9
) In principle, these nanoparticles can be conjugated with aptamers(10
) or antibodies(11
) and selectively delivered to malignant cells in vivo
permitting thermal ablation to be used in a molecularly targeted fashion. In practice, issues relating to the aqueous solubility, biocompatibility, and toxicology of nanoparticles must be addressed prior to successfully translating this approach into the clinic.
Although less well-studied than SWNTs, MWNTs are potentially of great use for the selective thermal ablation of malignant cells as a consequence of the efficient conversion of nIR irradiation into heat by this material which greatly exceeds that of a graphite control.(12
) MWNTs are composed of concentric SWNTs and like SWNTs the hydrophobic outer surface must be modified with amphiphilic materials(13
) to confer sufficient aqueous solubility for in vivo
applications. DNA has been utilized to confer aqueous solubility to SWNTs14,15
with the hydrophobic nucleobases interacting with the aromatic structure of the SWNTs through π−π stacking(16
) while the deoxyribose sugars and phosphodiester backbone of DNA provide the hydrophilicity necessary for aqueous solubility of DNA-encased SWNTs. Several studies have demonstrated a sequence- and length-dependence to the interaction of SWNTs with DNA with alternating dG-dT copolymers being among the most preferred sequences.(17
) The interaction of MWNTs with DNA is less well-studied and MWNTs have larger diameters than SWNTs and thus present a surface with a larger radius of curvature that may interact differently with DNA than that of SWNTs.
The present study was undertaken to establish the feasibility of conferring aqueous solubility to MWNTs using DNA and to investigate to what extent DNA-encased MWNTs are useful for thermal ablation of malignant tissue. The relative efficiency of conversion of nIR irradiation into heat for DNA-encased MWNTs relative to non-DNA-encased MWNTs and other materials is an important consideration for identifying which type of nanomaterial is best-suited for in vivo
thermal ablation approaches.(12
) We have undertaken an analysis of the time-, power-, and concentration-dependence of heat generation from DNA-encased MWNTs. We demonstrate that DNA-encased MWNTs produce larger amounts of heat than non-DNA-encased MWNTs when irradiated under identical conditions indicating that DNA-encasement increases the utility of MWNTs for thermal ablative applications. Further, we demonstrate for the first time that DNA-encased MWNTs efficiently eradicate tumor xenografts in vivo
in a mouse model of human cancer. Complete tumor eradication was achieved with a single treatment under conditions that resulted in no injury or damage to normal tissues. These findings demonstrate that DNA-encased MWNTs may be useful for development of molecularly targeted nanoparticles for selective thermal ablation of malignant tissue in humans.