Matthew A. Cheney

Stability of antibody-conjugated gold nanoparticles in the endolysosomal nanoenvironment: implications for noninvasive radiofrequency-based cancer therapy.

UNLABELLED The use of noninvasive radiofrequency (RF) electric fields as an energy source for thermal activation of nanoparticles within cancer cells could be a valuable addition to the emerging field of nano-mediated cancer therapies. Based on investigations of cell death through hyperthermia, and offering the ability for total-body penetration by RF fields, this technique is thought to complement and possibly outperform existing nano-heat treatments that utilize alternative heat production via optical or magnetic stimuli. However, it remains a challenge to understand fully the complex RF-nanoparticle-intracellular interactions before full system optimization can be engineered. Herein we have shown that liver cancer cells can selectively internalize antibody-conjugated gold nanoparticles (AuNPs) through receptor-mediated endocytosis, with the nanoparticles predominantly accumulating and aggregating within cytoplasmic endolysosomes. After exposure to an external RF field, nonaggregated AuNPs absorbed and dissipated energy as heat, causing thermal damage to the targeted cancer cells. We also observed that RF absorption and heat dissipation is dependent on solubility of AuNPs in the colloid, which is pH dependent. Furthermore, by modulating endolysosomal pH it is possible to prevent intracellular AuNP aggregation and enhance thermal cytotoxicity in hepatocellular cancer cells. FROM THE CLINICAL EDITOR Gold nanoparticles absorb energy from RF fields and can exert hyperthermic effects leading to cell death. Combining this known effect with antibody-based targeting of the nanoparticles, selective cancer specific hyperthermia induced cell death therapies can be designed, as demonstrated in this article.

Internalization of C60 fullerenes into cancer cells with accumulation in the nucleus via the nuclear pore complex

A highly water-soluble, non-ionic, and non-cytotoxic fullerene malonodiserinolamide-derivatized fullerene C(60) (C(60)-ser) is under investigation as a potential nanovector to deliver biologic and cancer drugs across biological barriers. Using laser-scanning confocal microscopy and flow cytometry, we find that PF-633 fluorophore conjugated C(60)-ser nanoparticles (C(60)-serPF) are internalized within living cancer cells in association with serum proteins through multiple energy-dependent pathways, and escape endocytotic vesicles to eventually localize and accumulate in the nucleus of the cells through the nuclear pore complex. Furthermore, in a mouse model of liver cancer, the C(60)-serPF conjugate is detected in most tissues, permeating through the altered vasculature of the tumor and the tightly-regulated blood brain barrier while evading the reticulo-endothelial system.

Gated and Near-Surface Diffusion of Charged Fullerenes in Nanochannels

Nanoparticles and their derivatives have engendered significant recent interest. Despite considerable advances in nanofluidic physics, control over nanoparticle diffusive transport, requisite for a host of innovative applications, has yet to be demonstrated. In this study, we performed diffusion experiments for negatively and positively charged fullerene derivatives (dendritic fullerene-1, DF-1, and amino fullerene, AC60) in 5.7 and 13 nm silicon nanochannels in solutions with different ionic strengths. With DF-1, we demonstrated a gated diffusion whereby precise and reproducible control of the dynamics of the release profile was achieved by tuning the gradient of the ionic strength within the nanochannels. With AC60, we observed a near-surface diffusive transport that produced release rates that were independent of the size of the nanochannels within the range of our experiments. Finally, through theoretical analysis we were able to elucidate the relative importance of physical nanoconfinement, electrostatic interactions, and ionic strength heterogeneity with respect to these gated and near-surface diffusive transport phenomena. These results are significant for multiple applications, including the controlled administration of targeted nanovectors for therapeutics.

Radiofrequency electric-field heating behaviors of highly enriched semiconducting and metallic single-walled carbon nanotubes

It is theorized that enhanced thermal heating may result from exposing single-walled carbon nanotubes (SWNTs) embedded in a conductive host to radiofrequency (RF) electric fields. We examine the RF-induced (13.56 MHz) heating behaviors of 95% metallic- and semiconducting-enriched SWNTs (m-/s-SWNTs) suspended in aqueous solutions with varying NaCl molarity (0.001 mM–1 M). The heating effects were only evident for host molarities below 1 mM (equivalent to 0.1 S/m) at which the s-SWNT heating rates dominated those of the m-SWNTs. The heating effects were localized to aligned and aggregated “SWNT ropes” ~1 cm in length that formed in suspension, parallel to the electric-field vector, during the RF exposure. For molarities above 1 mM, no enhancements were evident, owing to the large heating effects of the bulk ionic NaCl suspensions, which were observed in previous studies. Although larger enhancement effects proportional to the host conductivity have been theoretically predicted for m-/s-SWNT suspensions, this was not observed most likely because of the aggregation and screening effects, which diminished the scattered electric field near the m-/s-SWNTs. Our research may further the development of better nanoparticle heating agents for applications such as non-invasive RF-induced cancer hyperthermia.

Cytotoxicity and variant cellular internalization behavior of water-soluble sulfonated nanographene sheets in liver cancer cells

Highly exfoliated sulfonated graphene sheets (SGSs), an alternative to graphene oxide and graphene derivatives, were synthesized, characterized, and applied to liver cancer cells in vitro. Cytotoxicity profiles were obtained using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, WST-1[2-(4-iodophenyl)-3-(4-nitrophenyl)-5-(2,4-disulfophenyl)-2H-tetrazolium, and lactate dehydrogenase release colorimetric assays. These particles were found to be non-toxic across the concentration range of 0.1 to 10 μg/ml. Internalization of SGSs was also studied by means of optical and electron microscopy. Although not conclusive, high-resolution transmission and scanning electron microscopy revealed variant internalization behaviors where some of the SGS became folded and compartmentalized into tight bundles within cellular organelles. The ability for liver cancer cells to internalize, fold, and compartmentalize graphene structures is a phenomenon not previously documented for graphene cell biology and should be further investigated.

Evidence for nuclear internalisation of biocompatible [60]fullerene1)

Abstract A [60]fullerene derivative has been synthesised that demonstrates the ability to enter the nuclear volume of a variety of mammalian cells. This property is unique and has not been previously observed for other types of fullerene derivatives. This ability may have important implications in its use for biomedical applications, such as non-viral gene therapy and cancer chemotherapy where delivery of active agents to the cell nucleus is desired.