Photodynamic therapy (PDT) of tumors relies on the delivery of a photosensitizer to the tumor site followed by external laser activation. The effectiveness of the therapy is determined by the fluence and irradiation of the laser, intratumoral photosensitizer retention, and availability of molecular oxygen. We hypothesized that retention and resulting therapeutic response may be improved with local hyperthermia. Tumors were grown in the rear limb then locally heated for 1 hour at 42.5 °C immediately following i.v. injection of the photosensitizer in an immunocompetent murine model. Laser exposure was applied at 2 h or 24 h after the heating session. Administration of heating caused a significant growth delay when a single laser treatment was applied only 2 hours following injection. However, in animals given photosensitizer only and irradiated 2 h later there was no measurable anti-tumor effect observed. The marked anti-tumor effects obtained with prior local hyperthermia were observed even as the dose was lowered from 10 mg/kg to 1.3 mg/kg. Additionally, histological analysis of our intial studies revealed that the majority of the tumor tissue (~75%) was necrotic after two days when heat was combined with PDT, while PDT alone resulted in only ~25% necrotic tissue. Additionally, a significant, though less notable, increase in the efficacy was observed if the laser treatment was applied 24 hours after hyperthermia and photosensitizer administration. This increase is in part ascribed to the increased retention of the photosensitizer in the tumor tissue and likely lasting effects on tumor blood flow and oxygenation in the heated vs. control groups.
We previously explored the use of antibody-conjugated, antibiotic-loaded gold nanocages for the treatment of bacterial infections. Using Staphylococcus aureus as a proof-of-principle pathogen, we confirmed that nanocages coated with polydopamine and loaded with daptomycin could be effectively targeted to bacterial cells using an antibody targeting S. aureus surface-associated protein A. We also confirmed that laser irradiation could then be used to achieve a lethal photothermal effect and localized release of the antibiotic, the synergistic effect of which was capable of eradicating viable bacteria even from a therapeutically recalcitrant biofilm. To assess the possibility that this comes at the cost of adverse side effects, we used multispectral optoacoustic tomography (MSOT) to track the biodistribution of our nanocages following intravenous administered and determined whether their administration was associated with toxic side effects. The results of our MSOT analysis confirmed that our nanocages accumulate primarily in the liver, spleen and kidney irrespective of infection status. However, in an infected animal, they also confirmed that nanocages ultimately do reach the site of infection. MSOT results were consistent with studies involving the direct analysis of these tissues, which confirmed the correlation between MSOT signals and the presence of gold nanocages. More importantly, they also demonstrated that the presence of nanocages was not associated with appreciable histopathology in the spleen, liver, kidney, lung or heart. This suggests that our use of antibody-conjugated, antibiotic-loaded gold nanocages for the treatment of infection offers significant promise that would not be compromised by systemic toxicity.
Radiation resistance remains a significant problem for cancer patients, especially due to the time required to definitively determine treatment outcome. For fractionated radiation therapy, nearly 7 to 8 weeks can elapse before a tumor is deemed to be radiation-resistant. We used the optical redox ratio of FAD/(FAD+NADH) to identify early metabolic changes in radiation-resistant lung cancer cells. These radiation-resistant human A549 lung cancer cells were developed by exposing the parental A549 cells to repeated doses of radiation (2 Gy). Although there were no significant differences in the optical redox ratio between the parental and resistant cell lines prior to radiation, there was a significant decrease in the optical redox ratio of the radiation-resistant cells 24 h after a single radiation exposure (p=0.01). This change in the redox ratio was indicative of increased catabolism of glucose in the resistant cells after radiation and was associated with significantly greater protein content of hypoxia-inducible factor 1 (HIF-1α), a key promoter of glycolytic metabolism. Our results demonstrate that the optical redox ratio could provide a rapid method of determining radiation resistance status based on early metabolic changes in cancer cells.
KEYWORDS: Tumors, Tissues, Solids, Temperature metrology, Laser ablation, Mouse models, Ultrasonography, Breast cancer, In vivo imaging, Connective tissue
Purpose: Develop a new combination therapy consisting of cryoablation and conductive high-temperature
ablation for enhanced thermal ablation of solid tumors.
Methods: We have constructed an invasive probe that can be used for consecutive cryoablation and hightemperature
ablation (C/HTA), with a single insertion. The C/HTA probe was tested, in Balb/c mice bearing
solid 4T1 tumors, in comparison to cryoablation and high temperature ablation, only. Three days after
ablation, the diameter of the ablated zone was evaluated with pathological examination.
Results: The C/HTA device can be used to induce larger ablation zones, in comparison to high temperature or
cryoablation alone, and at lower thermal doses and temperatures than either modality alone.
Conclusions: The relatively high thermal conductivity of ice, in comparison to water and native tissue,
enables rapid heating of the ice-ball that result in improved conductive high temperature ablation. The new
dual thermal modality improves ablation outcomes at lower thermal doses in comparison to a single ablation
modality.
Background and Purpose. Determine the efficacy of indocyanine green (ICG) dye in enhancing near
infrared (NIR) laser ablation of tumors in a mouse model.
Methods. Mammary carcinoma cells of A/J mice were injected subcutaneously in the lower back of female
A/J mice (n=6). Five to seven days post inoculation the tumors (7-9 mm) were treated with 755-nm laser
using 70 J/cm2 radiant exposures and 3-ms pulse time. Epidermal cooling was accomplished by cryogen spray
cooling. Two minutes prior to laser irradiation mice were injected, intravenously, with 4 mg/kg body weight
of ICG solution.
Results. Complete tumor ablation was observed in the tumor region and minor damage was seen in the
healthy skin. No major skin damage was observed post treatment. Substantial damage (up to 100%
coagulative necrosis) was observed in tissue collected from tumors that were treated with laser/ICG.
Conclusions. Intravenous administration of 4 mg/kg ICG significantly enhanced thermal ablation of tumors
during NIR laser irradiation while sparing healthy skin.
The SonoKnife is a scan-able high intensity line-focused ultrasound device for thermal ablation (52 - 60°C) of
superficially located advanced tumors or nodal disease in the head and neck. Based on preliminary simulation results, a
prototype cylindrical section transducer operating at 3.5 MHz, with a 60 mm radius of curvature, an elevation of 30 mm
and an aperture of 60 mm, was constructed for laboratory testing. The three-dimensional distribution of the acoustic field
was measured in water and compared to preliminary numerical results. Ablation experiments were performed in gel
phantoms, in porcine liver ex vivo and in live piglets. The experimental results agreed well with the theoretical
simulations and showed that the SonoKnife transducer had a narrow acoustic edge and is able to ablate living biological
tissues at practical power levels.
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