Aim-In this study, we describe the biodistribution of CYT-6091, a colloidal gold (Au)-based nanomedicine that targets the delivery of TNF-α to solid tumors.Materials & methods-A single intravenous injection of CYT-6091 coated with 5 µg TNF-α was given to human prostate tumor-bearing or naive (without tumor) nude mice. Tissues were harvested and analyzed at specific time points for Au nanoparticles by atomic emission spectroscopy and TNF-α by ELISA.Results-The two constituents of CYT-6091, TNF-α and Au, exhibited different behavior in blood, with TNF-α showing a faster decay than the Au nanoparticles. Between 0 and 4 h after injection, TNF-α showed a preferential accumulation in the tumor. Au was observed to accumulate preferentially in the liver between 4 and 12 h, and showed some clearance over time (4 months).Conclusion-These data suggest that CYT-6091 delivers TNF-α preferentially to the tumor and that upon TNF-α degradation, the liver takes up Au, which is cleared slowly over time. Keywordsbiodistribution; cryosurgery; CYT-6091; gold nanoparticle; TNF Nanomedicines currently being developed for the treatment of cancer, although diverse in chemical composition, size and shape, must address similar key physiologic and engineering barriers to warrant their testing in a clinical setting. First, these nanosystems must be engineered to avoid initial clearance and uptake by the reticuloendothelial system [1][2][3]. Second, the putative nanomedicines must alter the biodistribution of their therapeutic payload(s) to allow
Heating induced near deep brain stimulation (DBS) lead electrodes during MRI with a 3T transceive head coil was measured, modeled, and imaged in three cadaveric porcine heads (mean body weight = 85.47±3.19 kg, mean head weight = 5.78±0.32 kg). The effect of the placement of the extra-cranial portion of the DBS lead on the heating was investigated by looping the extra-cranial lead on the top, side, and back of the head; and placing it parallel to the coil’s longitudinal axial direction. The heating was induced using a 641 s long turbo spin echo sequence with the mean whole head average SAR of 3.16 W/kg. Temperatures were measured using fluoroptic probes at the scalp, first and second electrodes from the distal lead tip, and 6 mm distal from electrode 1 (T6mm). The heating was modeled using the maximum T6mm and imaged using a proton resonance frequency shift based MR thermometry method. Results showed that the heating was significantly reduced when the extra-cranial lead was placed in the longitudinal direction compared to the other placements (peak temperature change = 1.5–3.2 °C vs 5.1–24.7 °C). Thermal modeling and MR thermometry may be used together to determine the heating and improve patient safety online.
Over the past several years, there has been an increasing interest in the use of nanoparticles as a tool for treatment of cancer. We have shown tremendous augmentation and control (without toxicity) of both heat and cold-based thermal therapy for cancer treatment with a gold based nanodrug-CYT-6091 (Cytimmune Sciences, Inc.) [1–3]. To reach the full potential of these nanodrugs for both stand-alone solid cancer treatment and as adjuvant to thermal therapy, there is a need to understand the in vivo biodistribution and their short-term and long-term tissue interaction.
Cryosurgical treatment of solid cancer can be greatly assisted by further translation of our finding that a cytokine adjuvant tumor necrosis factor-A (TNF-A) can achieve complete cancer destruction out to the intraoperatively imaged iceball edge (-0.5°C) over the current clinical recommendation of reaching temperatures lower than -40°C. The present study investigates the cellular and tissue level dose dependency and molecular mechanisms of TNF-A-induced enhancement in cryosurgical cancer destruction. Microvascular endothelial MVEC and human prostate cancer LNCaP Pro 5 (LNCaP) cells were frozen as monolayers in the presence of TNF-A. Normal skin and LNCaP tumor grown in a nude mouse model were also frozen at different TNF-A doses. Molecular mechanisms were investigated by using specific inhibitors to block nuclear factor-KB -mediated inflammatory or caspasemediated apoptosis pathways. The amount of cryoinjury increased in a dose-dependent manner with TNF-A both in vitro and in vivo. MVEC were found to be more cryosensitive than LNCaP cells in both the presence and the absence of TNF-A. The augmentation in vivo was significantly greater than that in vitro, with complete cell death up to the iceball edge in tumor tissue at local TNF-A doses greater than 200 ng. The inhibition assays showed contrasting results with caspase-mediated apoptosis as the dominant mechanism in MVEC in vitro and nuclear factor-KB -mediated inflammatory mechanisms within the microvasculatures the dominant mechanism in vivo. These results suggest the involvement of endothelialmediated injury and inflammation as the critical mechanisms in cryoinjury and the use of vascular-targeting molecules such as TNF-A to enhance tumor killing and achieve the clinical goal of complete cell death within an iceball.
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