Nano-Targeting of Thyrointegrin αvß3 Receptor in Solid Tumors and Impact on Radiosensitization.

Tetraiodothyroacetic acid is a ligand of thyrointegrin αvß3, a protein that is highly expressed in various solid tumors and surrounding neovascular regions. Its nano derivative, Nano-diamino-tetrac (NDAT), has anticancer properties in preclinical models, enhances radiosensitivity, and inhibits cancer cell growth in vitro after X-ray irradiation. Using a novel experimental system developed to deliver accurate radiation dose to tumors under sterile conditions, this study establishes NDAT's radiosensitizing effect in SUIT-2 pancreatic cancer and H1299 non-small cell lung carcinoma xenografts in athymic mice for tumor-targeted radiation. In this work, low-melting-point Lipowitz alloy was used to shield normal organs and allow accurate tumor-targeted irradiation. Over a three-week period, mice with SUIT-2 xenografts received daily NDAT treatment at different doses (0, 1, 3, or 10 mg/kg body weight) and tumor-targeted irradiation (1 or 5 Gy). Validation was performed with a test dose of 30 Gy to mice bearing SUIT-2 xenografts and resulted in more than 80% reduction in tumor weight, compared to nonirradiated tumor weight. The results of this work showed that NDAT had a radiosensitizing effect in a dose-dependent manner in decreasing tumor growth and viability. An enhanced anticancer effect of NDAT (1 mg/kg body weight) was observed in mice with H1299 xenografts receiving 5 Gy tumor-targeted irradiation, indicated by decreased tumor weight and increased necrosis, compared to nonirradiated tumors. This technique demonstrated accurate tumor-targeted irradiation with new shielding methodology, and combined with thyrointegrin antagonist NDAT treatment, showed anticancer efficacy in pancreatic cancer and non-small cell lung carcinoma.

Measurements and simulations of focused beam for orthovoltage therapy.

PURPOSE: Megavoltage photon beams are typically used for therapy because of their skin-sparing effect. However, a focused low-energy x-ray beam would also be skin sparing, and would have a higher dose concentration at the focal spot. Such a beam can be produced with polycapillary optics. MCNP5 was used to model dose profiles for a scanned focused beam, using measured beam parameters. The potential of low energy focused x-ray beams for radiation therapy was assessed. METHODS: A polycapillary optic was used to focus the x-ray beam from a tungsten source. The optic was characterized and measurements were performed at 50 kV. PMMA blocks of varying thicknesses were placed between optic and the focal spot to observe any variation in the focusing of the beam after passing through the tissue-equivalent material. The measured energy spectrum was used to model the focused beam in MCNP5. A source card (SDEF) in MCNP5 was used to simulate the converging x-ray beam. Dose calculations were performed inside a breast tissue phantom. RESULTS: The measured focal spot size for the polycapillary optic was 0.2 mm with a depth of field of 5 mm. The measured focal spot remained unchanged through 40 mm of phantom thickness. The calculated depth dose curve inside the breast tissue showed a dose peak several centimeters below the skin with a sharp dose fall off around the focus. The percent dose falls below 10% within 5 mm of the focus. It was shown that rotating the optic during scanning would preserve the skin-sparing effect of the focused beam. CONCLUSIONS: Low energy focused x-ray beams could be used to irradiate tumors inside soft tissue within 5 cm of the surface.

Dose Response of MTLn3 Cells to Serial Dilutions of Arsenic Trioxide and Ionizing Radiation.

MTLn3 cells derived from mouse mammary epithelium are known to be highly malignant and are resistant to both radio- and chemo-therapy. We exposed MTLn3 cells to various doses of inorganic Arsenic trioxide (As2O3) in combination with ionizing radiation. Cells were treated with a series of As2O3 concentrations ranging from 20 µM to 1.22 nM for 8 hour, 24 hour and 48 hour periods. Post-treated cell proliferation was quantified by measuring mitochondrial activity and DNA analysis. Cells exposed to radiation and As2O3 at concentration greater than 1.25 µM showed apoptosis and radiations alone treated cells were statistically not different from the control. Hormesis was observed for As2O3 concentrations in the range of 0.078 µM to 0.625 µM while the combined chemo and radiation treatments of the cells did not affect the hormetic effect. We have demonstrated that As2O3 (in the presence and absence of ionizing radiation) in specific low concentrations induced apoptosis in the otherwise chemoresistant cancer cells. This low concentration-mediated cell death is immediately followed by a surge in cell survival. Low dosing dosimetry is highly desirable in metronomic therapy however, it has a narrow window since necrosis, hormesis, apoptosis and other dose-dependent biological processes take place in this region. Further quantifiable dosimetry is highly desired for routine clinical practice.

Practical implications of nanodosimetry in medicine.

The grandiose promises made decades ago of cost reduction, miracle cures for cancers and universal availability of nanomedicine are still a far cry. Even we do not have any viable model to exploit nanotechnology in medicine. The most important arena of the nanotechnology is the development of nanoscale drugs for routine clinical practice. The current chemo protocols are based on maximum tolerable dose philosophy. Such a dose, when translated into active nanoscale clusters, quantitatively outnumbers the cells in an average human body. These nanoscale drug issues are discussed in this paper. A theoretical framework for commonly used drug aspirin has been considered as an example. The possible quantum physical effects have also been theoretically evaluated. Further, the amount of drug molecules in a standardized aspirin dose of 100 milligram has been computed into nanoclusters. The calculations show that the processing of nanoscale drug is a monumental task which requires new types of manufacturing facilities. Also there is a need to develop new protocols which will help realize the practical implementation of nanodosimetry in day to day drug administrations. These protocols will need to examine the implications of dose-responses such as necrosis, apoptosis and hormesis in medicine for routine clinical practice.

The emerging low-dose therapy for advanced cancers.

Generally minute doses of drugs have been prescribed in biotherapies, homeopathy, immunization and vaccinations for centuries. Now the use of low doses of drugs is on the rise to combat serious diseases such as advanced cancers around the world. This new therapeutic approach to address solid tumors and other advanced diseases is a departure from the conventional use of maximum dose protocol. A small dose of the prescribed drug is frequently administered in a continuous fashion, at regular intervals, either as a standard treatment or as a maintenance therapy for a long time. However, this new treatment method lacks any standard for drug quantization, dose fractionation, repetition frequency and duration of a treatment course for an individual patient. This paper reviews literature about metronomic therapy and discusses hormesis: both phenomena occur in low dose ranges. Better mathematical models, computer simulations, process optimization and clinical trials are warranted to fully exploit the potential of low dose metronomic therapy to cure chronic and complicated diseases. New protocols to standardize metronomic dosimetry will answer the age old questions related to hormesis and homeopathy. It appears that this new low-dose metronomic therapy will have far reaching effects in curing chronic diseases throughout the world.

Evaluation of the transmitted exposure through lead equivalent aprons used in a radiology department, including the contribution from backscatter.

A study was conducted to evaluate the radiation transmission through lead equivalent aprons that are used in a radiology department. A large area beam (poor geometry) was employed for the transmission measurements, and backscatter was simulated by placing 7" of Lucite behind each apron. Separate ionization chambers were used to measure the incident and transmitted x-ray beams. Transmission measurements were made at 70 kVp and 100 kVp through aprons and protective shields from eight different vendors that were marked 0.25 mm and 0.5 mm lead equivalent. Transmissions through 0.254 mm and 0.508 mm of pure lead were also measured and were compared with the transmissions through the lead equivalent materials. In addition, the area densities of the aprons were measured to compare radiation transmission with respect to the weights of the aprons. At 70 kVp, the transmission through 0.254 mm of pure lead was 5.4% and the transmissions through the 0.25 mm lead equivalent materials were 4.3% to 10.2% with a mean value of 7.1% and a standard deviation (s.d.) of 1.4%. At 100 kVp, the values were 15% for 0.254 mm pure lead and 12.3% to 20.7% (mean 16.8%, s.d. 2.1%) for the 0.25 mm lead equivalent materials. The transmission through the 0.508 mm pure lead sample was 0.9% at 70 kVp, and the corresponding transmissions through the 0.5 mm lead equivalent materials were 0.6% to 1.6% (mean 1.0%, s.d. 0.2%). At 100 kVp, the transmission through the 0.508 mm lead sample was 5% and those through the 0.5 mm lead equivalent materials were 3.5% to 6.7% (mean 4.9%, s.d. 0.7%). The radiation transmissions at 70 kVp, through two "lead-free" 0.5 mm lead equivalent aprons, were 1.7% and 1.9% and at 100 kVp the transmissions were 6.1% and 6.8%, respectively. This study indicates that there is a need to establish methods for acceptance testing of aprons and a need to establish acceptance limits for the x-ray transmission of aprons at specific kVp values. There is also a need for the establishment of appropriate methods and frequencies of routine quality assurance testing of radiation protection aprons.