ABSTRACT
Radioimmunotherapy (RIT) aims to deliver a high radiation dose to cancer cells, while minimizing the exposure of normal cells. Typically, monoclonal antibodies are used to target the radionuclides to cancer cell surface antigens. However, antibodies face limitations due to their poor tumor penetration and suboptimal pharmacokinetics, while the expression of their target on the cancer cell surface may be gradually lost. In addition, most antigens are expressed in a limited number of tumor types. To circumvent these problems, we developed a Nanobody (Nb)-based RIT against a prominent stromal cell (stromal-targeting radioimmunotherapy or STRIT) present in nearly all tumors, the tumor-associated macrophage (TAM). Macrophage Mannose Receptor (MMR) functions as a stable molecular target on TAM residing in hypoxic areas, further allowing the delivery of a high radiation dose to the more radioresistant hypoxic tumor regions. Since MMR expression is not restricted to TAM, we first optimized a strategy to block extra-tumoral MMR to prevent therapy-induced toxicity. A 100-fold molar excess of unlabeled bivalent Nb largely blocks extra-tumoral binding of 177Lu-labeled anti-MMR Nb and prevents toxicity, while still allowing the intra-tumoral binding of the monovalent Nb. Interestingly, three doses of 177Lu-labeled anti-MMR Nb resulted in a significantly retarded tumor growth, thereby outcompeting the effects of anti-PD1, anti-VEGFR2, doxorubicin and paclitaxel in the TS/A mammary carcinoma model. Together, these data propose anti-MMR STRIT as a valid new approach for cancer treatment.
Subject(s)
Adenocarcinoma/radiotherapy , Mammary Neoplasms, Experimental/radiotherapy , Radioimmunotherapy/methods , Single-Domain Antibodies/immunology , Adenocarcinoma/immunology , Adenocarcinoma/pathology , Animals , Disease Progression , Doxorubicin/pharmacology , Female , Lectins, C-Type/metabolism , Macrophages/metabolism , Mammary Neoplasms, Experimental/immunology , Mammary Neoplasms, Experimental/pathology , Mannose Receptor , Mannose-Binding Lectins/metabolism , Mice , Mice, Inbred BALB C , Paclitaxel/pharmacology , Receptors, Cell Surface/metabolism , Stromal Cells/immunologyABSTRACT
Percutaneous coronary interventions (PCI) of coronary chronic total occlusions (CTO) increase the risk of high radiation exposure for both the patient and the cardiologist. This study evaluated the maximum dose to the patients' skin (MSD) and the exposure of the cardiologists during CTO-PCI. Moreover, the efficiency of radioprotective drapes to reduce cardiologist exposure was assessed. Patient dose was measured during 31 procedures; dose to the cardiologist's extremities were measured during 65 procedures, among which 31 were performed with radioprotective drapes. The MSD was high (median: 1254 mGy; max: 6528 mGy), and higher than 2 Gy for 33% of the patients. The dose to the cardiologists' extremities per procedure was also of concern (median: 25-465 µSv), particularly to the left eye (median: 68 µSv; max: 187 µSv). Radioprotective drapes reduced the exposure to physician's upper limbs and eyes; especially to the left side (from -28 to -49%).
Subject(s)
Coronary Occlusion/surgery , Organs at Risk/radiation effects , Percutaneous Coronary Intervention/methods , Radiation Injuries/prevention & control , Radiation Protection/methods , Skin/radiation effects , Adult , Aged , Aged, 80 and over , Female , Humans , Male , Middle Aged , Prospective Studies , Radiation Dosage , Radiation Exposure/adverse effects , Radiation Injuries/etiology , Radiometry/methodsABSTRACT
OBJECTIVE: Nuclear medicine technologists are exposed daily to the risk of skin contamination with radiopharmaceuticals. This study deal with the different elements associated with skin contaminations. METHODS: To assess the incidence, routes and contamination activities, a long-term on-site survey was organized using a measurement system built in-house, together with a protocol based on fast detection, localization and quantification. Dosimetry calculations were carried out using Monte Carlo simulations and combined with the efficacy of skin decontamination, which was studied both in the context of daily practice of nuclear medicine and in vitro using pig skin samples. RESULTS: In 10 months 560 inspections were carried out. Local contamination was found on the fingers of nuclear medicine technologists in 40 cases, but the increasing awareness caused a significant reduction over time. The measured activities ranged from 211 Bq/cm2 to 460 kBq/cm2, resulting in cumulated skin doses between 0.02 and 809 mSv. The poor efficacy of the decontamination during daily practice is supported by the in-vitro results. The course of a contamination is characterized by an effective first decontamination, followed by relatively ineffective steps. The efficacy of dedicated decontamination agents is indicated in only a few cases. CONCLUSION: Skin contamination can be found in large doses on the skin among nuclear medicine technologists. Single contaminations can result in local skin doses exceeding the yearly dose limit because of the contribution of electrons at shallow depths and should therefore be prevented at any time. The use of a neutral hand soap should generally be preferred during decontamination. A general simplified method is proposed to assess the skin dose after a contamination with 99mTc-labelled radiopharmaceuticals or 18F-fluorodeoxyglucose.
