载体铂（Carrier platin）联合低剂量局部SmART+ X射线照射比单独使用任一疗法均能获得更好的肿瘤控制

Background: Carrier platin is a novel nanoparticle based chemotherapeutic that has shown greater tumor toxicity than other platinum-based therapies with few off-target effects. X-ray radiation therapy is a widely used cancer treatment known to have the ability to cure some types of cancer. Combining the two therapies offers the opportunity to reduce prescribed doses of both therapies leading to less heavy metal and radiation induced side effects. Methods: The response of YTN16, HeLa, 293T and KPCY7 cancer cells to SmART+ radiation therapy alone, to carrier platin alone and to the combination of SmART+ radiation therapy and carrier platin was studied in a 96-well plate and in C57BL/6 mice. For the radiation alone in vitro studies, focal plane (at isocenter) X-rays were applied to the plate in six doses of 0 (control), 2, 4, 6, 8, and 10 Gray. For the carrier platin alone in vitro studies, eleven doses of 0.0 (control), 0.5, 1.0, 1.5, 2.0, 3.0, 4.0, 5.0, 6.0, 8.0 and 10.0 µg/mL were applied to the plate in 9-well groups with the control group containing 6-wells. For the combination in vitro studies, low doses of X-rays (0, 2, 4 and 6 Gray) and carrier platin (0.0, 0.5, 1.0 and 2.0 µg/mL) were arranged in a grid of 6-well groups. Bioluminescence (Tecan Spark) along with bright field and green fluorescent protein microscopy (EVOS M5000) was used to quantify cell survival. For the in vivo study, sixteen male C57BL/6 mice were subcutaneously xenografted with one million KPCY7 cancer cells per hundred microliters media in a 50% - 50% mixture with Matrigel. Tumors were monitored with a caliper and allowed to grow until they were measured to be one hundred cubic millimeters. Mice were then divided into four treatment groups of four mice per cohort. After which, two of the cohorts received X-ray radiation locally to the tumor in four doses of two Gray once per week and two of the cohorts received four doses of 2 mg(Pt)/kg once per week. After the four doses of radiation and carrier platin, one mouse from each cohort was sacrificed and tumors were harvested for tumor microenvironment imaging. Results: In the dish, carrier platin treated cancer cells all showed a knee in the survival curve around 2.0 µg/mL resulting in approximately 80% killing suggesting a lower dose should be used in the combination therapy. Also in the dish, tumor cells expressed various radiosensitivities with HeLa being the least sensitive (~35% killing at 6 Gray) and 293T being the most (~80% killing at 6 Gray) again suggesting that a lower dose should be used for the combination approach. In C57BL/6 mice, the combination therapy of X-ray radiation and carrier platin showed the best tumor control. Conclusions: Our studies demonstrate that focal SmART+ X-ray radiation and targeted nanoparticles can be used to slow or halt tumor growth in the petri dish and in immunocompetent mice. Coupling X-ray radiation with carrier platin may have the ability to reduce tumor activity completely.