Enhanced Delivery of Radiolabeled Polyoxazoline into Tumors via Self-Aggregation under Hyperthermic Conditions
Enhanced Delivery of Radiolabeled Polyoxazoline into Tumors via Self-Aggregation under Hyperthermic Conditions
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DOI：
10.1021/acs.molpharmaceut.8b00441
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发表时间：
2018-09-01
影响因子：
4.9
通讯作者：
Saji, Hideo
中科院分区：
文献类型：
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作者：
Sano, Kohei;Kanada, Yuko;Saji, Hideo
为了开发用于内部放射治疗的放射性药物，其具有高抗癌效果，同时将正常组织暴露于低辐射水平，我们合成了放射性标记的聚恶唑啉（POZ），一种温度响应性聚合物，并通过在高温（42-43摄氏度）条件下通过自聚集加速放射性标记的POZ的积累来建立用于靶向肿瘤的新型药物递送系统。通过使用2-乙基-2-恶唑啉和2-异丙基-2-恶唑啉的活性阳离子聚合，合成了具有37-38摄氏度的低临界溶解温度（LCST）的POZ衍生物（Et-IspPOZ）（10、20和30 kDa）; POZ衍生物在体温下可溶，但在热处理（42-43摄氏度）时自聚集。接下来，制备铟-111（In-111）标记的Et-IspPOZ，并且在高温条件下在携带结肠26的小鼠中静脉内注射探针时，研究分子量和注射的POZ剂量对肿瘤中放射性蓄积的影响。当POZ的分子量大于20 kDa时，肿瘤中放射性摄取增加，而与注射POZ的剂量（4-40 nmol）无关。肿瘤中保留的放射性量在停止暴露于热处理后长达3小时内没有变化。此外，具有大于42摄氏度的LCST的Et-IspPOZ衍生物的肿瘤摄取显著低于具有37-38摄氏度的LCST的Et-IspPOZ的肿瘤摄取，表明POZ的自聚集参与肿瘤摄取。最后，使用体内共聚焦激光显微镜评价荧光标记的Et-IspPOZ的肿瘤内定位。在热处理的肿瘤附近和血管内观察到许多明亮的荧光斑点。总之，在高温条件下阐明了放射性标记的Et-IspPOZ的高肿瘤摄取;从而证明了使用放射性标记的POZ衍生物开发新型内部放射治疗的可能性。
In order to develop a radiopharmaceutical for internal radiotherapy that had a high anticancer effect while exposing normal tissues to low radiation levels, we synthesized a radiolabeled polyoxazoline (POZ), a thermoresponsive polymer, and established a novel drug delivery system for targeting tumors by accelerating the accumulation of the radiolabeled POZ via self-aggregation under hyperthermic (42-43 degrees C) conditions. By living-cationic polymerization using 2-ethyl-2-oxazoline and 2-isopropyl-2-oxazoline, POZ derivatives (Et-IspPOZ) (10, 20, and 30 kDa) with lower critical solution temperatures (LCSTs) of 37-38 degrees C were synthesized; the POZ derivatives were soluble at the body temperature but self-aggregated upon heat treatment (42-43 degrees C). Next, the indium-111 (In-111)-labeled Et-IspPOZ was prepared, and the effect of molecular weight and injected POZ dose on the accumulation of radioactivity in the tumors was investigated upon intravenous injection of probes under hyperthermic conditions in colon 26-bearing mice. The uptake of radioactivity in tumors was increased when the molecular weight of POZ was greater than 20 kDa, while it was independent of the injected POZ dose (4-40 nmol). The amount of radioactivity retained in the tumor did not change for up to 3 h after exposure to heat treatment was stopped. Furthermore, the tumor uptake of the Et-IspPOZ derivative with an LCST greater than 42 degrees C was significantly lower than that of Et-IspPOZ, which had an LCST of 37-38 degrees C, suggesting the involvement of the self-aggregation of POZ on tumor uptake. Finally, the intratumoral localization of fluorescence-labeled Et-IspPOZ was evaluated using in vivo confocal laser microscopy. Many bright fluorescence spots were observed in the heat-treated tumors nearby and within blood vessels. In conclusion, the high tumor uptake of radiolabeled Et-IspPOZ was elucidated under hyperthermic conditions; thereby, the possibility of developing a novel internal radiotherapy using radiolabeled POZ derivatives was demonstrated.