Thermal ablation has been commonly used as an effective treatment for hepatocellular carcinoma; however, peri-necrotic tumor residues after ablation play a significant role in tumor recurrence and poor prognosis. Therefore, developing agents that can effectively target and eliminate residual tumors is critically needed. Necrosis targeting strategies have potential implications for evaluating tumor necrosis areas and treating the surrounding residual tumors. To address this issue, we have developed a biodegradable nanoparticle with necrosis avidity that is compatible with fluorescence imaging, single photon emission computed tomography (SPECT) imaging, and necrosis targeted radiotherapy. The nanoparticles were synthesized using iodine-131-labeled hypericin (¹³¹I-Hyp) as the core and amphiphilic copolymer poly(ethylene glycol)-block-poly(ε-caprolactone) (PEG–PCL) as the shell. The developed nanoparticle, PNP@(¹³¹I-Hyp), has a uniform spherical morphology with a size of 33.07 ± 3.94 and 45.93 ± 0.58 nm determined by cryogenic transmission electron microscopy (cryo-TEM) and dynamic light-scattering analysis (polydispersity index = 0.19 ± 0.01), respectively, and having a good stability and blood compatibility in vitro. In mouse subcutaneous ablated-residual tumor models, fluorescence and SPECT imaging demonstrated that PNP@(¹³¹I-Hyp) prominently accumulated in the tumor and was retained for as long as 168 h following intravenous injection. Moreover, ex vivo analyses showed that PNP@(¹³¹I-Hyp) mainly gathered in the necrotic zones of subcutaneous tumors and inhibited residual tumors by radiotherapy. In addition, histological examination of harvested organs and hematological analysis demonstrated that intravenous injection of 5 mCi/kg nanoparticles caused no gross abnormalities. This multifunctional nanoparticle, therefore, has necrosis imaging and targeted therapeutic effects on residual tumors after thermal ablation of hepatocellular carcinoma, showing potential for clinical application.

中文翻译：

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用于肝细胞癌消融后残留肿瘤的坏死靶向、荧光/SPECT 成像和放射治疗的多模式治疗诊断纳米颗粒

热消融已被普遍用作肝细胞癌的有效治疗方法。然而，消融后坏死周围肿瘤残留在肿瘤复发和不良预后中起着重要作用。因此，迫切需要开发能够有效靶向并消除残留肿瘤的药物。坏死靶向策略对于评估肿瘤坏死区域和治疗周围残留肿瘤具有潜在意义。为了解决这个问题，我们开发了一种具有坏死亲合力的可生物降解纳米颗粒，它与荧光成像、单光子发射计算机断层扫描 (SPECT) 成像和坏死靶向放射治疗兼容。以碘131标记的金丝桃素（¹³¹ I-Hyp）为核心，两亲性共聚物聚（乙二醇）-嵌段-聚（ε-己内酯）（PEG-PCL）为壳合成纳米颗粒。通过低温透射电子显微镜（cryo-TEM）和动态光散射分析（多分散指数）测定，所开发的纳米颗粒 PNP@（¹³¹ I-Hyp）具有均匀的球形形态，尺寸为 33.07 ± 3.94 和 45.93 ± 0.58 nm =0.19±0.01)，并在体外具有良好的稳定性和血液相容性。在小鼠皮下消融残留肿瘤模型中，荧光和 SPECT 成像表明 PNP@( ¹³¹ I-Hyp) 在肿瘤中显着积聚，并在静脉注射后保留长达 168 小时。此外，离体分析表明，PNP@( ¹³¹ I-Hyp)主要聚集在皮下肿瘤的坏死区，并通过放射治疗抑制残留肿瘤。此外，收获器官的组织学检查和血液学分析表明，静脉注射5 mCi/kg纳米颗粒没有引起明显异常。因此，这种多功能纳米颗粒对肝细胞癌热消融后残留肿瘤具有坏死成像和靶向治疗作用，具有临床应用潜力。