Department of Ultrasound, First Hospital of Shanxi Medical University, 85 Jiefang Nan Road, Taiyuan, Shanxi 030001, China; Department of Ultrasound, Heping Hospital Affiliated to Changzhi Medical College, Changzhi 046000, China.
State Key Laboratory of Radiation Medicine and Protection, School for Radiological and Interdisciplinary Sciences (RAD-X) and Collaborative Innovation Centre of Radiation Medicine of Jiangsu Higher Education Institutions, Soochow University, Suzhou 215123, China.
Acta Biomater. 2024 Aug;184:409-418. doi: 10.1016/j.actbio.2024.06.019. Epub 2024 Jun 20.
Sonodynamic therapy (SDT) is emerging as a promising modality for cancer treatment. However, improving the tumor bioavailability and anti-hypoxia capability of sonosensitizers faces a big challenge. In this work, we present a tumor microenvironment (TME)-mediated nanomorphology transformation and oxygen (O) self-production strategy to enhance the sonodynamic therapeutic efficacy of tumors. A smart probe Ce6-Leu@Mn that consists of a glutathione (GSH) and leucine amino peptidase (LAP) dual-responsive unit, a 2-cyanobenzothiazole (CBT) group, and a Mn-chelated Ce6 as sonosensitizer for tumor SDT was synthesized, and its SDT potential for liver tumor HepG2 in living mice was systematically studied. It was found that the probes could self-assemble into large nanoparticles in physiological condition and spontaneously transformed into small particles under the dual stimulation of GSH and LAP in TME resulting in enhanced tumor accumulation and deep penetration. More notably, Ce6-Leu@Mn could convert endogenous hydrogen peroxide to O, thereby alleviating the hypoxia and achieving effective SDT against hypoxic tumors under the excitation of ultrasound. We thus believe this smart TME-responsive probe may provide a noninvasive and efficient means for malignant tumor treatment. STATEMENT OF SIGNIFICANCE: Sonodynamic therapy (SDT) is emerging as a promising therapeutic modality for cancer treatment. However, how to improve the tumor bioavailability and anti-hypoxia capability of sonosensitizers remains a huge challenge. Herein, we rationally developed a theranostic probe Ce6-Leu@Mn that can transform into small-size nanoparticles from initial large particles under the dual stimulation of LAP and GSH in tumor microenvironment (TME) resulting in enhanced tumor accumulation, deep tissue penetration as well as remarkable O self-production for enhanced sonodynamic therapy of human liver HepG2 tumor in living mice. This smart TME-responsive probe may provide a noninvasive and efficient means for hypoxic tumor treatment.
声动力学疗法（SDT）作为一种有前途的癌症治疗方法正在兴起。然而，提高声敏剂的肿瘤生物利用度和抗缺氧能力仍然是一个巨大的挑战。在这项工作中，我们提出了一种肿瘤微环境（TME）介导的纳米形态转变和氧气（O）自产生策略，以增强肿瘤的声动力学治疗效果。我们合成了一种智能探针 Ce6-Leu@Mn，它由谷胱甘肽（GSH）和亮氨酸氨肽酶（LAP）双响应单元、2-氰基苯并噻唑（CBT）基团和 Mn 螯合的 Ce6 作为声敏剂组成，用于活体小鼠肝癌 HepG2 的肿瘤 SDT 进行了系统研究。结果发现，探针在生理条件下可以自组装成大纳米颗粒，而在 TME 中 GSH 和 LAP 的双重刺激下，探针可以自发转化为小颗粒，从而增强肿瘤的积累和深层渗透。更值得注意的是，Ce6-Leu@Mn 可以将内源性过氧化氢转化为 O，从而缓解缺氧，并在超声激发下对缺氧肿瘤进行有效的 SDT。因此，我们相信这种智能 TME 响应探针可能为恶性肿瘤的治疗提供一种非侵入性和有效的手段。
