Department of Medical Ultrasonics, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510080, People's Republic of China.
Department of Microsurgery and Orthopedic Trauma, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510080, People's Republic of China.
Int J Nanomedicine. 2020 Aug 6;15:5687-5700. doi: 10.2147/IJN.S256038. eCollection 2020.
Sonodynamic therapy (SDT) has been widely used for the noninvasive treatment of solid tumors, but the hypoxic tumor microenvironment limits its therapeutic effect. The current methods of reoxygenation to enhance SDT have limitations, prompting reconsideration of the design of therapeutic approaches. Here, we developed a tumor microenvironment-responsive nanoplatform by reducing oxygen consumption to overcome hypoxia-induced resistance to cancer therapy.
A pH-responsive drug-loaded liposome (MI-PEOz-lip) was prepared and used to reduce oxygen consumption, attenuating hypoxia-induced resistance to SDT and thereby improving therapeutic efficiency. Photoacoustic imaging (PAI) and fluorescence imaging (FI) of MI-PEOz-lip were evaluated in vitro and in breast xenograft tumor models. The pH-sensitive functionality of MI-PEOz-lip was applied for pH-triggered cargo release, and its capacity was evaluated. The MI-PEOz-lip-mediated SDT effect was compared with other treatments in vivo.
MI-PEOz-lip was demonstrated to specifically accumulate in tumors. Metformin molecules in liposomes selectively accumulate in tumors by pH-responsive drug release to inhibit the mitochondrial respiratory chain while releasing IR780 to the tumor area. These pH-responsive liposomes demonstrated PAI and FI imaging capabilities in vitro and in vivo, providing potential for treatment guidance and monitoring. In particular, the prepared MI-PEOz-lip combined with ultrasound irradiation effectively inhibited breast tumors by producing toxic reactive singlet oxygen species (ROS), while the introduction of metformin inhibited mitochondrial respiration and reduced tumor oxygen consumption, resulting in excellent sonodynamic therapy performance compared with other treatments.
In this study, we present a novel strategy to achieve high therapeutic efficacy of SDT by the rational design of multifunctional nanoplatforms. This work provides a new strategy that can solve the current problems of inefficient oxygen delivery strategies and weaken resistance to various oxygen-dependent therapies.
声动力学疗法（SDT）已广泛用于实体瘤的非侵入性治疗，但缺氧的肿瘤微环境限制了其治疗效果。目前的再氧合方法增强 SDT 存在局限性，促使人们重新考虑治疗方法的设计。在这里，我们通过减少耗氧量来开发一种肿瘤微环境响应型纳米平台，以克服缺氧诱导的癌症治疗耐药性。
制备了一种 pH 响应载药脂质体（MI-PEOz-lip），用于减少耗氧量，减轻缺氧对 SDT 的耐药性，从而提高治疗效率。在体外和乳腺癌异种移植肿瘤模型中评估了 MI-PEOz-lip 的光声成像（PAI）和荧光成像（FI）。应用 MI-PEOz-lip 的 pH 敏感性功能进行 pH 触发的货物释放，并评估其能力。将 MI-PEOz-lip 介导的 SDT 效果与其他治疗方法进行了体内比较。
MI-PEOz-lip 被证明可以特异性地在肿瘤中积累。脂质体中的二甲双胍分子通过 pH 响应药物释放选择性地在肿瘤中积累，以抑制线粒体呼吸链，同时将 IR780 释放到肿瘤区域。这些 pH 响应脂质体在体外和体内均具有 PAI 和 FI 成像能力，为治疗指导和监测提供了潜力。特别是，所制备的 MI-PEOz-lip 与超声辐照相结合，通过产生有毒的活性单线态氧（ROS）有效地抑制了乳腺癌，而二甲双胍的引入抑制了线粒体呼吸并减少了肿瘤耗氧量，与其他治疗方法相比，具有优异的声动力学治疗性能。
在这项研究中，我们提出了一种通过合理设计多功能纳米平台实现 SDT 高治疗效果的新策略。这项工作提供了一种新的策略，可以解决目前氧气输送策略效率低下和削弱各种依赖氧气的治疗方法耐药性的问题。
