College of Materials Science and Engineering, Zhejiang University of Technology, Hangzhou 310014, PR China.
College of Materials Science and Engineering, Zhejiang University of Technology, Hangzhou 310014, PR China.
Acta Biomater. 2023 Sep 15;168:565-579. doi: 10.1016/j.actbio.2023.07.022. Epub 2023 Jul 20.
Nanomedicines combining multimodal therapeutic modalities supply opportunities to eliminate tumors in a safe and efficient manner. However, the rigid encapsulation and covalent conjugation of different therapeutic reagents suffer from the complicated preparation process, premature drug leakage and severe adverse events. Herein, we report a self-enhanced supramolecular nanomedicine (SND) based on the host-guest molecular recognition between β-cyclodextrin (β-CD) and camptothecin (CPT) for trimodal synergistic chemotherapy, photodynamic therapy (PDT) and photothermal therapy (PTT) using a single 670 nm near-infrared (NIR) laser. Thioketal bond and polyethylene glycol (PEG) segment are introduced into the structure of CPT-tk-PEG prodrug, thus the premature release of CPT is efficiently inhibited and the specific drug release is realized at tumor site where singlet oxygen (O)-generated PDT is performed. A boron dipyrromethene (BODIPY) theranostic agent is anchored onto β-CD, endowing SND with capabilities of fluorescence imaging, PDT and PTT. Benefiting from the supramolecular assembly, not only the solubility of CPT is improved by 40 times, but also the blood circulation time and tumor accumulation of SND are greatly promoted. In vivo, SND can effectively induce the immunogenic cell death (ICD) of tumor cells, thus performing prominent inhibition against both primary and distal tumors, and even anti-metastasis effect against liver without causing obvious systemic toxicity. STATEMENT OF SIGNIFICANCE: Although nanomedicines supply opportunities to eliminate tumors in an efficient manner, they usually suffer from premature drug leakage, complicated preparation process and severe side effects owing to the rigid encapsulation or covalent conjugation. Based on the host-guest molecular recognition, we developed a self-enhanced SND for synergistic chemotherapy, photodynamic therapy and photothermal therapy. Introduction of thioketal bond in CPT prodrug avoided the premature drug release, and the specific drug release was realized in the tumor cells. Profiting from the facile supramolecular assembly strategy, SND not only displayed a primary anticancer efficacy with a low systemic toxicity, but also efficiently inhibited the growth of distal tumors, contributing a vaccine-like function to eradicate the recurrent and metastatic tumors.
纳米药物将多种治疗模式相结合，为安全有效地消除肿瘤提供了机会。然而，不同治疗试剂的刚性封装和共价偶联存在制备过程复杂、药物早期泄漏和严重不良反应等问题。在此，我们报告了一种基于β-环糊精（β-CD）和喜树碱（CPT）之间主客体分子识别的自增强超分子纳米药物（SND），用于使用单一 670nm 近红外（NIR）激光进行三模式协同化疗、光动力疗法（PDT）和光热疗法（PTT）。硫代缩酮键和聚乙二醇（PEG）片段被引入 CPT-tk-PEG 前药的结构中，从而有效地抑制了 CPT 的早期释放，并在进行单线态氧（O）生成 PDT 的肿瘤部位实现了特异性药物释放。将硼二吡咯甲川（BODIPY）治疗剂锚定在β-CD 上，使 SND 具有荧光成像、PDT 和 PTT 的能力。得益于超分子组装，不仅提高了 CPT 的溶解度 40 倍，而且还大大促进了 SND 的血液循环时间和肿瘤积累。在体内，SND 能有效地诱导肿瘤细胞的免疫原性细胞死亡（ICD），从而对原发性和远端肿瘤均表现出显著的抑制作用，甚至对肝脏的转移也有抑制作用，而不会引起明显的全身毒性。
尽管纳米药物提供了高效消除肿瘤的机会，但由于刚性封装或共价偶联，它们通常会因药物早期泄漏、复杂的制备过程和严重的副作用而受到限制。基于主客体分子识别，我们开发了一种用于协同化疗、光动力疗法和光热疗法的自增强 SND。CPT 前药中硫代缩酮键的引入避免了药物的早期释放，并在肿瘤细胞中实现了特异性药物释放。得益于简便的超分子组装策略，SND 不仅表现出低系统毒性的原发性抗癌疗效，而且还能有效地抑制远端肿瘤的生长，发挥类似疫苗的功能，以根除复发性和转移性肿瘤。
