Abstract:
Hypoxia-activated prodrugs (HAPs) have drawn increasing attention for improving the antitumor effects while minimizing side effects. However, the heterogeneous distribution of the hypoxic region in tumors severely impedes the curative effect of HAPs. Additionally, most HAPs are not amenable to optical imaging, and it is difficult to precisely trace them in tissues. Herein, we carefully designed and synthesized a multifunctional therapeutic BAC prodrug by connecting the chemotherapeutic drug camptothecin (CPT) and the fluorescent photothermal agent boron dipyrromethene (BODIPY) via hypoxia-responsive azobenzene linkers. To enhance the solubility and tumor accumulation, the prepared BAC was further encapsulated into a human serum albumin (HSA)-based drug delivery system to form HSA@BAC nanoparticles. Since the CPT was caged by a BODIPY-based molecule at the active site, the BAC exhibited excellent biosafety. Importantly, the activated CPT could be quickly released from BAC and could perform chemotherapy in hypoxic cancer cells, which was ascribed to the cleavage of the azobenzene linker by overexpressed azoreductase. After irradiation with a 730 nm laser, HSA@BAC can efficiently generate hyperthermia to achieve irreversible cancer cell death by oxygen-independent photothermal therapy. Under fluorescence imaging-guided local irradiation, both in vitro and in vivo studies demonstrated that HSA@BAC exhibited superior antitumor effects with minimal side effects.
摘要:
缺氧激活的前药(HAP)在提高抗肿瘤效果的同时将副作用降至最低方面已引起越来越多的关注。然而,肿瘤中缺氧区域的分布不均严重阻碍了HAP的疗效。此外,大多数HAP不适合光学成像,很难在组织中精确追踪它们。在这里,我们精心设计并合成了一种多功能治疗性BAC前药,方法是将化疗药物喜树碱(CPT)和荧光光热剂硼二吡咯亚甲基(BODIPY)通过缺氧响应性偶氮苯接头连接。为了提高溶解度和肿瘤的积累,将制备的BAC进一步包封到基于人血清白蛋白(HSA)的药物递送系统中以形成HSA@BAC纳米颗粒。由于CPT在活性位点被基于BODIPY的分子笼住,BAC表现出优异的生物安全性。重要的是,激活的CPT可以从BAC中快速释放,并可以在缺氧的癌细胞中进行化疗,归因于过表达的偶氮还原酶对偶氮苯接头的裂解。用730nm激光照射后,HSA@BAC可以有效地产生热疗,通过不依赖氧的光热疗法实现不可逆的癌细胞死亡。在荧光成像引导的局部照射下,体外和体内研究均表明,HSA@BAC具有优异的抗肿瘤作用,副作用最小。