Xiao Yafang, An Fei-Fei, Chen Jiaxiong, Xiong Shiyun, Zhang Xiao-Hong
Jiangsu Key Laboratory for Carbon-Based Functional Materials & Devices, Institute of Functional Nano & Soft Materials (FUNSOM), Joint International Research Laboratory of Carbon-Based Functional Materials and Devices, Soochow University, 199 Ren'ai Road, Suzhou, 215123, Jiangsu, P. R. China.
J Mater Chem B. 2018 Jun 14;6(22):3692-3702. doi: 10.1039/c8tb00427g. Epub 2018 May 10.
Photo/chemo combination therapy has been demonstrated to be a generally more powerful strategy for treating cancers than a single treatment modality. However, it is unknown whether the timing of light irradiation has any impact on therapeutic efficacy. We designed a carrier-free and self-monitoring nanodrug to monitor the entire dual-drug release profile and determined the impact of photodynamic therapy (PDT) at different time points. The designed nanodrug consists of the chemotherapeutic doxorubicin (DOX) and the photosensitizer pheophorbide A (PhA). The drugs form a fluorescence resonance energy transfer (FRET) pair (DOX transferring energy to PhA) when present at a precise ratio in the combination nanodrug. Due to the FRET effect, the DOX-PhA nanoparticles (NPs) show PhA fluorescence in a normal pH environment (such as cytoplasm). However, the FRET effect is lost when the NPs are disassembled in an acidic environment (such as lysosomes), and the DOX fluorescence is recovered. By real-time fluorescence variation monitoring, we determined the key time points when the drugs reached various subcellular locations, which helped us to determine the PDT-triggering time points and investigate the impact on the therapeutic effect in the combination therapy. Furthermore, the PDT was triggered at these established time points both in vitro and in vivo, which revealed that the best PDT-triggering time point in the combination therapy was achieved after nuclear entry of DOX. The study suggests that the optimization of combination therapy, not only photo/chemo but also chemo/chemo combination therapy, may require not only a controlled drug ratio but also a controlled drug release profile and target arrival time.
光/化疗联合疗法已被证明是一种比单一治疗方式更有效的癌症治疗策略。然而，光照射的时间是否会对治疗效果产生影响尚不清楚。我们设计了一种无载体且能自我监测的纳米药物，以监测整个双药释放过程，并确定光动力疗法（PDT）在不同时间点的影响。所设计的纳米药物由化疗药物阿霉素（DOX）和光敏剂脱镁叶绿酸A（PhA）组成。当这两种药物以精确比例存在于联合纳米药物中时，它们形成荧光共振能量转移（FRET）对（DOX将能量转移给PhA）。由于FRET效应，DOX-PhA纳米颗粒（NPs）在正常pH环境（如细胞质）中显示出PhA荧光。然而，当NPs在酸性环境（如溶酶体）中分解时，FRET效应消失，DOX荧光恢复。通过实时荧光变化监测，我们确定了药物到达各个亚细胞位置的关键时间点，这有助于我们确定PDT触发时间点，并研究其对联合治疗中治疗效果的影响。此外，在体外和体内的这些既定时间点触发PDT，结果表明联合治疗中最佳的PDT触发时间点是在DOX进入细胞核之后。该研究表明，联合治疗的优化，不仅包括光/化疗联合，也包括化疗/化疗联合，可能不仅需要控制药物比例，还需要控制药物释放过程和靶向到达时间。
