School of Chemistry and Chemical Engineering, Shanghai Key Laboratory of Electrical Insulation and Thermal Aging, Shanghai Jiao Tong University, Shanghai 200240, P. R. China.
J Mater Chem B. 2019 Jan 21;7(3):415-432. doi: 10.1039/c8tb02432d. Epub 2018 Dec 19.
Although photothermal therapy (PT) and photothermal-chemotherapy (PT-CT) treatments have been used to achieve complete ablation of solid tumors, they are often implemented at more than 50 °C under high intensity and using a high dose of NIR irradiation, concomitantly inducing heavy skin burning, tissue damage, and ugly scarring. Moreover, the residual tumor cells at the treated site cannot be completely eradicated, resulting in tumor recurrence and metathesis. These key obstacles have prohibited PT and PT-CT treatments from transitioning to clinical use, therefore achieving traceless ablation of solid tumors without recurrence is still a challenge for real applications. To balance hyperthermia and a high drug-loading capacity in polyprodrugs to achieve mild PT-CT, we rationally designed a novel type of intracellular pH and reduction-cleavable chlorambucil prodrug and synthesized high drug-loading polydopamine-chlorambucil conjugate nanoparticles (PDCBs). The PDCBs show good photothermal properties and demonstrate intracellular pH-, reduction-cleavable, and external near infrared (NIR)-triggered drug release profiles. Polydopamine-chlorambucil conjugate nanoparticles with 40 wt% CB (PDCB) and mild NIR irradiation could facilitate cellular internalization and subcellular trafficking, generating an excellent and synergistic antitumor effect in vitro. Pharmacokinetics and small animal fluorescent and photoacoustic imaging demonstrate that PDCB has a 3.6-fold longer blood circulation time compared to free CB and attained selective tumor accumulation, simultaneously inducing a 4.1-fold stronger photoacoustic signal than the control. By using one intravenous injection of PDCB and a single dose of mild NIR irradiation, this simple and mild PT-CT treatment achieved a non-discerned tumor on the sixth day, and traceless and complete ablation of a solid MCF-7 tumor without recurrence within 50 days, opening up a new avenue for precise cancer therapy with the potential for real applications.
尽管光热治疗（PT）和光热化疗（PT-CT）已被用于实现实体瘤的完全消融，但它们通常在高强度和高剂量近红外辐射下超过 50°C 实施，同时导致严重的皮肤灼伤、组织损伤和难看的疤痕。此外，治疗部位的残留肿瘤细胞不能完全被根除，导致肿瘤复发和转移。这些关键障碍阻止了 PT 和 PT-CT 治疗向临床应用的转化，因此实现无复发的实体瘤无痕消融仍然是实际应用的挑战。为了平衡前药中的高热和高载药量以实现温和的 PT-CT，我们合理设计了一种新型的细胞内 pH 和还原可裂解的苯丁酸氮芥前药，并合成了高载药量的聚多巴胺-苯丁酸氮芥偶联纳米粒子（PDCBs）。PDCBs 表现出良好的光热性能，并表现出细胞内 pH、还原可裂解和外部近红外（NIR）触发的药物释放特征。载药量为 40wt% 的苯丁酸氮芥的聚多巴胺-苯丁酸氮芥偶联纳米粒子（PDCB）和温和的 NIR 照射可促进细胞内化和亚细胞转运，在体外产生优异的协同抗肿瘤作用。药代动力学和小动物荧光和光声成像表明，与游离 CB 相比，PDCB 的血液循环时间延长了 3.6 倍，并具有选择性的肿瘤积累，同时产生的光声信号比对照强 4.1 倍。通过单次静脉注射 PDCB 和单次温和 NIR 照射，这种简单温和的 PT-CT 治疗在第六天实现了无肿瘤的肿瘤，并且在 50 天内无痕且完全消融 MCF-7 实体瘤，没有复发，为精确癌症治疗开辟了新途径，具有实际应用的潜力。
