State Key Laboratory of Polymer Physics and Chemistry, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, PR China; School of Applied Chemistry and Engineering, University of Science and Technology of China, Hefei 230026, PR China.
State Key Laboratory of Polymer Physics and Chemistry, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, PR China; Department of Medical Oncology, Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou 450008, PR China.
Acta Biomater. 2019 Aug;94:459-468. doi: 10.1016/j.actbio.2019.05.047. Epub 2019 May 22.
The synergistic efficacy and clinical application of light-responsive polymeric co-delivery systems are severely restricted by uncontrollable/imprecise drug loading, release, and adverse effects caused by the introduction of additional light-responsive molecules or contrast agents when diagnostic imaging is applied to guide therapy. Here, we report the design of a light-activatable dual prodrug polymer nanoparticle (DPP NP) for precise synergistic chemotherapy guided by drug-mediated computed tomography (DMCT) imaging without the introduction of any additional diagnostic imaging agent. DPP NP enables visible light-triggered prodrug polymer backbone cleavage and bioactive Pt(II) release in cancer cell/tumor site; the light-cleaved polymer fragments are further hydrolyzed to produce demethyl cantharidin (DMC). Notably, the drug loading ratio of Pt(IV) and DMC in DPP NP was fixed at an optimal value to achieve maximum synergistic cancer cell killing, which was kept even after cellular uptake, thereby resulting in enhanced synergistic antitumor efficacy both in vitro and in vivo. Because of the high content of the heavy metal Pt in the polymer chain, the spatial/temporal dynamic biodistribution as well as metabolism of DPP NP in vivo can be monitored by Pt DMCT imaging to guide the light irradiation parameters for optimized light-activatable synergistic chemotherapy. Guided by Pt DMCT imaging, DPP NP was able to achieve an improved light-activatable antitumor efficacy, with 75% tumors fully cured and low toxicity. The light-activatable DDP NP system exhibits tremendous potential as precise theranostic nanomedicine. STATEMENT OF SIGNIFICANCE: The synergistic efficacy and clinical application of light-responsive polymeric co-delivery systems are severely restricted by uncontrollable/imprecise drug loading, delivery, and release, as well as adverse effects caused by the introduction of additional light-responsive molecules or contrast agents when diagnostic imaging is applied to guide therapy. Herein, we report the design of a light-activatable dual prodrug polymer nanoparticle (DPP NP) for precise synergistic chemotherapy guided by drug-mediated computed tomography imaging without the introduction of any additional diagnostic imaging agents. Notably, the drug loading ratio of Pt(II) and DMC in DPP NP was fixed at an optimal value to achieve maximum synergistic cancer cell killing, which was kept even after cellular uptake, thereby resulting in enhanced synergistic antitumor efficacy both in vitro and in vivo. The light-activatable DDP NP system exhibits tremendous potential as precise theranostic nanomedicine.
光响应型聚合物共递药系统的协同疗效和临床应用受到严重限制，这是由于在应用诊断成像来指导治疗时，不可控/不精确的药物负载、释放以及引入额外的光响应分子或对比剂而产生的不良反应。在这里，我们报告了一种光活化双前药聚合物纳米粒子（DPP NP）的设计，该纳米粒子可通过药物介导的计算机断层扫描（DMCT）成像进行精确的协同化疗引导，而无需引入任何额外的诊断成像剂。DPP NP 能够在癌细胞/肿瘤部位实现可见光触发的前药聚合物主链断裂和生物活性 Pt(II)释放；光裂解的聚合物片段进一步水解生成去甲基斑蝥素（DMC）。值得注意的是，DPP NP 中 Pt(IV)和 DMC 的药物载量比固定在最佳值，以实现最大的协同癌细胞杀伤作用，即使在细胞摄取后也能保持，从而在体外和体内都增强了协同抗肿瘤疗效。由于聚合物链中含有大量重金属 Pt，因此可以通过 Pt DMCT 成像监测 DPP NP 在体内的时空动态生物分布和代谢，以指导优化光活化协同化疗的光照射参数。在 Pt DMCT 成像的指导下，DPP NP 能够实现改善的光活化抗肿瘤疗效，75%的肿瘤完全治愈，且毒性低。光活化 DDP NP 系统作为精确的治疗诊断纳米医学具有巨大的潜力。
意义声明：光响应型聚合物共递药系统的协同疗效和临床应用受到严重限制，这是由于在应用诊断成像来指导治疗时，不可控/不精确的药物负载、释放以及引入额外的光响应分子或对比剂而产生的不良反应。在此，我们报告了一种光活化双前药聚合物纳米粒子（DPP NP）的设计，该纳米粒子可通过药物介导的计算机断层扫描（DMCT）成像进行精确的协同化疗引导，而无需引入任何额外的诊断成像剂。值得注意的是，DPP NP 中 Pt(II)和 DMC 的药物载量比固定在最佳值，以实现最大的协同癌细胞杀伤作用，即使在细胞摄取后也能保持，从而在体外和体内都增强了协同抗肿瘤疗效。光活化 DDP NP 系统作为精确的治疗诊断纳米医学具有巨大的潜力。
