Photodynamic Priming Mitigates Chemotherapeutic Selection Pressures and Improves Drug Delivery.
Photodynamic Priming Mitigates Chemotherapeutic Selection Pressures and Improves Drug Delivery.
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光动力引发可减轻化疗选择压力并改善药物输送。
DOI：
10.1158/0008-5472.can-17-1700
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发表时间：
2018-01-15
期刊：
影响因子：
11.2
通讯作者：
Hasan T
中科院分区：
文献类型：
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作者：
Huang HC;Rizvi I;Liu J;Anbil S;Kalra A;Lee H;Baglo Y;Paz N;Hayden D;Pereira S;Pogue BW;Fitzgerald J;Hasan T
药物输送的生理障碍和耐药性的选择限制了癌症患者的生存结局。在这项研究中，我们提出了临床前证据，即亚肿瘤杀伤光动力引发（PDP）策略可以缓解肿瘤微环境中的药物递送障碍，以安全地拓宽纳米细胞毒性药物的治疗窗口。在胰腺癌的原位异种移植模型中，PDP与纳米脂质体伊立替康（nal-IRI）的组合预防了肿瘤复发，减少了转移，并增加了无进展生存期和1年无病生存期。PDP通过靶向多个肿瘤区室来实现这些持久的改善，以（1）增加肿瘤内药物积聚>10倍，（2）增加药物暴露超过临界治疗阈值的持续时间，和（3）减弱CD 44和CXCR 4表达的激增，其介导多周期化疗后经常观察到的化学抗性。总体而言，我们的研究结果为PDP的有效性提供了临床前概念证明，以最大限度地降低肿瘤复发，进展和耐药性的风险，并延长患者的生存期。
Physiological barriers to drug delivery and selection for drug resistance limit survival outcomes in cancer patients. In this study, we present preclinical evidence that a subtumoricidal photodynamic priming (PDP) strategy can relieve drug delivery barriers in the tumor microenvironment to safely widen the therapeutic window of a nanoformulated cytotoxic drug. In orthotopic xenograft models of pancreatic cancer, combining PDP with nanoliposomal irinotecan (nal-IRI) prevented tumor relapse, reduce metastasis and increase both progression-free survival and 1-year disease-free survival. PDP enabled these durable improvements by targeting multiple tumor compartments to (1) increase intratumoral drug accumulation by >10-fold, (2) increase the duration of drug exposure above a critical therapeutic threshold, and (3) attenuate surges in CD44 and CXCR4 expression which mediate chemoresistance often observed after multi-cycle chemotherapy. Overall, our results offer preclinical proof of concept for the effectiveness of PDP to minimize risks of tumor relapse, progression and drug resistance and to extend patient survival.