Bypassing the EPR effect with a nanomedicine harboring a sustained-release function allows better tumor control
Bypassing the EPR effect with a nanomedicine harboring a sustained-release function allows better tumor control
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DOI：
10.2147/ijn.s78321
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发表时间：
2015-01-01
影响因子：
8
通讯作者：
Chuang, Chi Mu
中科院分区：
文献类型：
--
作者：
Shen, Yao An;Shyu, Ing Luen;Chuang, Chi Mu
目前批准的基于增强渗透性和保留性（EPR）的纳米药物在延长癌症患者的总生存期方面几乎没有影响。例如，比较美国食品和药物管理局批准的第一种纳米药物Doxil (R)与游离阿霉素的两项III期试验并没有发现EPR效应实际转化为总体生存期的统计学显着增加，但确实显示出较少的心脏毒性。在目前的工作中，我们采用了双因素因子实验设计，将腹腔内给药与静脉给药、纳米药物与游离药物作为因素来检验我们的假设，即与全身给药相比，局部（腹腔内）给药可能更好地提高生存率。在这项研究中，我们证明，通过腹腔内递送具有缓释功能的纳米药物来绕过EPR效应，而不是利用EPR效应，具有双重药代动力学优势，可以更有效地控制肿瘤，抑制肿瘤微环境中干细胞标记物、上皮-间质转化、血管生成信号和多药耐药的表达。腹腔注射纳米药物也比标准的全身释放相应的游离药物更能控制转移到重要器官（如肺、肝脏和淋巴系统）。此外，腹腔内给药纳米药物具有替代腹腔内高温化疗的潜力，因为它具有相同的疗效和更低的毒性。就功效而言，利用EPR效应可能不是开发纳米药物的最佳方法。由于腹腔内化疗是一种区域化疗，制药行业可能会考虑将纳米药物的区域递送作为一种有效的替代途径来开发其纳米药物，以实现更好的肿瘤控制。
The current enhanced permeability and retention (EPR)-based approved nanomedicines have had little impact in terms of prolongation of overall survival in patients with cancer. For example, the two Phase III trials comparing Doxil (R), the first nanomedicine approved by the US Food and Drug Administration, with free doxorubicin did not find an actual translation of the EPR effect into a statistically significant increase in overall survival but did show less cardiotoxicity. In the current work, we used a two-factor factorial experimental design with intraperitoneal versus intravenous delivery and nanomedicine versus free drug as factors to test our hypothesis that regional (intraperitoneal) delivery of nanomedicine may better increase survival when compared with systemic delivery. In this study, we demonstrate that bypassing, rather than exploiting, the EPR effect via intraperitoneal delivery of nanomedicine harboring a sustained-release function demonstrates dual pharmacokinetic advantages, producing more efficient tumor control and suppressing the expression of stemness markers, epithelial-mesenchymal transition, angiogenesis signals, and multidrug resistance in the tumor microenvironment. Metastases to vital organs (eg, lung, liver, and lymphatic system) are also better controlled by intraperitoneal delivery of nanomedicine than by standard systemic delivery of the corresponding free drug. Moreover, the intraperitoneal delivery of nanomedicine has the potential to replace hyperthermic intraperitoneal chemotherapy because it shows equal efficacy and lower toxicity. In terms of efficacy, exploiting the EPR effect may not be the best approach for developing a nanomedicine. Because intraperitoneal chemotherapy is a type of regional chemotherapy, the pharmaceutical industry might consider the regional delivery of nanomedicine as a valid alternative pathway to develop their nanomedicine(s) with the goal of better tumor control in the future.