Heinrich Anne-Kathrin, Lucas Henrike, Schindler Lucie, Chytil Petr, Etrych Tomáš, Mäder Karsten, Mueller Thomas
Institute of Pharmacy, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany.
Institute of Pharmacy, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany. Department of Internal Medicine IV, Oncology/Hematology, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany.
Mol Cancer Ther. 2016 May;15(5):998-1007. doi: 10.1158/1535-7163.MCT-15-0824. Epub 2016 Mar 3.
The success of chemotherapy is limited by poor selectivity of active drugs combined with occurrence of tumor resistance. New star-like structured N-(2-hydroxypropyl) methacrylamide (HPMA) copolymer-based drug delivery systems containing doxorubicin attached via a pH-sensitive hydrazone bond were designed and investigated for their ability to overcome chemotherapy resistance. These conjugates combine two strategies to achieve a high drug concentration selectively at the tumor site: (I) high accumulation by passive tumor targeting based on enhanced permeability and retention effect and (II) pH-sensitive site-specific drug release due to an acidic tumor microenvironment. Mice bearing doxorubicin-resistant xenograft tumors were treated with doxorubicin, PBS, poly HPMA (pHPMA) precursor or pHPMA-doxorubicin conjugate at different equivalent doses of 5 mg/kg bodyweight doxorubicin up to a 7-fold total dose using different treatment schedules. Intratumoral drug accumulation was analyzed by fluorescence imaging utilizing intrinsic fluorescence of doxorubicin. Free doxorubicin induced significant toxicity but hardly any tumor-inhibiting effects. Administering at least a 3-fold dose of pHPMA-doxorubicin conjugate was necessary to induce a transient response, whereas doses of about 5- to 6-fold induced strong regressions. Tumors completely disappeared in some cases. The onset of response was differential delayed depending on the tumor model, which could be ascribed to distinct characteristics of the microenvironment. Further fluorescence imaging-based analyses regarding underlying mechanisms of the delayed response revealed a related switch to a more supporting intratumoral microenvironment for effective drug release. In conclusion, the current study demonstrates that the concept of tumor site-restricted high-dose chemotherapy is able to overcome therapy resistance. Mol Cancer Ther; 15(5); 998-1007. ©2016 AACR.
化疗的成功受到活性药物选择性差以及肿瘤耐药性出现的限制。设计并研究了新型星状结构的基于N-（2-羟丙基）甲基丙烯酰胺（HPMA）共聚物的药物递送系统，该系统含有通过pH敏感腙键连接的阿霉素，以研究其克服化疗耐药性的能力。这些缀合物结合了两种策略，以在肿瘤部位选择性地实现高药物浓度：（I）基于增强的渗透和滞留效应通过被动肿瘤靶向实现高积累，以及（II）由于酸性肿瘤微环境导致的pH敏感的位点特异性药物释放。用阿霉素、磷酸盐缓冲液（PBS）、聚HPMA（pHPMA）前体或pHPMA-阿霉素缀合物以不同的等效剂量（相当于5mg/kg体重阿霉素）治疗携带阿霉素耐药异种移植肿瘤的小鼠，使用不同的治疗方案，总剂量可达7倍。利用阿霉素的固有荧光通过荧光成像分析瘤内药物积累。游离阿霉素诱导显著毒性，但几乎没有任何肿瘤抑制作用。给予至少3倍剂量的pHPMA-阿霉素缀合物才能诱导短暂反应，而约5至6倍剂量则诱导强烈消退。在某些情况下肿瘤完全消失。反应的开始根据肿瘤模型有不同程度的延迟，这可归因于微环境的不同特征。关于延迟反应潜在机制的进一步基于荧光成像的分析揭示了向更有利于有效药物释放的瘤内微环境的相关转变。总之，当前研究表明肿瘤部位受限的高剂量化疗概念能够克服治疗耐药性。《分子癌症治疗》；15（5）；998 - 1007。©2016美国癌症研究协会。
