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首页> 外文期刊>Molecular cancer therapeutics >Improved Tumor-Specific Drug Accumulation by Polymer Therapeutics with pH-Sensitive Drug Release Overcomes Chemotherapy Resistance
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Improved Tumor-Specific Drug Accumulation by Polymer Therapeutics with pH-Sensitive Drug Release Overcomes Chemotherapy Resistance

机译：通过具有pH敏感性药物释放的聚合物疗法改善了针对肿瘤的药物蓄积，克服了化疗耐药性

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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. (C) 2016 AACR.
机译：化疗的成功受到活性药物选择性差和发生肿瘤抵抗力的限制。设计并研究了新的星形结构化N-（2-羟丙基）甲基丙烯酰胺（HPMA）共聚物基药物传递系统，该系统包含通过pH敏感的bond键连接的阿霉素，并研究了其克服化疗耐药性的能力。这些结合物结合了两种策略以选择性地在肿瘤部位实现高药物浓度：（I）基于增强的通透性和保留效应，通过被动靶向肿瘤实现高积累，以及（II）酸性肿瘤导致的pH敏感部位特异性药物释放微环境。用阿霉素，PBS，聚HPMA（pHPMA）前体或pHPMA-阿霉素缀合物以不同的当量剂量5 mg / kg体重阿霉素以高达7倍的总剂量使用不同的治疗方案治疗携带阿霉素抗性异种移植瘤的小鼠。利用阿霉素的固有荧光通过荧光成像分析肿瘤内药物的积累。游离的阿霉素诱导了明显的毒性，但几乎没有抑制肿瘤的作用。至少需要3倍剂量的pHPMA-阿霉素结合物才能诱导瞬时反应，而约5至6倍剂量则可以引起强烈的退化。在某些情况下，肿瘤完全消失。取决于肿瘤模型，反应的发作是差异性延迟的，这可以归因于微环境的独特特征。关于延迟反应的潜在机制的进一步基于荧光成像的分析揭示了向有效药物释放的更支持肿瘤内微环境的相关转换。总之，当前的研究表明，肿瘤部位限制性高剂量化疗的概念能够克服治疗耐药性。 （C）2016 AACR。

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