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首页> 外文期刊>Materials science & engineering >A stimuli-responsive combination therapy for recovering p53-inactivation associated drug resistance
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A stimuli-responsive combination therapy for recovering p53-inactivation associated drug resistance

机译：刺激反应的联合疗法，用于恢复p53失活相关的耐药性

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摘要

Drug resistance is a major hindrance in the anticancer treatment, which encourages the development of effective therapeutic strategies. For the first time, MDM2-mediated p53 degradation was identified as a critical factor for developing acquired resistance of doxorubicin (DOX) in HepG2 tumor spheroids, which could be effectively reversed by MDM2 inhibitor MI-773, thereby improving anticancer effects. Therefore, a pH-sensitive liposomal formulation of DOX and MI-773 (LipD/M@CMCS) were developed for recovering p53-mediated DOX resistance in hepatocellular carcinoma. LipD/M@CMCS were composed of cationic liposomes covered with carboxymethyl chitosan (pI = 6.8), and were stable in the physiological condition (pH 7.4), but rapidly converted to cationic liposomes in tumor acidic microenvironment (pH 6.5), endowing them with tumor specificity and enhanced cellular uptake. We showed that LipD/M@CMCS could not only effectively induce cell apoptosis in HepG2 tumor spheroids, but significantly inhibit tumor growth with minimal adverse effects. In summary, selective regulation of MDM2 in cancer cells is a promising strategy to overcome DOX resistance, and may provide a perspective on the management of malignant tumors.
机译：耐药性是抗癌治疗的主要障碍，这鼓励了有效治疗策略的发展。首次将MDM2介导的p53降解鉴定为在HepG2肿瘤球体中产生后天抗阿霉素（DOX）的关键因素，MDM2抑制剂MI-773可以有效逆转它，从而提高抗癌作用。因此，开发了pH敏感的DOX和MI-773脂质体制剂（LipD / M @ CMCS），以恢复肝细胞癌中p53介导的DOX耐药性。 LipD / M @ CMCS由覆盖有羧甲基壳聚糖的阳离子脂质体（pI = 6.8）组成，在生理条件下（pH 7.4）稳定，但在肿瘤酸性微环境（pH 6.5）中迅速转化为阳离子脂质体，并赋予它们肿瘤特异性和增强的细胞摄取。我们表明，LipD / M @ CMCS不仅可以有效诱导HepG2肿瘤球体中的细胞凋亡，而且可以显着抑制肿瘤的生长，并将不良反应降至最低。总之，在癌细胞中选择性调节MDM2是克服DOX耐药性的一种有前途的策略，并可能为恶性肿瘤的治疗提供一个前景。

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  • 来源
    《Materials science & engineering》 |2020年第3期|110403.1-110403.11|共11页
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    China Pharmaceut Univ State Key Lab Nat Med Ctr Drug Discovery Ctr Adv Pharmaceut & Biomat Nanjing 210009 Peoples R China|China Pharmaceut Univ Jiangsu Key Lab Drug Discovery Metab Dis Ctr Drug Discovery Ctr Adv Pharmaceut & Biomat Nanjing 210009 Peoples R China|Nanjing Univ Coll Engn & Appl Sci Natl Lab Solid State Microstruct Nanjing 210093 Peoples R China|Nanjing Univ Chem & Biomed Innovat Ctr Nanjing 210093 Peoples R China;

    Nanjing Univ Coll Engn & Appl Sci Natl Lab Solid State Microstruct Nanjing 210093 Peoples R China|Nanjing Univ Chem & Biomed Innovat Ctr Nanjing 210093 Peoples R China;

    Nanjing Univ Model Anim Res Ctr Lab Bone & Joint Dis Nanjing 210093 Peoples R China;

    China Pharmaceut Univ State Key Lab Nat Med Ctr Drug Discovery Ctr Adv Pharmaceut & Biomat Nanjing 210009 Peoples R China|China Pharmaceut Univ Jiangsu Key Lab Drug Discovery Metab Dis Ctr Drug Discovery Ctr Adv Pharmaceut & Biomat Nanjing 210009 Peoples R China;

    Nanjing Univ Chem & Biomed Innovat Ctr Nanjing 210093 Peoples R China;

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  • 正文语种 eng
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  • 关键词

    Chemotherapy; Drug resistance; Tumor spheroids; MDM2 inhibitor; pH sensitive delivery systems;

    机译：化学疗法耐药性;肿瘤球体;MDM2抑制剂;pH敏感的输送系统;

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