Pramanik Dipankar, Campbell Nathaniel R, Das Samarjit, Gupta Sonal, Chenna Venugopal, Bisht Savita, Sysa-Shah Polina, Bedja Djahida, Karikari Collins, Steenbergen Charles, Gabrielson Kathleen L, Maitra Amarnath, Maitra Anirban
The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Oncotarget. 2012 Jun;3(6):640-50. doi: 10.18632/oncotarget.543.
Acquired chemotherapy resistance is a major contributor to treatment failure in oncology. For example, the efficacy of the common anticancer agent doxorubicin (DOX) is limited by the emergence of multidrug resistance (MDR) phenotype in cancer cells. While dose escalation of DOX can circumvent such resistance to a degree, this is precluded by the appearance of cardiotoxicity, a particularly debilitating condition in children. In vitro studies have established the ability of the natural phytochemical curcumin to overcome MDR; however, its widespread clinical application is restricted by poor solubility and low bioavailability. Building upon our recently developed polymer nanoparticle of curcumin (NanoCurc or NC) that significantly enhances the systemic bioavailability of curcumin, we synthesized a doxorubicin-curcumin composite nanoparticle formulation called NanoDoxCurc (NDC) for overcoming DOX resistance. Compared to DOX alone, NDC inhibited the MDR phenotype and caused striking growth inhibition both in vitro and in vivo in several models of DOX-resistant cancers (multiple myeloma, acute leukemia, prostate and ovarian cancers, respectively). Notably, NDC-treated mice also demonstrated complete absence of cardiac toxicity, as assessed by echocardiography, or any bone marrow suppression, even at cumulative dosages where free DOX and pegylated liposomal DOX (Doxil®) resulted in demonstrable attenuation of cardiac function and hematological toxicities. This improvement in safety profile was achieved through a reduction of DOX-induced intracellular oxidative stress, as indicated by total glutathione levels and glutathione peroxidase activity in cardiac tissue. A composite DOX-curcumin nanoparticle that overcomes both MDR-based DOX chemoresistance and DOX-induced cardiotoxicity holds promise for providing lasting and safe anticancer therapy.
获得性化疗耐药是肿瘤治疗失败的主要原因。例如，常见抗癌药物阿霉素（DOX）的疗效受到癌细胞中多药耐药（MDR）表型出现的限制。虽然DOX剂量递增在一定程度上可以规避这种耐药性，但由于心脏毒性的出现，这一方法受到了限制，心脏毒性在儿童中是一种特别使人衰弱的病症。体外研究证实天然植物化学物质姜黄素具有克服MDR的能力；然而，其广泛的临床应用受到溶解度差和生物利用度低的限制。基于我们最近开发的姜黄素聚合物纳米颗粒（NanoCurc或NC），其显著提高了姜黄素的全身生物利用度，我们合成了一种名为NanoDoxCurc（NDC）的阿霉素 - 姜黄素复合纳米颗粒制剂，用于克服DOX耐药性。与单独使用DOX相比，NDC在几种DOX耐药癌症模型（分别为多发性骨髓瘤、急性白血病、前列腺癌和卵巢癌）中，在体外和体内均抑制了MDR表型并引起显著的生长抑制。值得注意的是，通过超声心动图评估，接受NDC治疗的小鼠也完全没有心脏毒性，也没有任何骨髓抑制，即使在游离DOX和聚乙二醇化脂质体DOX（Doxil®）导致明显的心功能减弱和血液学毒性的累积剂量下也是如此。心脏组织中的总谷胱甘肽水平和谷胱甘肽过氧化物酶活性表明，这种安全性的改善是通过减少DOX诱导的细胞内氧化应激实现的。一种既能克服基于MDR的DOX化疗耐药性又能克服DOX诱导的心脏毒性的复合DOX - 姜黄素纳米颗粒有望提供持久且安全的抗癌治疗。
