Multifunctional Nanoparticles Delivering Small Interfering RNA and Doxorubicin Overcome Drug Resistance in Cancer
Multifunctional Nanoparticles Delivering Small Interfering RNA and Doxorubicin Overcome Drug Resistance in Cancer
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DOI：
10.1074/jbc.m110.125906
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发表时间：
2010-07-16
影响因子：
4.8
通讯作者：
Huang, Leaf
中科院分区：
文献类型：
--
作者：
Chen, Yunching;Bathula, Surendar Reddy;Huang, Leaf
耐药性是癌症有效治疗面临的主要挑战。我们已经开发了两种纳米颗粒配方，阳离子脂质体-聚阳离子- dna （LPD）和阴离子脂质体-聚阳离子- dna (LPD- ii)，用于系统共递送阿霉素（Dox）和治疗性小干扰RNA (siRNA)，以治疗多重耐药（MDR）肿瘤。在这项研究中，我们提供了四种克服耐药性的策略。首先，我们用一种含胍的阳离子脂质，即N，N-二芳基-N-甲基-N-2-（N'-精氨酸基）氨基乙基氯化铵形成LPD纳米颗粒，它可以诱导活性氧，下调MDR转运体表达，增加Dox摄取。其次，为了阻断血管生成和增加药物渗透，我们进一步配制了LPD纳米颗粒来共同递送血管内皮生长因子siRNA和Dox。当与纳米颗粒中的血管内皮生长因子siRNA联合使用时，观察到增强的Dox摄取和治疗效果。第三，为了避免p -糖蛋白介导的药物外排，我们进一步设计了另一种递送载体LPD- ii，其对Dox的包裹效率远高于LPD。最后，我们传递了一种抑制MDR转运体的治疗性siRNA。我们首次证明了LPD-II纳米颗粒递送的c-Myc siRNA在体内下调MDR表达并增加Dox摄取。每日三次静脉注射治疗性siRNA和Dox (1.2 mg/kg)，共同配制LPD或LPD- ii纳米颗粒，显示出肿瘤生长抑制的显著改善。这项研究强调了多功能纳米颗粒的潜在临床应用，它具有有效的递送特性和克服癌症耐药的功能。比较了LPD-和LPD- ii介导治疗的活性和毒性。
Drug resistance is a major challenge to the effective treatment of cancer. We have developed two nanoparticle formulations, cationic liposome-polycation-DNA (LPD) and anionic liposome-polycation-DNA (LPD-II), for systemic co-delivery of doxorubicin (Dox) and a therapeutic small interfering RNA (siRNA) to multiple drug resistance (MDR) tumors. In this study, we have provided four strategies to overcome drug resistance. First, we formed the LPD nanoparticles with a guanidinium-containing cationic lipid, i.e. N,N-distearyl-N-methyl-N-2-(N'-arginyl) aminoethyl ammonium chloride, which can induce reactive oxygen species, down-regulate MDR transporter expression, and increase Dox uptake. Second, to block angiogenesis and increase drug penetration, we have further formulated LPD nanoparticles to co-deliver vascular endothelial growth factor siRNA and Dox. An enhanced Dox uptake and a therapeutic effect were observed when combined with vascular endothelial growth factor siRNA in the nanoparticles. Third, to avoid P-glycoprotein-mediated drug efflux, we further designed another delivery vehicle, LPD-II, which showed much higher entrapment efficiency of Dox than LPD. Finally, we delivered a therapeutic siRNA to inhibit MDR transporter. We demonstrated the first evidence of c-Myc siRNA delivered by the LPD-II nanoparticles down-regulating MDR expression and increasing Dox uptake in vivo. Three daily intravenous injections of therapeutic siRNA and Dox (1.2 mg/kg) co-formulated in either LPD or LPD-II nanoparticles showed a significant improvement in tumor growth inhibition. This study highlights a potential clinical use for the multifunctional nanoparticles with an effective delivery property and a function to overcome drug resistance in cancer. The activity and the toxicity of LPD- and LPD-II-mediated therapy are compared.