Youm Ibrahima, West Matthew B, Li Wei, Du Xiaoping, Ewert Donald L, Kopke Richard D
Hough Ear Institute, Oklahoma City, OK, USA.
Hough Ear Institute, Oklahoma City, OK, USA; Oklahoma Medical Research Foundation, Oklahoma City, OK, USA; Departments of Physiology and Otolaryngology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
Int J Pharm. 2017 Aug 7;528(1-2):611-623. doi: 10.1016/j.ijpharm.2017.06.035. Epub 2017 Jun 13.
Ototoxicity represents a major adverse side-effect of cis-diamminedichloroplatinum-II (cisplatin, CDDP). The mitogen-activated protein kinase (MAPK) pathway is thought to play a central role in potentiating the apoptotic effect of CDDP within the cochlea. We hypothesized that prophylactic inhibition of MAPK signaling, using small interfering RNA (siRNA), might confer a protective effect against CDDP-induced apoptosis within the auditory sensory epithelia. To enhance the therapeutic utility of this approach, we synthesized biocompatible siMAPK1-loaded nanoparticles (NPs) and performed physicochemical characterizations for size, morphology, drug loading and release kinetics, using dynamic light scattering, electron microscopy and spectrophotometric analyses, respectively. Our findings show 183.88±6.26 nm-sized spherical siMAPK1-loaded NPs with -27.12±6.65mV zeta potential and 112.78±0.24pmol/mg of siMAPK1 loading that exhibit a sustained release profile for prolonged therapeutic efficacy. Synthesized NPs were validated for biocompatibility and prophylactically protected against CDDP-induced cytotoxicity in HEI-OC1 cells and hair cell loss in murine organotypic cochlear explants. Our study confirms a pivotal role for MAPK1 signaling as a potentiating factor for CDDP-induced apoptosis and cochlear hair cell loss, and highlights siMAPK1 NP treatment as a therapeutic strategy for limiting the ototoxic side-effects associated with systemic CDDP administration.
耳毒性是顺二氯二氨铂（顺铂，CDDP）的主要不良副作用。丝裂原活化蛋白激酶（MAPK）通路被认为在增强顺铂在耳蜗内的凋亡作用中起核心作用。我们假设，使用小干扰RNA（siRNA）预防性抑制MAPK信号传导可能对顺铂诱导的听觉感觉上皮细胞凋亡具有保护作用。为了提高这种方法的治疗效用，我们合成了负载生物相容性siMAPK1的纳米颗粒（NPs），并分别使用动态光散射、电子显微镜和分光光度分析对其大小、形态、药物负载和释放动力学进行了物理化学表征。我们的研究结果表明，负载siMAPK1的纳米颗粒呈球形，大小为183.88±6.26 nm，zeta电位为-27.12±6.65 mV，siMAPK1负载量为112.78±0.24 pmol/mg，具有持续释放特性，可延长治疗效果。合成的纳米颗粒经生物相容性验证，并在HEI-OC1细胞中对顺铂诱导的细胞毒性以及在小鼠耳蜗组织型外植体中对毛细胞损失具有预防性保护作用。我们的研究证实了MAPK1信号传导作为顺铂诱导的凋亡和耳蜗毛细胞损失的增强因子的关键作用，并强调了siMAPK1纳米颗粒治疗作为一种治疗策略，可限制与全身应用顺铂相关的耳毒性副作用。
