Chattopadhyay Niladri, Fonge Humphrey, Cai Zhongli, Scollard Deborah, Lechtman Eli, Done Susan J, Pignol Jean-Philippe, Reilly Raymond M
Departments of †Pharmaceutical Sciences, ‡Medical Biophysics, §Medical Imaging and ∥Laboratory Medicine and Pathobiology, University of Toronto , Toronto, ON, Canada.
Mol Pharm. 2012 Aug 6;9(8):2168-79. doi: 10.1021/mp300016p. Epub 2012 Jul 18.
In this study, we have looked at enhancing tumor uptake and intracellular delivery of gold nanoparticles (AuNPs) while reducing the systemic exposure by systematic evaluation of the impact of targeting and route of administration on organ distribution. High-resolution microSPECT/CT imaging was used to track the in vivo fate of (111)In-labeled nontargeted and human epidermal growth factor receptor-2 (HER-2) targeted AuNPs following intravenous (i.v.) or intratumoral (i.t.) injection. For i.v. injection, the effects of GdCl3 (for deactivation of macrophages) and nonspecific (anti-CD20) antibody rituximab (for blocking of Fc mediated liver and spleen uptake) were studied. It was found that HER-2 targeting via attachment of trastuzumab paradoxically decreased tumor uptake as a result of faster elimination of the targeted AuNPs from the blood while improving internalization in HER-2-positive tumor cells as compared to nontargeted AuNPs. I.T. injections with HER-2 targeted AuNPs resulted in high tumor retention with low systemic exposure and represents an attractive delivery strategy. Our results provide a strategy for optimizing tumor delivery and quantifying organ distribution of this widely studied class of nanomaterial.
在本研究中，我们通过系统评估靶向作用和给药途径对器官分布的影响，来研究如何提高金纳米颗粒（AuNPs）的肿瘤摄取和细胞内递送，同时减少全身暴露。使用高分辨率显微SPECT/CT成像来追踪静脉内（i.v.）或瘤内（i.t.）注射后（111）In标记的非靶向和人表皮生长因子受体2（HER-2）靶向AuNPs的体内命运。对于静脉注射，研究了GdCl3（用于使巨噬细胞失活）和非特异性（抗CD20）抗体利妥昔单抗（用于阻断Fc介导的肝脏和脾脏摄取）的作用。结果发现，通过连接曲妥珠单抗进行HER-2靶向，由于靶向AuNPs从血液中更快清除，反而降低了肿瘤摄取，而与非靶向AuNPs相比，提高了HER-2阳性肿瘤细胞的内化。用HER-2靶向AuNPs进行瘤内注射导致肿瘤高保留率和低全身暴露，是一种有吸引力的递送策略。我们的结果为优化这类广泛研究的纳米材料的肿瘤递送和量化器官分布提供了一种策略。
