Gao Ning, Bozeman Erica N, Qian Weiping, Wang Liya, Chen Hongyu, Lipowska Malgorzata, Staley Charles A, Wang Y Andrew, Mao Hui, Yang Lily
Department of Surgery, Emory University School of Medicine, Atlanta, GA 30322.
Department of Radiology and Imaging Sciences, Emory University School of Medicine, Atlanta, GA 30322.
Theranostics. 2017 Apr 10;7(6):1689-1704. doi: 10.7150/thno.18125. eCollection 2017.
The major obstacles in intraperitoneal (i.p.) chemotherapy of peritoneal tumors are fast absorption of drugs into the blood circulation, local and systemic toxicities, inadequate drug penetration into large tumors, and drug resistance. Targeted theranostic nanoparticles offer an opportunity to enhance the efficacy of i.p. therapy by increasing intratumoral drug delivery to overcome resistance, mediating image-guided drug delivery, and reducing systemic toxicity. Herein we report that i.p. delivery of urokinase plasminogen activator receptor (uPAR) targeted magnetic iron oxide nanoparticles (IONPs) led to intratumoral accumulation of 17% of total injected nanoparticles in an orthotopic mouse pancreatic cancer model, which was three-fold higher compared with intravenous delivery. Targeted delivery of near infrared dye labeled IONPs into orthotopic tumors could be detected by non-invasive optical and magnetic resonance imaging. Histological analysis revealed that a high level of uPAR targeted, PEGylated IONPs efficiently penetrated into both the peripheral and central tumor areas in the primary tumor as well as peritoneal metastatic tumor. Improved theranostic IONP delivery into the tumor center was not mediated by nonspecific macrophage uptake and was independent from tumor blood vessel locations. Importantly, i.p. delivery of uPAR targeted theranostic IONPs carrying chemotherapeutics, cisplatin or doxorubicin, significantly inhibited the growth of pancreatic tumors without apparent systemic toxicity. The levels of proliferating tumor cells and tumor vessels in tumors treated with the above theranostic IONPs were also markedly decreased. The detection of strong optical signals in residual tumors following i.p. therapy suggested the feasibility of image-guided surgery to remove drug-resistant tumors. Therefore, our results support the translational development of i.p. delivery of uPAR-targeted theranostic IONPs for image-guided treatment of peritoneal tumors.
腹膜肿瘤腹腔内化疗的主要障碍包括药物快速吸收进入血液循环、局部和全身毒性、药物对大肿瘤的渗透不足以及耐药性。靶向诊疗纳米颗粒提供了一个机会，可通过增加肿瘤内药物递送以克服耐药性、介导图像引导的药物递送以及降低全身毒性来提高腹腔内治疗的疗效。在此，我们报告在原位小鼠胰腺癌模型中，腹腔内递送尿激酶型纤溶酶原激活物受体（uPAR）靶向的磁性氧化铁纳米颗粒（IONPs）导致肿瘤内积聚的纳米颗粒占总注射量的17%，这比静脉注射高出三倍。通过非侵入性光学和磁共振成像可检测到近红外染料标记的IONPs靶向递送至原位肿瘤。组织学分析显示，高水平的uPAR靶向、聚乙二醇化的IONPs有效地渗透到原发性肿瘤以及腹膜转移性肿瘤的外周和中央肿瘤区域。IONPs向肿瘤中心的改进诊疗递送并非由非特异性巨噬细胞摄取介导，且与肿瘤血管位置无关。重要的是，腹腔内递送携带化疗药物顺铂或阿霉素的uPAR靶向诊疗IONPs可显著抑制胰腺肿瘤的生长，且无明显全身毒性。用上述诊疗IONPs治疗的肿瘤中增殖肿瘤细胞和肿瘤血管的水平也显著降低。腹腔内治疗后在残留肿瘤中检测到强烈的光学信号表明图像引导手术切除耐药肿瘤具有可行性。因此，我们的结果支持将uPAR靶向诊疗IONPs腹腔内递送用于腹膜肿瘤图像引导治疗的转化研究。
