Tumor Penetrating Theranostic Nanoparticles for Enhancement of Targeted and Image-guided Drug Delivery into Peritoneal Tumors following Intraperitoneal Delivery.
Tumor Penetrating Theranostic Nanoparticles for Enhancement of Targeted and Image-guided Drug Delivery into Peritoneal Tumors following Intraperitoneal Delivery.
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作者：
Gao N;Bozeman EN;Qian W;Wang L;Chen H;Lipowska M;Staley CA;Wang YA;Mao H;Yang L
腹膜内（i.p.）腹膜肿瘤的化疗的缺点是药物快速吸收进入血液循环、局部和全身毒性、药物不充分渗透到大肿瘤中以及耐药性。靶向治疗诊断纳米颗粒通过增加肿瘤内药物递送以克服耐药性、介导图像引导药物递送和降低全身毒性，提供了增强腹腔注射治疗功效的机会。在本文中，我们报告了尿激酶纤溶酶原激活物受体（uPAR）靶向磁性氧化铁纳米颗粒（IONP）的腹膜内递送导致原位小鼠胰腺癌模型中总注射纳米颗粒的17%的瘤内累积，这是静脉内递送的三倍。近红外染料标记的IONP靶向递送到原位肿瘤中可以通过非侵入性光学和磁共振成像来检测。组织学分析显示，高水平的uPAR靶向的PEG化IONP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中。改进的治疗诊断IONP递送到肿瘤中心不是由非特异性巨噬细胞摄取介导的，并且与肿瘤血管位置无关。重要的是，i.p.递送uPAR靶向的携带化疗剂顺铂或多柔比星的治疗诊断性IONP显著抑制胰腺肿瘤的生长，而没有明显的全身毒性。用上述治疗诊断性IONP处理的肿瘤中增殖的肿瘤细胞和肿瘤血管的水平也显著降低。腹腔注射治疗后残留肿瘤中的强光学信号的检测表明了图像引导手术切除耐药肿瘤的可行性。因此，我们的结果支持腹膜内递送uPAR靶向治疗诊断性IONP用于腹膜肿瘤的图像引导治疗的转化发展。
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.