Kirtane Ameya R, Sadhukha Tanmoy, Kim Hyunjoon, Khanna Vidhi, Koniar Brenda, Panyam Jayanth
Department of Pharmaceutics, University of Minnesota, Minneapolis, Minnesota.
Research Animal Resources, University of Minnesota, Minneapolis, Minnesota.
Cancer Res. 2017 Mar 15;77(6):1465-1475. doi: 10.1158/0008-5472.CAN-16-1646. Epub 2017 Jan 20.
Elevated interstitial fluid pressure and solid stress within tumors contribute to poor intratumoral distribution of nanomedicine. In this study, we hypothesized that the presence of fibrin in tumor extracellular matrix contributes to hindered intratumoral distribution of nanocarriers and that this can be overcome through the use of a fibrinolytic enzyme such as tissue plasminogen activator (tPA). Analysis of fibrin expression in human tumor biopsies showed significant fibrin staining in nearly all tumor types evaluated. However, staining was heterogeneous across and within tumor types. We determined the effect of fibrin on the diffusion, intratumoral distribution, and therapeutic efficacy of nanocarriers. Diffusivity of nanocarriers in fibrin matrices was limited and could be improved significantly by coincubation with tPA. , coadministration of tPA improved the anticancer efficacy of nanoparticle-encapsulated paclitaxel in subcutaneous syngeneic mouse melanoma and orthotopic xenograft lung cancer models. Furthermore, treatment with tPA led to decompression of blood vessels and improved tumor perfusion. Cotreatment with tPA resulted in greater intratumoral penetration of a model nanocarrier (Doxil), leading to enhanced availability of the drug in the tumor core. Fibrinolytics such as tPA are already approved for other indications. Fibrinolytic cotherapy is therefore a rapidly translatable strategy for improving therapeutic effectiveness of anticancer nanomedicine. .
肿瘤内升高的间质液压力和固体应力导致纳米药物在肿瘤内分布不佳。在本研究中，我们假设肿瘤细胞外基质中纤维蛋白的存在会导致纳米载体在肿瘤内的分布受阻，并且这可以通过使用纤溶酶（如组织纤溶酶原激活剂（tPA））来克服。对人类肿瘤活检组织中纤维蛋白表达的分析表明，在几乎所有评估的肿瘤类型中都有明显的纤维蛋白染色。然而，染色在肿瘤类型之间和肿瘤内部是不均匀的。我们确定了纤维蛋白对纳米载体的扩散、肿瘤内分布和治疗效果的影响。纳米载体在纤维蛋白基质中的扩散率有限，与tPA共同孵育可显著提高扩散率。此外，tPA的共同给药提高了纳米颗粒包裹的紫杉醇在皮下同基因小鼠黑色素瘤和原位异种移植肺癌模型中的抗癌效果。此外，tPA治疗导致血管减压并改善肿瘤灌注。与tPA联合治疗导致模型纳米载体（阿霉素脂质体）在肿瘤内的穿透性增强，从而提高了药物在肿瘤核心的可用性。诸如tPA之类的纤溶药物已被批准用于其他适应症。因此，纤溶联合治疗是一种可迅速转化的策略，用于提高抗癌纳米药物的治疗效果。
