Personalizing EPR-mediated passive drug targeting to tumors using non-invasive imaging

纳米药物是1-100纳米大小的载体材料，旨在改善静脉给药（化学）治疗剂的生物分布。通过将药物更特异性地递送到病理部位，同时防止它们在潜在危害健康的组织中积累，纳米药物旨在改善全身（化学）治疗干预的疗效和毒性之间的平衡。绝大多数（预）临床使用的纳米药物依赖于增强渗透性和保留（EPR）效应来实现有效和选择性的药物递送，它们主要用于促进药物靶向肿瘤。然而，EPR效应是一种相对不为人所知且高度可变的（病理）生理现象，在不同患者之间、不同肿瘤（模型）之间存在很大差异。为了更好地了解EPR效应，预先选择可能对EPR靶向纳米化疗干预有反应的患者，从而个体化和改进被动肿瘤靶向纳米药物治疗，我们在这里提出：1)使用解剖学、功能和分子成像技术来识别与EPR相关的可成像血管参数；II)使用治疗结构和概念来证明epr介导的药物靶向程度与治疗效果相关。关于前者，我们将使用解剖微CT，功能MRI和分子US，定量表征五种不同肿瘤模型中的肿瘤血管系统（已知在侵袭性和血管生成谱方面存在显着差异），并且我们将将可成像血管参数与epr介导的荧光团标记聚合物（5 nm），胶束（50 nm）和脂质体（100 nm）的肿瘤积累联系起来。这些临床相关的载体材料将用近红外染料和标准荧光团进行双重标记，以实现体内微CT-FMT成像的整体肿瘤积累，以及离体双光子激光扫描显微镜对肿瘤渗透和肿瘤内分布的分析。对于后者，这些原型和图像引导的纳米药物将被阿霉素进一步功能化，首次证明epr介导的肿瘤积累程度与抗肿瘤疗效相关，并且肿瘤积累的个体间和个体内差异可用于预测被动肿瘤靶向纳米药物治疗的结果。总之，这些努力将I)提供有助于EPR的血管参数的定量成像信息；II)增进我们对环境再造效应的机理认识；III)提供开创性的原理证明，证明epr介导的药物靶向程度与治疗效果相关；IV)实质性地有助于实现个性化和改进的纳米医学治疗。

Nanomedicines are 1-100 nm-sized carrier materials designed to improve the biodistribution of i.v. administered (chemo-) therapeutic agents. By delivering drugs more specifically to pathological sites, and by at the same preventing them from accumulating in potentially endangered healthy tissues, nanomedicines aim to improve the balance between efficacy and the toxicity of systemic (chemo-) therapeutic interventions. The vast majority of (pre-) clinically used nanomedicines rely on the Enhanced Permeability and Retention (EPR) effect for enabling effective and selective drug delivery, and they have been primarily used for facilitating drug targeting to tumors. The EPR effect, however, is a relatively poorly understood and highly variable (patho-) physiological phenomenon, which varies substantially from patient to patient, and from tumor (model) to tumor (model). To better understand the EPR effect, to preselect patients likely to respond to EPR-targeted nano-chemotherapeutic interventions, and to thereby individualize and improve passively tumor-targeted nanomedicine treatments, we here propose to I) use anatomical, functional and molecular imaging techniques to identify image-able vascular parameters correlating with EPR; and to II) use theranostic constructs and concepts to demonstrate that the degree of EPR-mediated drug targeting correlates with therapeutic efficacy. Regarding the former, we will use anatomical µCT, functional MRI and molecular US, to quantitatively characterize the tumor vasculature in five different tumor models (known to differ significantly in aggressiveness and angiogenic profile), and we will correlate image-able vascular parameters with the EPR-mediated tumor accumulation of fluorophore-labeled polymers (5 nm), micelles (50 nm) and liposomes (100 nm). These clinically relevant carrier materials will be double-labeled with a near-infrared dye and with a standard fluorophore, to enable in vivo µCT-FMT imaging of overall tumor accumulation, and ex vivo two-photon laser scanning microscopy analysis of tumor penetration and intratumoral distribution. Regarding the latter, these prototypic and image-guided nanomedicines with be further functionalized with doxorubicin, to demonstrate - for the first time - that the degree of EPR-mediated tumor accumulation correlates with antitumor efficacy, and that inter- and intra-individual differences in tumor accumulation can be used to predict the outcome of passively tumor-targeted nanomedicine treatment. Together, these efforts will I) provide quantitative imaging information of the vascular parameters contributing to EPR; II) improve our mechanistic understanding of the EPR effect; III) provide pioneering proof-of-principle demonstrating that the degree EPR-mediated drug targeting correlates with therapeutic efficacy; and IV) substantially contribute to the realization of personalized and improved nanomedicine treatment.