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

使用非侵入性成像个性化 EPR 介导的被动药物靶向肿瘤

• 批准号: 194806083
• 负责人: Professor Dr. Fabian Kiessling
• 金额: --
• 依托单位: Institut für Experimentelle Molekulare Bildgebung (ExMI)
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2011
• 资助国家: 德国
• 起止时间: 2010-12-31 至 2016-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/194806083?language=en
• 关键词: Personalizing; EPR; mediated; passive; drug

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.

纳米药物是1-100 nm大小的载体材料，旨在改善静脉注射（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，并同时防止它们在潜在危险的健康组织中积累，纳米医学旨在改善全身（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的渗透性和保留（EPR）效应，以实现有效和选择性的药物递送，并且它们主要用于促进药物靶向肿瘤。然而，EPR效应是一种相对知之甚少且高度可变的（病理）生理现象，其在患者与患者之间以及在肿瘤（模型）与肿瘤（模型）之间变化很大。为了更好地理解EPR效应，预选可能对EPR靶向纳米化疗干预有反应的患者，从而个性化和改善被动肿瘤靶向纳米药物治疗，我们在这里提出：I）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;和II）使用治疗诊断学构建体和概念来证明EPR介导的药物靶向程度与治疗功效相关。对于前者，我们将使用解剖学µCT、功能性MRI和分子US来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方面显着不同），并且我们将使可成像的血管参数与荧光团标记的聚合物（5纳米）、胶束（50纳米）和脂质体（100纳米）的EPR介导的肿瘤积聚相关。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标记，以实现整体肿瘤蓄积的体内µCT-FMT成像，以及肿瘤渗透和肿瘤内分布的离体双光子激光扫描显微镜分析。关于后者，这些原型和图像引导的纳米药物将进一步用阿霉素功能化，以首次证明EPR介导的肿瘤累积的程度与抗肿瘤功效相关，并且肿瘤累积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）提高我们对EPR效应的机械理解; 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功效相关;以及IV）实质上有助于实现个性化和改进的纳米医学治疗。

项目成果

Sonoporation enhances liposome accumulation and penetration in tumors with low EPR.

• DOI: 10.1016/j.jconrel.2016.02.021
• 发表时间: 2016-06-10
• 期刊: Journal of controlled release : official journal of the Controlled Release Society
• 作者: Theek B;Baues M;Ojha T;Möckel D;Veettil SK;Steitz J;van Bloois L;Storm G;Kiessling F;Lammers T
• 通讯作者: Lammers T

Tumor targeting via EPR: Strategies to enhance patient responses.

• DOI: 10.1016/j.addr.2018.07.007
• 发表时间: 2018-05
• 期刊: Advanced drug delivery reviews
• 影响因子: 16.1
• 作者: Golombek SK;May JN;Theek B;Appold L;Drude N;Kiessling F;Lammers T
• 通讯作者: Lammers T

Micro-CT imaging of tumor angiogenesis: quantitative measures describing micromorphology and vascularization.

• DOI: 10.1016/j.ajpath.2013.10.014
• 发表时间: 2014-02
• 期刊: AMERICAN JOURNAL OF PATHOLOGY
• 影响因子: 6
• 作者: Ehling, Josef;Theek, Benjamin;Gremse, Felix;Baetke, Sarah;Moeckel, Diana;Maynard, Juliana;Ricketts, Sally-Ann;Gruell, Holger;Neeman, Michal;Knuechel, Ruth;Lederle, Wiltrud;Kiessling, Fabian;Lammers, Twan
• 通讯作者: Lammers, Twan

Fluorophore labeling of core-crosslinked polymeric micelles for multimodal in vivo and ex vivo optical imaging.

• DOI: 10.2217/nnm.14.170
• 发表时间: 2015
• 期刊: Nanomedicine (London, England)
• 作者: Shi Y;Kunjachan S;Wu Z;Gremse F;Moeckel D;van Zandvoort M;Kiessling F;Storm G;van Nostrum CF;Hennink WE;Lammers T
• 通讯作者: Lammers T