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.

纳米医学是1-100 nm大小的载体材料，旨在改善静脉内生物分布。给药（化学）治疗剂。通过更具体地将药物传递到病理部位，并在同一药物中阻止它们在潜在濒危的健康组织中积累，纳米医学旨在提高有效性与全身性（化学）治疗干预措施之间的平衡。绝大多数（临床前）使用的纳米医学依赖于增强的渗透性和保留率（EPR）效应来实现有效和选择性的药物递送，并且主要用于支持对肿瘤的药物靶向。然而，EPR效应是一种相对较少的理解和高度可变（病原）的物理现象，它因患者而异，并且从肿瘤（模型）到肿瘤（模型）。为了更好地理解EPR效应，为可能对EPR靶向的纳米化学化学干预措施做出反应，从而个性化并改善被动性肿瘤靶向的纳米医学治疗，我们在这里提出建议，我们对I）使用i）使用解剖学，功能性和分子成像技术来识别图像 - 可识别图像 - 可见的血管参数以及EPRELELECERERE ePRELELINE EPRELERINADE ePRELERATION EPRELER; ii）使用theranotic构建体和概念来证明EPR介导的靶向药物的程度与治疗效率相关。关于前者，我们将使用解剖学µCT，功能性MRI和US进行定量表征五个不同的肿瘤模型中的肿瘤血管（在侵袭性和血管生成型中已知有显着不同的肿瘤模型），我们将与图像 - 可观的血管参数与EPR介导的肿瘤参数与EPR介导的肿瘤参数（50 NM）（5 NM）（5 NM）（5 NM）（5）脂质体（100 nm）。这些与临床相关的载体材料将通过近红外染料和标准的荧光团二重标记，以实现整体肿瘤积累的体内µCT-FMT成像，以及对肿瘤渗透和肿瘤内分布的体内两光子激光扫描显微镜分析。 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 efficiency, and that inter- and intra-individual differences in tumor accumulation can be used to predict the outcome of passively tumor-targeted nanomedicine treatment.这些努力将共同提供促成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，证明了EPR介导的药物靶向与治疗有效性相关； 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

Cancer nanomedicine: is targeting our target?

• DOI: 10.1038/natrevmats.2016.69
• 发表时间: 2016-09-01
• 期刊: NATURE REVIEWS MATERIALS
• 影响因子: 83.5
• 作者: Lammers, Twan;Kiessling, Fabian;Storm, Gert
• 通讯作者: Storm, Gert

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