Targeted Photoactivable Nanocells: Image-based Drug Delivery and Dosimetry in GBM

靶向光敏纳米细胞：GBM 中基于图像的药物输送和剂量测定

• 批准号: 8786064
• 负责人: Tayyaba Hasan
• 金额: $ 49.81万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-01-01 至 2016-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8786064
• 关键词: Architecture; Avastin; Binding; Cell Culture Techniques; Cell model; Cells; Cetuximab; Clinical Research; Clinical Treatment; Clinical Trials; Comparative Study; Contrast Media; Development; Diagnostic; Disease; Drug Delivery Systems; Drug Kinetics; Dyes; Epidermal Growth Factor Receptor; Excision; Fluorescence; Gadolinium DTPA; Glioblastoma; Glioma; Glutamate Carboxypeptidase II; Goals; Health; Image; Image Analysis; In Vitro; Individual; Label; Laboratories; Light; Lighting; Longitudinal Studies; Magnetic Resonance; Magnetic Resonance Imaging; Measurement; Measures; Methods; Modality; Modeling; Molecular Target; Monitor; Monoclonal Antibodies; Monoclonal Antibody C225; Mus; Nanotechnology; Optical Methods; Outcome; Outcome Study; PUVA Photochemotherapy; Patients; Pharmaceutical Preparations; Photochemistry; Phototoxicity; Primary Neoplasm; Radioactive; Resectable; Specificity; Surface; Survival Rate; System; Technology; Testing; Therapeutic; Therapeutic Agents; Therapeutic Studies; Three-Dimensional Image; Time; Treatment outcome; Tumor Burden; Unresectable; Validation; base; biophysical properties; cytotoxicity; dosimetry; fluorescence imaging; fluorophore; image guided; imaging agent; in vitro Model; in vivo; in vivo Model; in vivo imaging; individualized medicine; model development; molecular marker; multidisciplinary; neoplastic cell; novel; optical imaging; overexpression; quantitative imaging; research study; response; targeted delivery; three-dimensional modeling; tomography; translational medicine; treatment effect; treatment planning; tumor; uptake

DESCRIPTION (provided by applicant): This collaborative application seeks to create an image-guided platform for the treatment of glioblastoma multiforme (GBM) by combining drug delivery using novel nanoconstructs with our unique magnetic resonance guided optical imaging quantification (MROQ) system for image analysis. We use targeted photodynamic therapy (PDT), a photochemistry-based technology to effectively treat GBM. PDT is in clinical studies for GBM treatment and PDT agents can also fluoresce thus enabling online imaging of drug for both image-guided drug delivery (IGDD) and light dosimetry (IGLD). The basic thesis being tested here is that treatment outcomes are superior when targeted delivery of therapeutic and imaging agents is combined with quantitative imaging to provide pharmacokinetic binding (PKB) models that guide treatment planning for PDT. The strategy is to fabricate nanotechnology-based, epidermal growth factor receptor (EGFR) targeting, fluorescent nanocells (TNC) that incorporate a PDT agent (benzoporphyrin derivatve, BPD), a biologic agent, Avastin and a surface conjugated MRI contrast agent Gadolinium-DTPA (Gd-DTPA). The EGFR is targeted using the monoclonal antibody (Mab) Cetuximab, C225, which is fluorescently labeled with an NIR dye LICOR 800CW for enabling IGDD and subsequent development of PK models of binding of the imaging and therapeutic agents to tumor cells. BPD fluorescence will provide the basis for IGLD. EGFR, overexpressed in >50% of GBMs is used as a molecular target primarily for delivering high payloads of probes. The TNC will be compared with non-specifically targeted nanocells (NNC) where the C225 is replaced by an irrelevant Mab targeted to prostate specific membrane antigen (PSMA) not expressed on U87 GBM cells. The study goals will be achieved in 4 specific aims that include TNC/NNC fabrication, 2D cell culture, newly developed 3D GBM models (recapitulating tumor architecture) and in vivo orthotopic tumor models combined with quantitative imaging using MROQ. Aim 1 will synthesize and characterize TNC and NNC. Aim 2: will test the TNC/NNC selectivity and phototoxicity in 3D cellular models of GBM (U87 cells) in vitro for establishing the basis for IGDD/IGLD by determining cell associated fractions. Aim 3 will develop predictive PKB models in vivo using our MROQ system for quantifying drug delivery and establishing cell-associated fractions of TNC in vivo to guide Aim 4, which will establish the impact of quantitative IGDD/IGLD and PKB models in vivo on treatment outcomes in orthotopic murine models of GBM in short-term (tumor burden) and long-term (survival) studies. The significance of this study is that it provides new multifunctional drug delivery constructs, new 3D GBM models, a dual modality system for quantitative imaging, establishes the impact of IGDD/IGLD on treatment outcome and resolves the controversy of the value of targeting of macromolecular carriers by direct comparative studies with TNC and NNC. If IGDD/IGLD show superior outcomes, the study forms the basis for patient-customized treatments where the timing and amount of illumination is adjusted to individuals.

描述（由申请人提供）：该协作应用程序旨在创建一个图像引导的平台，用于治疗胶质母细胞瘤多形式（GBM），通过使用新型纳米构造与我们独特的磁共振指导的光学成像量化（MROQ）系统结合药物输送，以进行图像分析。我们使用靶向光动力疗法（PDT），这是一种基于光化学的技术来有效治疗GBM。 PDT正在用于GBM治疗的临床研究中，PDT药物也可以荧光，从而实现在线成像，以用于图像引导的药物递送（IGDD）和光剂量测定法（IGLD）（IGLD）。这里测试的基本论文是，当针对治疗和成像剂的靶向递送与定量成像结合使用时，治疗结果是优越的，以提供指导PDT治疗计划的药代动力学结合（PKB）模型。该策略是制造基于纳米技术的表皮生长因子受体（EGFR）靶向，荧光纳米细胞（TNC）（TNC），该（TNC）结合了PDT剂（Benzoporphyrin derivatve，bpd），生物学剂，avastin，Avastin和表面是表面成形的MRI对比剂Gadolinium gadolinium-DTPA（GDTPA）。 EGFR使用单克隆抗体（MAB）西妥昔单抗C225靶向，该抗体用NIR Dye Licor 800CW荧光标记，以启用IGDD，并随后开发了成像和治疗剂与肿瘤细胞结合的PK模型。 BPD荧光将为IGLD提供基础。 EGFR，> 50％的GBM中过表达的EGFR主要用作分子靶标，主要用于传递高有效探针。将TNC与非特异性靶向纳米球（NNC）进行比较，其中C225被靶向前列腺特异性膜抗原（PSMA）的无关的mAb取代，未在U87 GBM细胞上表达。研究目标将在4个特定目标中实现，包括TNC/NNC制造，2D细胞培养，新开发的3D GBM模型（概括肿瘤结构）和体内原动体肿瘤模型，结合了使用MROQ进行定量成像。 AIM 1将合成并表征TNC和NNC。 AIM 2：将在体外测试GBM（U87细胞）3D细胞模型中TNC/NNC的选择性和光毒性，以通过确定相关的细胞分数来建立IGDD/IGLD的基础。 AIM 3将使用我们的MROQ系统在体内开发预测性的PKB模型，以量化药物输送并建立与体内TNC相关的细胞相关分数，以指导AIM 4，这将确定Vivo中量化IGDD/IGLD和PKB模型的量化IgDD/IgLD和PKB模型的影响。这项研究的意义在于，它提供了新的多功能药物输送构建体，新的3D GBM模型，一种用于定量成像的双模式系统，确定了IGDD/IGLD对治疗结果的影响，并通过对TNC和NNC的验证比较研究的靶向靶向靶向的靶向值。如果IGDD/IGLD表现出卓越的结果，则该研究构成了患者注定治疗的基础，在该治疗中，将照明的时间和照明量调整为个人。

项目成果

Beyond the Barriers of Light Penetration: Strategies, Perspectives and Possibilities for Photodynamic Therapy.

• DOI: 10.7150/thno.16183
• 发表时间: 2016
• 期刊: Theranostics
• 影响因子: 12.4
• 作者: Mallidi S;Anbil S;Bulin AL;Obaid G;Ichikawa M;Hasan T
• 通讯作者: Hasan T

A new nanoconstruct for epidermal growth factor receptor-targeted photo-immunotherapy of ovarian cancer.

• DOI: 10.1016/j.nano.2013.02.005
• 发表时间: 2013-10
• 期刊: NANOMEDICINE-NANOTECHNOLOGY BIOLOGY AND MEDICINE
• 影响因子: 5.4
• 作者: Mir, Youssef;Elrington, Stefan A.;Hasan, Tayyaba
• 通讯作者: Hasan, Tayyaba

Spatial frequency analysis of anisotropic drug transport in tumor samples.

肿瘤样品中各向异性药物转运的空间频率分析。

• DOI: 10.1117/1.jbo.19.1.015005
• 发表时间: 2014
• 期刊: Journal of biomedical optics
• 影响因子: 3.5
• 作者: Russell,Stewart;Samkoe,KimberleyS;Gunn,JasonR;Hoopes,PJack;Nguyen,ThienanA;Russell,MiloJ;Alfano,RobertR;Pogue,BrianW
• 通讯作者: Pogue,BrianW