Optimization and validation of integrated microscale technologies for low-cost, automated production of PET molecular imaging tracers for cancer research
Optimization and validation of integrated microscale technologies for low-cost, automated production of PET molecular imaging tracers for cancer research
批准号:
10224825
负责人:
Robert Michael van Dam
金额:
$37.91万
依托单位国家:
美国
项目类别:
财政年份:
2019
资助国家:
美国
项目状态:
已结题
起止时间:
2019-08-01 至 2023-07-31
关键词:
3-DimensionalAdvanced DevelopmentAmino AcidsAnimal ModelAnimalsApoptosisBiochemical ProcessBiologicalBiological AssayBiological ProcessCell Culture TechniquesCellsCellular AssayClinicalComputer softwareConsumptionCost SharingDataDevelopmentDevicesDiseaseEquipmentFluorineGamma RaysGlucoseGoalsHigh Pressure Liquid ChromatographyHuman ResourcesHypoxiaImageIn VitroIndividualInfrastructureInstitutionIsotopesLabelLiquid substanceMalignant NeoplasmsMeasurementMetabolismMethodsMicrofluidic MicrochipsMicrofluidicsModelingMolecularMolecular ProbesPatientsPenetrationPerformancePositronPositron-Emission TomographyPreparationProblem SolvingProductionPublic HealthPumpRadiationRadioactiveRadioactivityRadiochemistryRadioisotopesRadiolabeledRadiometryReagentReportingResearchResearch ActivityResearch PersonnelResearch Project GrantsSamplingScanningScheduleSystemTechnologyThickTissuesTracerTranslatingTranslationsTreatment EfficacyValidationangiogenesisanticancer researchattenuationbasecostdesignflexibilityfluorodeoxyglucosefluorophorein vivoin vivo imaginginsightmolecular imagingneoplastic cellnoveloperationoverexpressionpre-clinicalpredicting responseprototypequantitative imagingradiochemicalradiotracerreceptor densitytechnology validationtooltreatment responsetumor microenvironmentwasting
中文摘要
项目概要
正电子发射断层扫描 (PET) 探针(或“示踪剂”)是含有正电子发射的生物分子
同位素,可以高灵敏度检测其衰变,以进行各种体外或体内 3D 分析
用于癌症研究的生化过程测定。放射性标记的一个显着优势是高组织
伽马射线的穿透——这使得细胞水平的发现能够转化为新的动物模型
(例如,研究疾病的机制和治疗),然后对患者进行检测(例如,预测反应)
来治疗或评估治疗效果),所有这些都使用相同的探头。数以千计的 PET 示踪剂已被
据报道可用于评估血管生成、肿瘤微环境(例如缺氧)、代谢(例如葡萄糖或氨基)
酸)、受体密度等。另一个优点是许多 PET 示踪剂都用单一放射性标记
与荧光团等大体积标签相比,通常对生物功能造成的破坏较小。
目前这些短寿命 PET 示踪剂的常规生产方法主要针对临床市场,
即用于大批量、多患者的生产。对于一些示踪剂(例如[18F]FDG),有足够的需求
可以协调安排(即同一天进行许多患者扫描和研究项目)以及
高生产成本可以由许多患者和研究人员分摊。在需求不足的情况下
为了分摊成本,PET 示踪剂的价格昂贵得令人望而却步。由于放射性同位素只是其中的一小部分
生产成本,缩小到更少量的放射性并不能显着降低成本
研究人员只需要少量的探针。其他成本驱动因素包括昂贵的设备和
专门设施(即热室,以在使用大量放射性同位素时保护操作员)
许多机构的癌症研究人员都可以使用,并且每批消耗的试剂成本很高
产生的示踪剂。由于成本高昂,许多研究人员选择替代标记方法(例如荧光、
尽管这些方法存在局限性,但生物发光)。
我们的初步数据表明,微流控合成仪可以成功生产多种 PET 示踪剂
同时为解决上述问题提供了独特的优势:(1)液滴微反应器消耗10-1000x
比传统系统更少的试剂; (2) 与传统系统不同,微反应器中的摩尔活性
即使产生少量(放射性)示踪剂,仍保持高水平; (3) 尺寸紧凑
微反应器可实现局部辐射屏蔽,无需热室; (4)小批量生产
与典型的热室相比,个人研究人员使用所需的辐射屏蔽(厚度)要少得多。
先前的研究已经确立了可行性,并表明微滴合成器有望实现
按需常规、低成本生产示踪剂。这可以使 PET“商品化”并制造多种示踪剂
任何调查员都可以使用。该提案旨在对此进行高级开发和验证
技术使放射性标记示踪剂广泛用于各种癌症研究应用的测定。
英文摘要
PROJECT SUMMARY
Positron-emission tomography (PET) probes (or “tracers”) are biological molecules containing positron-emitting
isotopes, the decay of which can be detected with high sensitivity to perform a variety of in vitro or 3D in vivo
assays of biochemical processes for cancer research. A significant advantage of radiolabels is the high tissue
penetration of gamma rays – this allows discoveries at the cellular level to be translated to new animal models
(e.g. to study the mechanisms and treatment of disease) and then to assays in patients (e.g. to predict response
to treatment or assess efficacy of treatment), all with the same probe. Thousands of PET tracers have been
reported for assessing angiogenesis, tumor microenvironment (e.g. hypoxia), metabolism (e.g., glucose or amino
acids), density of receptors, etc. Another advantage is that many PET tracers are labeled with a single radioactive
atom, typically causing less disruption to biological function compared to bulky labels such as fluorophores.
Current methods for routine production of these short-lived PET tracers are aimed largely at the clinical market,
i.e. for production of large, multi-patient batches. For a few tracers (e.g. [18F]FDG), there is sufficient demand
that scheduling can be coordinated (i.e. many patient scans and research projects on the same day) and the
high production cost can be divided among many patients and researchers. In cases where demand is insufficient
to enable cost-sharing, PET tracers are prohibitively expensive. Since the radioisotope is only a fraction of the
production cost, scaling down to a smaller amount of radioactivity does not provide significant cost reduction for
researchers that only need a small quantity of the probe. Other drivers of cost are the expensive equipment and
specialized facilities (i.e. hot cells, to protect operators when using high amounts of radioisotope) that are not
available to cancer researchers at many institutions, and the high cost of reagents consumed for each batch of
tracer produced. Due to the high cost, many researchers choose alternative labeling methods (e.g. fluorescent,
bioluminescent) despite the limitations of these approaches.
Our preliminary data have shown that microfluidic synthesizers can successfully produce diverse PET tracers
while providing unique advantages to solve the above problems: (1) Droplet microreactors consume 10-1000x
less reagents than conventional systems; (2) Unlike conventional systems, molar activity in microreactors
remains high even when producing small quantities (radioactivity) of the tracer; (3) The compact size of
microreactors enables local radiation shielding and avoids the need for hot cells; (4) Production of small batches
for individual researcher use will require much less radiation shielding (thickness), compared to typical hot cells.
Previous studies have established feasibility and suggest that microdroplet synthesizers are poised to enable
routine, low-cost production of tracers on demand. This could “commoditize” PET and make diverse tracers
available to any investigator. This proposal seeks to perform advanced development and validation of this
technology to make radiolabeled tracers widely available for assays in a variety of cancer research applications.
期刊论文(1)
专著(0)
科研奖励(0)
会议论文
DOI:
10.3791/62056
发表时间:
2021-02-12
期刊:
Journal of visualized experiments : JoVE
影响因子:
--
作者:
[Rios A, Holloway TS, Wang J, van Dam RM]
通讯作者:
van Dam RM
Optimization and validation of integrated microscale technologies for low-cost, automated production of PET molecular imaging tracers for cancer research
-
批准号:9795734
-
项目类别:
-
资助金额:$37.91万
-
财政年份:2019
-
负责人:Robert Michael van Dam
-
依托单位:
Optimization and validation of integrated microscale technologies for low-cost, automated production of PET molecular imaging tracers for cancer research
-
批准号:9982914
-
项目类别:
-
资助金额:$37.91万
-
财政年份:2019
-
负责人:Robert Michael van Dam
-
依托单位:
High-throughput radiochemistry platform for accelerated discovery and development of novel PET imaging agents for cancer
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批准号:9231796
-
项目类别:
-
资助金额:$30.8万
-
财政年份:2017
-
负责人:Robert Michael van Dam
-
依托单位:
Automated microfluidic production of high specific activity PET tracers to enable routine CNS imaging
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批准号:8870224
-
项目类别:
-
资助金额:$23.1万
-
财政年份:2015
-
负责人:Robert Michael van Dam
-
依托单位:
Automated microfluidic production of high specific activity PET tracers to enable routine CNS imaging
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批准号:9060851
-
项目类别:
-
资助金额:$23.1万
-
财政年份:2015
-
负责人:Robert Michael van Dam
-
依托单位:
Compact microfluidic PET probe concentrator for preclinical and in vitro imaging
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批准号:8737815
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项目类别:
-
资助金额:$22.74万
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财政年份:2013
-
负责人:Robert Michael van Dam
-
依托单位:
Compact microfluidic PET probe concentrator for preclinical and in vitro imaging
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批准号:8624154
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项目类别:
-
资助金额:$23.45万
-
财政年份:2013
-
负责人:Robert Michael van Dam
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依托单位:
Microliter radiosynthesizer for producing high specific activity PET ligands
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批准号:8508266
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项目类别:
-
资助金额:$21.54万
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财政年份:2012
-
负责人:Robert Michael van Dam
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依托单位:
海外基金