Increasing sensitivity and discrimination of breast cancer diagnosis using molecularly targeted, extravascular ultrasound imaging with ultrasound-activated, phase-change nanodroplet contrast agent
Increasing sensitivity and discrimination of breast cancer diagnosis using molecularly targeted, extravascular ultrasound imaging with ultrasound-activated, phase-change nanodroplet contrast agent
批准号:
9768466
负责人:
JAMES K TSURUTA
金额:
$7.63万
依托单位国家:
美国
项目类别:
财政年份:
2018
资助国家:
美国
项目状态:
已结题
起止时间:
2018-09-01 至 2021-05-31
关键词:
AcousticsBackBenignBiodistributionBiological AssayBiotinBloodBlood CirculationBlood VesselsBody TemperatureCaliberCarrying CapacitiesContrast MediaCustomDNADNA BindingDNA ProbesDetectionDevelopmentDiagnosisDiagnosticDiagnostic SensitivityDiscriminationDoseEncapsulatedEndothelial CellsExtravasationFDA approvedFluorocarbonsFormulationFutureGasesHalf-LifeImageImmunohistochemistryKidneyKnowledgeLabelLipidsLiquid substanceMalignant - descriptorMeasuresMethodsMicrobubblesMolecularMolecular TargetNormal tissue morphologyOrganPermeabilityPhasePhysiologic pulsePolymerase Chain ReactionProteinsPublic HealthReagentSignal TransductionSpecificityStainsTechniquesTemperatureTestingTimeTissuesTumor TissueTumor VolumeUltrasonographyVascular Endotheliumbreast cancer diagnosisbreast lesioncancer biomarkerscancer diagnosiscancer therapycontrast enhanceddensityimaging agentin vivointerstitialmalignant breast neoplasmmolecular imagingnanonanoDropletnanoparticlenanoscalenovelphase changepressurepreventtargeted agenttumor
中文摘要
摘要
脂壳全氟碳(PFC)微泡的直径从0.5微米到8微米不等
FDA批准增强血液对比度,用于诊断超声成像。中国的微观尺度
超声造影剂将它们限制在血液中,消除了增强的渗透性和滞留。
(EPR)在许多肿瘤中观察到。从现有的脂壳微泡中产生纳米颗粒的能力
造影剂让我们利用这些试剂的无毒配方,并让我们创建新的靶向
使用任何既定的策略形成靶向微泡的纳米颗粒。微泡
靶向分泌Frizzled2相关蛋白2(SFRP2)在肿瘤和肿瘤之间有明显的区别
血管系统正常,SFRP2在多种乳腺癌中高表达。我们和我们的同事
发现寒冷和压力增加会导致常规气相超声造影剂凝结成
液体PFC的脂壳纳米液滴。有了足够的能量,这些非回声物质就会恢复到
常规超声造影剂。纳米液滴具有纳米颗粒固有的优点
癌症治疗策略:通过EPR效应增强肿瘤中的被动蓄积,有针对性
通过靶向部分帮助肿瘤内的蓄积,并减少全身剂量。激活纳米液滴
与超声波提供了高度的空间选择性,防止微小气泡再次进入
血管系统,因此保持较高的局部造影剂浓度。分子成像
询问肿瘤内的间隙扩大了成像的物理范围,其回报是更高的
整个肿瘤体积的结合对比度密度,以及靶向肿瘤分子的更多机会
在血管内皮细胞中没有发现。我们建议用SFRP2-进行血管外分子成像。
与微泡相比,靶向纳米液滴将提高检测乳腺癌的敏感性
分子成像,同时保持减少误诊所需的分子特异性。一位批评者
利用分子靶向、脂壳全氟碳纳米液滴的障碍是根本缺乏
了解它们在正常组织和肿瘤组织中的生物分布。我们建议将现有的、已建立的
制备携带生物素和DNA的SFRP2靶向和非靶向纳米液滴制剂的技术
标记,测定它们的循环半衰期,并用免疫组织化学方法检测生物素或定量
聚合酶链式反应分析我们独特的DNA有效载荷,以表征这些液体的生物分布
正常组织和肿瘤组织中的全氟碳滴。确定靶向纳米液滴的交叉能力
内皮细胞层利用现有微泡造影剂,促进新型纳米材料的开发
试剂,并通过开发一种新的、高度有效的方法来增加超声波对检测乳腺癌的影响
灵敏的超声方法,利用靶向分子成像的分辨能力
乳腺病变的血管和血管外间隙。
英文摘要
ABSTRACT
Lipid shelled perfluorocarbon (PFC) microbubbles ranging from 0.5 to 8 microns in diameter have been
approved by the FDA to enhance the contrast of blood for diagnostic ultrasound imaging. The micro scale of
ultrasound contrast agents limits them to the bloodstream, eliminating the enhanced permeability and retention
(EPR) observed in many tumors. The ability to create nanoparticles from existing lipid-shelled microbubble
contrast agents lets us leverage the non-toxic formulations of these agents, and lets us create novel targeted
nanoparticles using any of the established strategies for formulating targeted microbubbles. Microbubbles
targeted to Secreted Frizzled Related Protein 2 (SFRP2) showed significant discrimination between tumor and
normal vasculature, and SFRP2 is highly expressed in a variety of breast cancers. We and our colleagues
found that cold and increased pressure caused conventional gas-phase ultrasound contrast to condense into
lipid-shelled nanodroplets of liquid PFC. With sufficient energy, these non-echogenic agents revert back to
conventional ultrasound contrast agents. Nanodroplets share the advantages inherent to nanoparticle
strategies for cancer therapy: passive accumulation in tumors enhanced by the EPR effect, targeted
accumulation within tumors aided by targeting moieties, and reduced systemic dosing. Activating nanodroplets
with ultrasound provides a high degree of spatial selectivity, preventing re-entry of the micro scale bubbles into
the vasculature, thus maintaining a high local concentration of contrast agent. Molecular imaging that
interrogates the interstitial space within tumors widens the physical scope of imaging with the payoff of a higher
density of bound contrast throughout the tumor volume, and additional opportunities to target tumor molecules
that are not found in the vascular endothelium. We propose that extravascular molecular imaging with SFRP2-
targeted nanodroplets will increase the sensitivity of detecting breast cancer compared to microbubble
molecular imaging while maintaining the molecular specificity needed to decrease false diagnoses. A critical
barrier to leveraging molecularly targeted, lipid shelled perfluorocarbon nanodroplets is a fundamental lack of
knowledge about their biodistribution in normal and tumor tissue. We propose to combine existing, established
techniques to create SFRP2-targeted, and non-targeted nanodroplet formulations carrying a biotin and DNA
label, determine their circulating half-lives, and use immunohistochemical detection of biotin or quantitative
polymerase chain reaction assays of our unique DNA payload to characterize the biodistribution of these liquid
perfluorocarbon droplets in normal and tumor tissues. Establishing the ability of targeted nanodroplets to cross
the endothelial cell layer leverages existing microbubble contrast agents, promotes development of novel nano
agents, and increases the impact of ultrasound for detecting breast cancer by developing a novel, highly
sensitive ultrasound method that leverages the discriminatory power of targeted molecular imaging in the
vascular and extravascular space of breast lesions.
期刊论文(1)
专著(0)
科研奖励(0)
会议论文
Accelerated blood clearance of targeted ultrasound contrast reduced molecular imaging signal intensity: Secreted Frizzled Related Protein-2 signal remained significantly higher than signal from either Vascular Endothelial Growth Factor Receptor-2 or alpha
目标超声造影剂的加速血液清除降低了分子成像信号强度:分泌的卷曲相关蛋白 2 信号仍然显着高于血管内皮生长因子受体 2 或 α 的信号
DOI:
10.1109/ultsym.2019.8925919
发表时间:
2019
期刊:
IEEE International Ultrasonics Symposium : [proceedings]. IEEE International Ultrasonics Symposium
影响因子:
--
作者:
[Tsuruta,James, White,Rachel, Klauber-DeMore,Nancy, Dayton,PaulA]
通讯作者:
Dayton,PaulA
Reversible vitamin A-dependent arrest of spermatogonia
-
批准号:6874405
-
项目类别:
-
资助金额:$23.0万
-
财政年份:2003
-
负责人:JAMES K TSURUTA
-
依托单位:
Reversible vitamin A-dependent arrest of spermatogonia
-
批准号:6772495
-
项目类别:
-
资助金额:$23.0万
-
财政年份:2003
-
负责人:JAMES K TSURUTA
-
依托单位:
Reversible vitamin A-dependent arrest of spermatogonia
-
批准号:6680614
-
项目类别:
-
资助金额:$23.0万
-
财政年份:2003
-
负责人:JAMES K TSURUTA
-
依托单位:
Reversible vitamin A-dependent arrest of spermatogonia
-
批准号:7228881
-
项目类别:
-
资助金额:$21.8万
-
财政年份:2003
-
负责人:JAMES K TSURUTA
-
依托单位:
Reversible vitamin A-dependent arrest of spermatogonia
-
批准号:7049394
-
项目类别:
-
资助金额:$22.45万
-
财政年份:2003
-
负责人:JAMES K TSURUTA
-
依托单位:
国内基金
海外基金
患者依从性与脑卒中后跌倒风险相关性及“Teach-Back ”护理干预效应研究
-
批准号:2026JJ81464
-
项目类别:省市级项目
-
资助金额:--
-
批准年份:2026
-
负责人:叶婷
-
依托单位:
基于Teach-back药学科普模式的慢阻肺患者吸入用药依从性及疗效研究
-
批准号:2024KP61
-
项目类别:省市级项目
-
资助金额:--
-
批准年份:2024
-
负责人:余丹
-
依托单位:
基于Quench-Back保护的超导螺线管磁体失超过程数值模拟研究
-
批准号:51307073
-
项目类别:青年科学基金项目
-
资助金额:25.0万元
-
批准年份:2013
-
负责人:郭兴龙
-
依托单位: