Drug-Loaded Nanobubbles for Ultrasound Enhanced Delivery to Colon Cancer Liver Metastasis
用于超声增强递送至结肠癌肝转移的载药纳米气泡
基本信息
- 批准号:10019356
- 负责人:
- 金额:$ 47.11万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-09-30 至 2024-06-30
- 项目状态:已结题
- 来源:
- 关键词:AddressAdvanced Malignant NeoplasmAntineoplastic AgentsAreaBiodistributionBlood CellsBlood VesselsBreastCaliberCell Culture TechniquesCell WallCell modelCellsChemotherapy-Oncologic ProcedureClinicClinicalColonColon CarcinomaColorectal CancerComplexContrast MediaDataDiagnosisDiseaseDoseDose-LimitingDrug CarriersDrug Delivery SystemsDrug KineticsDrug TransportEffectivenessEngineeringEquipmentEsophagusExcisionExtravasationFormulationFrequenciesGasesGoalsHCT116 CellsHumanHybridsImageIn VitroInjectionsIntestinesIntravenousKidneyLS174T colon cancer cell lineLarge Intestine CarcinomaLeadLipidsLiposomesLiverLungMeasuresMediatingMetastatic Neoplasm to the LiverMicellesMicrobubblesModelingMusNanotechnologyOralOrganOutcomeOutcomes ResearchPancreasPatientsPenetrationPerformancePermeabilityPharmaceutical PreparationsPhysiologic pulsePlayPolymersResearchResearch SupportRoleSignal TransductionSiteSolid NeoplasmStomachSystemTechniquesTechnologyTestingTherapeuticTherapeutic AgentsTimeTissuesToxic effectTransducersTranslatingTreatment EfficacyTreatment outcomeTumor TissueTumor VolumeUltrasonographyUnited StatesVascular blood supplyVisualizationWorkbasecancer cellcancer diagnosiscell killingchemosensitizing agentchemotherapeutic agentchemotherapyclinically relevantcolon cancer patientscolorectal cancer metastasisdesigndrug distributiondrug efficacyeffective therapyimage-guided drug deliveryimaging propertiesimprovedin vivointerestmelanomametastatic colorectalnanobubblenanoparticleneoplastic cellparticleresponsescale upsuccesssystemic toxicitytheranosticstime usetreatment strategytumortumor growthtumor heterogeneitytumor microenvironmentuptake
项目摘要
PROJECT SUMMARY
Drug-Loaded Nanobubbles for Ultrasound Enhanced Delivery to Colon Cancer Liver Metastasis
Most advanced cancers can spread to the liver including those of the breast, esophagus, stomach, pancreas,
colon, lungs, kidneys and even melanoma. Liver metastases (also referred to as secondary liver cancer) cannot
be cured in the majority of cases, and most patients presenting with liver metastases will die of the disease. The
problem is most pronounced in colorectal cancer, where nearly 85% of the 150,000 patients diagnosed in the
United States each year will eventually develop metastatic disease in the liver due to the shared blood supply
between the intestine and the liver. Effective treatment options at this stage are severely limited, and most cases
are treated with oral or intravenous chemotherapy. The median survival for patients receiving systemic
chemotherapy is still only 21 months due primarily to low drug uptake in the tumor, serious systemic toxicity and
heterogeneous drug distribution at tumor sites. To meet the urgent need for more effective treatment options for
liver metastases, we plan to develop a hybrid theranostic nanobubble which is inherently ultrasound
visible and ultrasound-deployable on demand in real time at the region of interest. Our exciting preliminary
data demonstrate that even after a single application of ultrasound immediately following particle injection,
ultrasound-triggered delivery leads to significantly higher drug concentration in tumors and results in more
homogeneous distribution within tumor compared to free drug and non-triggered particles. This suggests that,
especially after parameters are optimized, treatment of tumors with the proposed construct has the potential to
maximize drug dose at the tumor site and should lead to improved survival. Within the scope of this project we
thus propose to optimize formulation and treatment parameters essential to the success of this approach. Some
aspects that distinguish our technology from others include 1) nanoparticles used in the study are 100-300 nm
in diameter and yet have strong ultrasound response making them visible at clinically relevant frequencies of 3-
12 MHz; 2) nanoparticles have augmented cargo capacity to enable simple and efficient drug loading directly
into the particle; 3) payload release can be triggered with the imaging transducer using standard pulse sequences
already available on clinical scanners; 4) nanoparticle is self-assembled and thus easily formulated and scaled
up. The project will be carried out in four aims with Aims 1 and 2 being dedicated to in vitro characterization and
optimization of the construct and Aims 3 and 4 evaluating in vivo performance. The ultimate goal of this work
is to develop and optimize an image-guided drug delivery strategy that will maximize drug accumulation
in tumors and lead to augmented, homogeneous drug distribution within the tumor volume while
minimizing systemic accumulation compared to free drug. The outcome of this research will be a more
effective strategy to improve delivery of chemotherapeutic agents to metastatic liver tumors.
Impact: We are confident that the advantages and unique aspects of our nanoparticles will enable successful
completion of this objective. These nanoparticles will overcome the drug transport challenges and will improve
the effectiveness of chemotherapy regimens used in treating secondary liver cancer with ultimate goal to
translate this research to the clinic.
项目概要
用于超声增强递送至结肠癌肝转移的载药纳米气泡
大多数晚期癌症可以扩散到肝脏,包括乳腺癌、食道癌、胃癌、胰腺癌、
结肠、肺、肾甚至黑色素瘤。肝转移(也称为继发性肝癌)不能
大多数病例可以治愈,并且大多数出现肝转移的患者将死于该病。这
结直肠癌的问题最为明显,在 150,000 名患者中,近 85% 是在结直肠癌中诊断出来的。
由于共享血液供应,美国每年最终都会出现肝脏转移性疾病
肠和肝脏之间。现阶段有效的治疗选择非常有限,而且大多数病例
通过口服或静脉化疗进行治疗。接受全身治疗的患者的中位生存期
化疗仍然只有21个月,主要是由于肿瘤药物摄取低、全身毒性严重以及
肿瘤部位的药物分布不均匀。满足对更有效治疗方案的迫切需求
肝转移,我们计划开发一种混合治疗诊断纳米气泡,其本质上是超声波
可见光和超声波可按需在感兴趣区域实时部署。我们激动人心的预赛
数据表明,即使在粒子注射后立即应用一次超声波,
超声触发的递送导致肿瘤中的药物浓度显着升高,并导致更多
与游离药物和非触发颗粒相比,肿瘤内分布均匀。这表明,
特别是在参数优化之后,用所提出的构建体治疗肿瘤有可能
最大限度地提高肿瘤部位的药物剂量,应该会提高生存率。在这个项目的范围内,我们
因此建议优化对该方法成功至关重要的配方和治疗参数。一些
我们的技术与其他技术的区别包括 1) 研究中使用的纳米粒子为 100-300 nm
直径,但具有强烈的超声响应,使其在临床相关频率 3-
12兆赫; 2) 纳米颗粒增强了载药能力,可以直接简单高效地装载药物
进入粒子; 3) 可以使用标准脉冲序列通过成像传感器触发有效负载释放
已在临床扫描仪上使用; 4) 纳米粒子是自组装的,因此易于配制和规模化
向上。该项目将实现四个目标,其中目标 1 和 2 致力于体外表征和
构建体的优化以及目标 3 和 4 评估体内性能。这项工作的最终目标
是开发和优化图像引导的药物输送策略,以最大限度地提高药物积累
并导致肿瘤体积内药物分布增强、均匀,同时
与游离药物相比,最大限度地减少全身蓄积。这项研究的成果将是一个更
改善化疗药物向转移性肝肿瘤的输送的有效策略。
影响:我们相信,我们的纳米颗粒的优势和独特之处将使我们取得成功
这一目标的完成。这些纳米颗粒将克服药物运输的挑战,并将改善
用于治疗继发性肝癌的化疗方案的有效性,最终目标是
将这项研究转化为临床。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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{{ truncateString('Agata A Exner', 18)}}的其他基金
Development of a novel imaging modality for adoptive cell therapy
开发用于过继细胞治疗的新型成像方式
- 批准号:
10316427 - 财政年份:2021
- 资助金额:
$ 47.11万 - 项目类别:
Drug-Loaded Nanobubbles for Ultrasound Enhanced Delivery to Colon Cancer Liver Metastasis
用于超声增强递送至结肠癌肝转移的载药纳米气泡
- 批准号:
10181954 - 财政年份:2019
- 资助金额:
$ 47.11万 - 项目类别:
Drug-Loaded Nanobubbles for Ultrasound Enhanced Delivery to Colon Cancer Liver Metastasis
用于超声增强递送至结肠癌肝转移的载药纳米气泡
- 批准号:
9764722 - 财政年份:2019
- 资助金额:
$ 47.11万 - 项目类别:
Drug-Loaded Nanobubbles for Ultrasound Enhanced Delivery to Colon Cancer Liver Metastasis
用于超声增强递送至结肠癌肝转移的载药纳米气泡
- 批准号:
10696225 - 财政年份:2019
- 资助金额:
$ 47.11万 - 项目类别:
Pressure-Driven Local Drug Delivery System for Treatment of Liver Cancer
用于治疗肝癌的压力驱动局部给药系统
- 批准号:
8653570 - 财政年份:2013
- 资助金额:
$ 47.11万 - 项目类别:
Pressure-Driven Local Drug Delivery System for Treatment of Liver Cancer
用于治疗肝癌的压力驱动局部给药系统
- 批准号:
8504165 - 财政年份:2013
- 资助金额:
$ 47.11万 - 项目类别:
Pressure-Driven Local Drug Delivery System for Treatment of Liver Cancer
用于治疗肝癌的压力驱动局部给药系统
- 批准号:
8843429 - 财政年份:2013
- 资助金额:
$ 47.11万 - 项目类别:
Pressure-Driven Local Drug Delivery System for Treatment of Liver Cancer
用于治疗肝癌的压力驱动局部给药系统
- 批准号:
9062872 - 财政年份:2013
- 资助金额:
$ 47.11万 - 项目类别:
Vascular Modulation for Enhancement of Image-Guided RF Ablation
用于增强图像引导射频消融的血管调制
- 批准号:
8027740 - 财政年份:2010
- 资助金额:
$ 47.11万 - 项目类别:
Vascular Modulation for Enhancement of Image-Guided RF Ablation
用于增强图像引导射频消融的血管调制
- 批准号:
7781804 - 财政年份:2010
- 资助金额:
$ 47.11万 - 项目类别:
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