Image-guided, ultrasound-enhanced long-term intracranial drug delivery
图像引导、超声增强的长期颅内药物输送
基本信息
- 批准号:9884240
- 负责人:
- 金额:$ 16.79万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-02-15 至 2022-01-31
- 项目状态:已结题
- 来源:
- 关键词:AcousticsBiological ProductsBlood - brain barrier anatomyBlood CirculationBolus InfusionBrainBrain DiseasesCephalicClinicalCombined Modality TherapyCraniotomyDegenerative DisorderDevelopmentDiseaseDisease ProgressionDoseDrug Delivery SystemsDrug ImplantsDrug ModelingsErlotinibErythrocytesExcisionExtracellular FluidExtravasationFocused UltrasoundGlioblastomaGoldGrowthHourImmunosuppressive AgentsImmunotherapeutic agentImplantInjectableLifeMagnetic Resonance ImagingMalignant neoplasm of brainMediatingMethodsModelingNatureNeuronsOperative Surgical ProceduresPathway interactionsPatient CarePatientsPenetrationPharmaceutical PreparationsPrimary Brain NeoplasmsProdrugsRadioRecurrenceSavingsSchemeSideSiteStrokeSurgical marginsSymptomsSystemTechniquesTechnologyTestingTherapeuticTherapeutic AgentsTimeTissuesTumor-DerivedUltrasonographyVisionblood-brain barrier disruptionblood-brain barrier permeabilizationcancer therapychemotherapeutic agentchemotherapyclinical applicationclinical translationcontrolled releasecraniumepidermal growth factor receptor VIIIflexibilityimage guidedimplantationimprovedinnovationnew technologynovelnovel therapeutic interventionpost strokepreclinical studypreventregenerative agentside effectstandard of caresubcutaneoustreatment strategytumortumor growth
项目摘要
PROJECT SUMMARY
The blood-brain barrier (BBB) serves as the major hindrance to efficient transport of life-saving therapeutics
to the brain. Image-guided focused ultrasound can disrupt the BBB, but only temporarily and for a short period
of time. Local implantation of drug-eluting depots is another option, but these are single-use systems that cannot
be refilled or reused after implantation at inaccessible sites, limiting their clinical utility. Recently, we introduced
click-modified refillable drug depots: injectable depots that capture prodrug refills from systemic circulation and
release active drugs locally in a sustained manner. Capture of systemically-administered refills serves as an
efficient and non-toxic method to repeatedly refill depots. Refillable depots in combination with prodrug refills
achieve sustained release at tumor sites to improve cancer therapy while eliminating systemic side effects.
Refillable depots have been successful in subcutaneous models of tumor recurrence, preventing tumor growth
while eliminating systemic side effects. Unfortunately, the prodrug refills do not cross the BBB and thus refillable
depots cannot be used alone in brain diseases such as stroke, degenerative disorders and brain cancers.
We now propose refilling intracranial drug depots through the combination of non-toxic therapeutic
prodrugs and image-guided transient disruption of the blood brain barrier. BBB disruption with focused-
ultrasound provide a transient (~1 hour) window for the refilling of intracranial depots. The use of nontoxic
prodrug refills allows us to administer large doses to maximally exploit the short window for drug delivery,
allowing weeks and potentially months worth of therapeutic to be given in the short time window. After BBB
reformation, the intracranial depots will release active drugs for a long period of time before being non-invasively
refilled again. We further propose testing this innovative drug-delivery strategy in a patient-derived orthotopic
GBM tumor model.
This innovative combination of these two promising new technologies provides an approach to present
therapeutic agents over a long period of time directly to the brain. Our efforts will further develop this promising
approach, optimize parameters, and validate efficacy in preclinical studies. Clinical applications include the local
release of chemotherapeutics, biologics and immunotherapy agents against GBM and other brain cancers, and
administration of regenerative and immunosuppressive agents after stroke. If successful, the improvements
made to this very innovative drug delivery strategy could open the pathway to clinical translation of refillable drug
delivery technology.
项目摘要
血脑屏障(BBB)是有效运输救生治疗剂的主要障碍
到大脑。图像引导的聚焦超声可以破坏BBB,但只是暂时的和短时间的
时间了局部植入药物洗脱贮库是另一种选择,但这些都是一次性使用的系统,
在植入难以接近的部位后,需要重新填充或重复使用,限制了它们的临床应用。最近,我们介绍了
点击修饰的可再填充药物贮库:从体循环捕获前药再填充物的可注射贮库,
以持续的方式局部释放活性药物。采集系统给药的再灌注液可作为
高效、无毒的方法来重复填充仓库。与前药再填充剂组合的可再填充贮库
在肿瘤部位实现持续释放,以改善癌症治疗,同时消除全身副作用。
可再填充的贮库在肿瘤复发的皮下模型中已经取得成功,
同时消除全身副作用。不幸的是,前药再填充剂不能穿过BBB,因此可再填充。
贮库不能单独用于脑疾病,如中风,退行性疾病和脑癌。
我们现在建议通过结合无毒的治疗药物,
前药和图像引导的血脑屏障的短暂破坏。BBB中断与集中-
超声为颅内储库的再填充提供了短暂的(约1小时)窗口。使用无毒
前药再填充物允许我们施用大剂量以最大限度地利用药物递送的短窗口,
允许在短时间窗口内给予数周和可能数月的治疗。BBB后
在非侵入性的重组之前,颅内贮库将长时间释放活性药物
又重新装满了。我们进一步建议在患者源性原位移植物中测试这种创新的药物递送策略。
GBM肿瘤模型。
这两种有前途的新技术的创新组合提供了一种方法,
治疗剂在很长一段时间内直接进入大脑。我们的努力将进一步发展这一有希望的
方法,优化参数,并在临床前研究中验证疗效。临床应用包括当地
释放针对GBM和其他脑癌的化学治疗剂、生物制剂和免疫治疗剂,以及
中风后给予再生和免疫抑制剂。如果成功,
这种创新的药物输送策略可以为可再填充药物的临床转化开辟道路
交付技术。
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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Yevgeny Brudno其他文献
Yevgeny Brudno的其他文献
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