Novel drug delivery strategies for treatment of breast cancer brain metastases
治疗乳腺癌脑转移的新型药物递送策略
基本信息
- 批准号:10367645
- 负责人:
- 金额:--
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-07-01 至 2026-06-30
- 项目状态:未结题
- 来源:
- 关键词:ABCB1 geneAbraxaneAdhesivesAffinityAnimalsAntineoplastic AgentsBindingBiodistributionBiologicalBlood - brain barrier anatomyBrainBrain NeoplasmsBreastBreast Cancer CellBreast Cancer PatientBreast Cancer TreatmentBreast Cancer therapyCapillary Endothelial CellCell Surface ReceptorsChargeClinicalClinical TrialsConvectionDetectionDevelopmentDiagnosisDiffuseDiseaseDistantDrug CombinationsDrug Delivery SystemsDrug EffluxDrug KineticsElectrostaticsEngineeringEpidermal Growth Factor ReceptorExtracellular SpaceFDA approvedFaceFatty acid glycerol estersFemaleFocused UltrasoundFocused Ultrasound TherapyFormulationGoalsHumanHuman ResourcesImmunocompetentIn VitroIntracranial NeoplasmsKineticsMDA MB 231Magnetic Resonance ImagingMalignant neoplasm of lungMammary NeoplasmsMaximum Tolerated DoseMediatingMetastatic breast cancerMetastatic malignant neoplasm to brainMicrofluidicsMilitary PersonnelModelingMonoclonal AntibodiesMulti-Drug ResistanceMusNeoplasm MetastasisNeurogliaNeuronsOrganPaclitaxelPatientsPenetrationPharmaceutical PreparationsPharmacotherapyPositioning AttributeProcessProductionPrognosisPropertyPumpRecurrenceRegimenResearchSafetyScreening for cancerSpecimenSurface PropertiesSystemSystemic TherapyTechnologyTestingTherapeuticTissuesTreatment EfficacyTumor Necrosis Factor ReceptorTumor TissueUnited StatesVeteransWomanWorkXenograft Modelactive dutyblood-brain barrier disruptionblood-brain tumor barrierbrain parenchymacancer cellcancer subtypescancer typecell killingcerebral capillaryclinical developmentclinical translationcytotoxicitydesigndrug clearancedrug standardefflux pumpglymphatic systemimprovedin vivoinnovationinstrumentinterstitialintravenous administrationmalemalignant breast neoplasmmammarymelanomamembermilitary servicenanoparticlenanoparticle deliverynanotherapeuticneoplastic cellnew therapeutic targetnovel therapeuticsoverexpressionpressureprogrammed cell death ligand 1receptorstandard caretreatment strategytriple-negative invasive breast carcinomatumortumor growth
项目摘要
With an increasing number of women serving in the military, there is a significant need to effectively manage our
active duty and Veteran women who develop breast cancer. In the United States alone, ~276,000 women will
be diagnosed with breast cancer, of whom ~42,000 are predicted to die from this disease this year. Patients
diagnosed with triple negative breast cancer (TNBC) and human epidermal growth factor receptor 2 (HER2)-
positive breast cancer have an increased likelihood of distant recurrence in the brain compared to other breast
cancer subtypes – exceeding 35% of metastatic breast cancer patients. Brain metastases (BMs) confer dismal
prognosis, as existing treatments have very limited efficacy; indeed, median survival for TNBC patients after
detection of metastatic disease is ~5 months. Multiple unique barriers limit effective drug delivery to breast cancer
BMs. These barriers include (i) the blood-brain barrier (BBB) within the normal brain parenchyma and the blood-
tumor barrier (BTB) within metastatic lesions; (ii) elevated tumor interstitial pressure and the dense
electrostatically charged brain extracellular spaces (ECS) which together limit convective and diffusive drug
penetration; (iii) the activity of multidrug resistance (MDR) pumps expressed by both brain capillary endothelial
cells and tumor cells, which reduce drug levels within tumor cells; and (iv) the brain glialymphatic system (GLS),
which acts as an efficient drug clearance system. Thus, new therapeutic delivery strategies designed to mitigate
and surmount these barriers will likely offer new promise towards effectively treating BMs.
Accordingly, we propose to couple an emerging therapeutic delivery technology, decreased nonspecific
adhesivity, receptor-targeted nanoparticles (DART NPs) with MRI-guided focused ultrasound (MRgFUS) for
treatment of breast cancer BMs (BCBMs). DART NPs will be engineered to target Fn14, a member of the TNF
receptor superfamily that is highly expressed in primary breast cancer and breast cancer BMs; but minimally in
normal breast, brain, or other organs. Research findings from our team related to the development and
application of DART NPs and MRgFUS-enhanced drug delivery that motivate the proposed studies include: (1)
DART NPs rapidly penetrate in brain and breast tumor tissues ex vivo, selectively targeting Fn14-positive tumor
cells both in vitro and in vivo, and significantly enhancing drug retention within intracranial tumors in vivo. (2)
MRgFUS-induced BBB disruption (BBBD) can safely increase DART nanoparticle delivery into the normal brain
parenchyma. (3) Fn14-targeted DART NPs containing the chemotherapeutic paclitaxel (PTX-DART NPs) are
more effective than free PTX in killing cancer cells that overexpress the MDR1 efflux pump. (4) PTX-DART NPs
more effectively reduce tumor growth and improve animal survival in mammary fat pad and intracranial TNBC
xenograft models compared to Abraxane, an FDA-approved nanotherapeutic currently used to treat breast
cancer patients. The proposed work will build on these findings to test the hypothesis that clinical-grade PTX-
DART NPs in combination with MRgFUS-induced BBBD will provide superior delivery, drug retention, and
therapeutic efficacy in BCBMs compared to the clinical standard drug treatments. The results from this study
also have the potential to make an impact on both male and female military service personnel with other Fn14+
cancer types that frequently metastasize to the brain; specifically, lung cancer and melanoma.
随着越来越多的女性在军队服役,有效地管理我们的
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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Anthony J. Kim其他文献
Nanotherapeutic treatment of the invasive glioblastoma tumor microenvironment
- DOI:
10.1016/j.addr.2022.114415 - 发表时间:
2022-09-01 - 期刊:
- 影响因子:17.600
- 作者:
Nikhil Pandey;Pavlos Anastasiadis;Christine P. Carney;Pranjali P. Kanvinde;Graeme F. Woodworth;Jeffrey A. Winkles;Anthony J. Kim - 通讯作者:
Anthony J. Kim
Toward the scale-up production of polymeric nanotherapeutics for cancer clinical trials
癌症临床试验的聚合物纳米疗法的扩大生产
- DOI:
10.1016/j.nantod.2024.102314 - 发表时间:
2024-06-01 - 期刊:
- 影响因子:10.900
- 作者:
Md. Musavvir Mahmud;Nikhil Pandey;Jeffrey A. Winkles;Graeme F. Woodworth;Anthony J. Kim - 通讯作者:
Anthony J. Kim
Anthony J. Kim的其他文献
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{{ truncateString('Anthony J. Kim', 18)}}的其他基金
Novel drug delivery strategies for treatment of breast cancer brain metastases
治疗乳腺癌脑转移的新型药物递送策略
- 批准号:
10655301 - 财政年份:2022
- 资助金额:
-- - 项目类别:
Impact of Fn14-targeted Nanoparticles for Triple-Negative Breast Cancer
Fn14 靶向纳米颗粒对三阴性乳腺癌的影响
- 批准号:
10113357 - 财政年份:2018
- 资助金额:
-- - 项目类别:
Impact of Fn14-targeted Nanoparticles for Triple-Negative Breast Cancer
Fn14 靶向纳米颗粒对三阴性乳腺癌的影响
- 批准号:
10772405 - 财政年份:2018
- 资助金额:
-- - 项目类别:
Impact of Fn14-targeted Nanoparticles for Triple-Negative Breast Cancer
Fn14 靶向纳米颗粒对三阴性乳腺癌的影响
- 批准号:
10341155 - 财政年份:2018
- 资助金额:
-- - 项目类别:
Fn14-targeted Therapeutics for Invasive Brain Cancer
Fn14 靶向治疗侵袭性脑癌
- 批准号:
8679868 - 财政年份:2014
- 资助金额:
-- - 项目类别:
Fn14-targeted Therapeutics for Invasive Brain Cancer
Fn14 靶向治疗侵袭性脑癌
- 批准号:
9134759 - 财政年份:2014
- 资助金额:
-- - 项目类别:
Fn14-targeted Therapeutics for Invasive Brain Cancer
Fn14 靶向治疗侵袭性脑癌
- 批准号:
8921999 - 财政年份:2014
- 资助金额:
-- - 项目类别:
Design of Non-viral Gene Carriers that Overcome Extra- and Intracellular Barriers
克服细胞外和细胞内屏障的非病毒基因载体的设计
- 批准号:
8329751 - 财政年份:2011
- 资助金额:
-- - 项目类别:
Design of Non-viral Gene Carriers that Overcome Extra- and Intracellular Barriers
克服细胞外和细胞内屏障的非病毒基因载体的设计
- 批准号:
8128093 - 财政年份:2011
- 资助金额:
-- - 项目类别:
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