A Multimodal Hierarchical Theranostic Nanoparticle for Castration Resistant Prostate Cancer
用于去势抵抗性前列腺癌的多模式分级治疗诊断纳米颗粒
基本信息
- 批准号:10259187
- 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:2022-01-01 至 2025-12-31
- 项目状态:未结题
- 来源:
- 关键词:ABCB1 geneAffinityAgeAgingAmericanAnimal ModelApoptosisAzidesBindingBiodistributionBypassCancer EtiologyCaringCationsCell Culture SystemCell LineCell SurvivalCellsCessation of lifeChargeChemistryClinical DataCopperCost MeasuresDataDevelopmentDiagnosisDimensionsDiseaseDoseDose-LimitingDoxorubicinDrug CarriersDrug Delivery SystemsDrug KineticsEconomic BurdenElectrostaticsEncapsulatedEngineeringExposure toFDA approvedFOLH1 geneGene SilencingGeneral PopulationGlycolatesGoalsHealthcare SystemsHerbicidesHistone Deacetylase InhibitorHumanHydrophobicityIL8 geneIn VitroIncidenceKnock-outLigandsLiverMalignant NeoplasmsMalignant neoplasm of lungMalignant neoplasm of prostateMediatingMicrotubulesModelingMulti-Drug ResistanceNatureNorth AmericaOperative Surgical ProceduresPaclitaxelPatientsPharmaceutical PreparationsPharmaceutical SolutionsPharmacodynamicsPharmacologyPharmacotherapyPhysiologicalPolysaccharidesPre-Clinical ModelPrimary NeoplasmPrognosisProstatic NeoplasmsPublic HealthRadiationReactionRefractoryResearchRiskRoleSiteSmall Interfering RNASpecificitySurfaceSurvival RateSystemTherapeuticTherapeutic IndexTimeToxic effectTreatment outcomeTumor MarkersTumor VolumeTumor WeightsVeteransVeterans Health AdministrationWorkXenograft procedureagent orangeandrogen deprivation therapybasebiomaterial compatibilitycancer cellcastration resistant prostate cancerchemical synthesischemotherapeutic agentchemotherapycopolymercytotoxicitydocetaxeleffective therapygene therapyhuman modelimaging agentimprovedin vivoinnovationliver metabolismmalemenmilitary veteranmolecular recognitionmultimodalitynanocarriernanoparticlenovelnovel therapeuticsoverexpressionpharmacokinetics and pharmacodynamicspre-clinicalpromoterresponseside effectsmall moleculespecific biomarkerstargeted deliverytargeted treatmenttheranosticstherapeutically effectivetumortumor growthvector
项目摘要
Prostate cancer (CaP) is the most commonly diagnosed non-cutaneous cancer in American males and
is the second leading cause of cancer-related deaths of men in North America after lung cancer (1). In 2019,
approximately 174,650 men were diagnosed with CaP and nearly 31,620 men will die from the disease. While
the overall cancer incidence among men in the U.S. Veterans Affairs Health Care System mirrored the general
population, it is important to understand that the U.S has an aging veteran population, and the risk of developing
CaP increases with age. Furthermore, veterans who were exposed to herbicides, such as Agent Orange, are at
increased risk of CaP. The first line of therapy for CaP is surgery or radiation, and the survival rate for patients
diagnosed with early stage CaP is excellent (~95%). However, the prognosis for men diagnosed with advanced
CaP is poor' with a five-year survival less than 30%. The major therapy for advanced CaP is androgen deprivation
therapy (ADT). When the disease progresses after ADT, a stage referred to as castration resistant prostate
cancer (CRPC) ensues. Efforts to develop new drugs for the treatment of CRPC have been hampered either by
rapid hepatic metabolism of histone deacetylase inhibitors (HDACi) or dose limiting cytotoxicity (docetaxel and
doxorubicin). To overcome this, innovative pharmaceutical solutions are needed to effectively deliver the drugs
specifically to the tumor site while minimizing systemic administration of frequent and high doses of toxic
chemotherapy. The enhanced, targeted, intracellular co-delivery of drug and gene therapy with novel
nanocarriers composed of biocompatible and biodegradable poly(lactic-co-glycolic) acid (PLGA) is a goal of this
proposal. PLGA is safe and highly effective in the targeted delivery of hydrophobic drugs such as docetaxel
(Doc) to specific tumors, demonstrating enhanced therapeutic activity at lower doses than when administered
alone. Active targeting, as opposed to passive targeting adds value to tumor specific-treatment. This targeting
strategy is based on the molecular recognition of tumor biomarkers which are over-expressed on cancer cells,
via specific vector molecules conjugated to the surface of the drug carrier. These vector molecules dictate the
carrier's biodistribution and its affinity for the desired site of action. Our long-term goal is the development of a
targeted hierarchical nanoparticle (HNP for the co-delivery of chemo- and gene therapies for CaP, which can
overcome the limitation in systemic delivery of currently available drugs. As proof-of-principle, we will use Doc,
a promoter and stabilizer of microtubule assembly, that shows excellent efficacy in vitro but which is rapidly
metabolized in the liver plus a gene-silencing agent together in our HNP. Our rationale that Doc can be targeted
specifically to prostate tumors in pre-clinical animal models will provide the impetus to encapsulate other
therapeutics (such as cabazitaxel and paclitaxel) that have dose-limiting toxicities to improve response to drug
therapies while reducing toxic side effects. Our specific aims are: Aim 1: To optimize the synthesis of a PSMA-
targeted PTCS-HNP for delivery of IL-8 siRNA and Doc to CaP cells and assess the IC50 of different PTCS-
HNPs; Aim 2: Determine the pharmacokinetics (PK) and pharmacodynamics (PD) of PTCS-HNP in CaP cell
lines; Aim 3: To assess the effects of PTCS-HNPs on primary tumor growth and metastatic dissemination of
CaP cells grown as xenografts in an orthotopic, preclinical model of human CaP. Upon conclusion of this project,
we will produce a highly effective, targeted drug and gene therapy NP delivery system for the treatment of
advanced CaP. The proposed research is innovative because of the exclusive chemical synthesis of our unique,
multifunctional HNP, the two-hit nature of the chemo- and gene therapy and its targeted specificity for CaP. The
tunable nature of our HNP will allow its application for the delivery of a host of different therapies to a wide range
of tumors. Lastly, the incorporation of imaging agents into our HNP will yield a truly theranostic approach for the
treatment of different cancers especially advanced CaP.
前列腺癌(CaP)是美国男性最常见的非皮肤癌症
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)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
STANLEY A SCHWARTZ其他文献
STANLEY A SCHWARTZ的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('STANLEY A SCHWARTZ', 18)}}的其他基金
A Multimodal Hierarchical Theranostic Nanoparticle for Castration Resistant Prostate Cancer
用于去势抵抗性前列腺癌的多模式分级治疗诊断纳米颗粒
- 批准号:
10513295 - 财政年份:2022
- 资助金额:
-- - 项目类别:
Integration of Clinical, Genomic and Proteomic Data using a Bioinformatic Approac
使用生物信息学方法整合临床、基因组和蛋白质组数据
- 批准号:
7685903 - 财政年份:2009
- 资助金额:
-- - 项目类别:
Integration of Clinical, Genomic and Proteomic Data using a Bioinformatic Approac
使用生物信息学方法整合临床、基因组和蛋白质组数据
- 批准号:
7897734 - 财政年份:2009
- 资助金额:
-- - 项目类别:
EPIDEMIOLOGY OF DIABETES INTERVENTION AND COMPLICATIONS
糖尿病干预和并发症的流行病学
- 批准号:
7199002 - 财政年份:2004
- 资助金额:
-- - 项目类别:
Epidemiology of Diabetes Intervention and Complications
糖尿病干预和并发症的流行病学
- 批准号:
7039541 - 财政年份:2003
- 资助金额:
-- - 项目类别:
EPIDEMIOLOGY OF DIABETES INTERVENTION AND COMPLICATIONS
糖尿病干预和并发症的流行病学
- 批准号:
6565883 - 财政年份:2001
- 资助金额:
-- - 项目类别:
相似海外基金
Construction of affinity sensors using high-speed oscillation of nanomaterials
利用纳米材料高速振荡构建亲和传感器
- 批准号:
23H01982 - 财政年份:2023
- 资助金额:
-- - 项目类别:
Grant-in-Aid for Scientific Research (B)
Affinity evaluation for development of polymer nanocomposites with high thermal conductivity and interfacial molecular design
高导热率聚合物纳米复合材料开发和界面分子设计的亲和力评估
- 批准号:
23KJ0116 - 财政年份:2023
- 资助金额:
-- - 项目类别:
Grant-in-Aid for JSPS Fellows
Platform for the High Throughput Generation and Validation of Affinity Reagents
用于高通量生成和亲和试剂验证的平台
- 批准号:
10598276 - 财政年份:2023
- 资助金额:
-- - 项目类别:
Development of High-Affinity and Selective Ligands as a Pharmacological Tool for the Dopamine D4 Receptor (D4R) Subtype Variants
开发高亲和力和选择性配体作为多巴胺 D4 受体 (D4R) 亚型变体的药理学工具
- 批准号:
10682794 - 财政年份:2023
- 资助金额:
-- - 项目类别:
Collaborative Research: DESIGN: Co-creation of affinity groups to facilitate diverse & inclusive ornithological societies
合作研究:设计:共同创建亲和团体以促进多元化
- 批准号:
2233343 - 财政年份:2023
- 资助金额:
-- - 项目类别:
Standard Grant
Collaborative Research: DESIGN: Co-creation of affinity groups to facilitate diverse & inclusive ornithological societies
合作研究:设计:共同创建亲和团体以促进多元化
- 批准号:
2233342 - 财政年份:2023
- 资助金额:
-- - 项目类别:
Standard Grant
Molecular mechanisms underlying high-affinity and isotype switched antibody responses
高亲和力和同种型转换抗体反应的分子机制
- 批准号:
479363 - 财政年份:2023
- 资助金额:
-- - 项目类别:
Operating Grants
Deconstructed T cell antigen recognition: Separation of affinity from bond lifetime
解构 T 细胞抗原识别:亲和力与键寿命的分离
- 批准号:
10681989 - 财政年份:2023
- 资助金额:
-- - 项目类别:
CAREER: Engineered Affinity-Based Biomaterials for Harnessing the Stem Cell Secretome
职业:基于亲和力的工程生物材料用于利用干细胞分泌组
- 批准号:
2237240 - 财政年份:2023
- 资助金额:
-- - 项目类别:
Continuing Grant
ADVANCE Partnership: Leveraging Intersectionality and Engineering Affinity groups in Industrial Engineering and Operations Research (LINEAGE)
ADVANCE 合作伙伴关系:利用工业工程和运筹学 (LINEAGE) 领域的交叉性和工程亲和力团体
- 批准号:
2305592 - 财政年份:2023
- 资助金额:
-- - 项目类别:
Continuing Grant














{{item.name}}会员




