Anti-vascular and cytotoxic nanoparticle formulations for ovarian cancer therapy
用于卵巢癌治疗的抗血管和细胞毒性纳米颗粒制剂
基本信息
- 批准号:10227030
- 负责人:
- 金额:$ 33.06万
- 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:2019-08-01 至 2024-07-31
- 项目状态:已结题
- 来源:
- 关键词:Adverse effectsAmino AcidsAngiogenesis InhibitorsAntineoplastic AgentsBiodistributionBiologicalBiological AssayBloodBlood VesselsCancer PatientCancer RelapseCancer cell lineCell ProliferationCell SurvivalCellsClinicClinicalCombretastatinConfocal MicroscopyCoupledDNA AdductsDNA DamageDNA RepairDataDiagnosisDiagnosticDiseaseDoseDose-LimitingDrug resistanceEffectivenessEncapsulatedEndothelial CellsEndotheliumEnsureEvaluationExhibitsFDA approvedFluorescenceFormulationGenerationsGlycolatesGoalsHalf-LifeHistologicHistologyImmune systemImmunochemistryIn VitroIntegrin alphaVbeta3Intraperitoneal InjectionsKineticsLigandsLiposomesMalignant Female Reproductive System NeoplasmMalignant NeoplasmsMalignant neoplasm of ovaryMeasuresMicroscopicMicroscopyMinorModificationMolecularMonoclonal AntibodiesNear-infrared optical imagingOvarianPatientsPeptidesPeripheral Nervous SystemPermeabilityPharmaceutical PreparationsPharmacologyPlatinumPolymersProgression-Free SurvivalsPropertyResistanceRouteSurfaceSystemTechniquesTestingTherapeuticTissue imagingToxic effectTreatment EfficacyTreatment ProtocolsTreatment outcomeUnited StatesVisualizationWomanWorkbasebevacizumabbioluminescence imagingcancer cellcancer therapychemotherapyclinical investigationcytotoxicdesigndosagedrug efficacydrug release profilefemale reproductive systemflexibilityfluorophoreimaging modalityimprovedin vitro testingin vivoin vivo imagingmortalitymouse modelnanoparticlenanoparticle deliverynanotherapynephrotoxicitynon-invasive imagingnon-invasive optical imagingnovelpre-clinicalreceptor mediated endocytosisreproductive outcomesystemic toxicitytargeted agenttargeted deliverytargeted treatmenttheranosticstherapy outcometreatment strategytumortumor growthuptake
项目摘要
Ovarian cancer (OC) has the highest mortality rate of all cancers of the female reproductive system and
outcomes have not changed over the past four decades. This year, over 20,000 women will be diagnosed with
OC in the United States more than 14,000 women will die from this disease. Platinum-based therapy is the
main therapeutic option for OC patients and ultimately, systemic toxicity limits the dosage given and this, in
part, limits its effectiveness. To overcome this therapeutic roadblock, alternative routes of administration have
been sought and include the practically difficult intraperitoneal (IP) injection, and more recently, the emerging
strategy of combining Pt (II) chemotherapy with tumor vasculature-targeting agents. The overarching goal of
this study is to develop a nanoparticle (NP)-based therapy for targeted delivery of high dose Pt (II) and a
vascular disrupting agent directly to cancer cells and endothelium, to enhance treatment outcomes. As proof-
of-principle, we have chosen combretastatin CA4 as the vascular targeting agent. Our proposal explores a
second generation, slow releasing polymer NP platform, with poly(lactic-co-glycolic) (PLGA) acid core
encapsulating Pt (II) and CA4. The NP’s coating is comprised of a RGDFFF peptide that stabilizes the NP and
simultaneously serves as a targeting ligand to αvβ3 integrin via its RGD moiety. The PLGA is FDA-approved
and amino acids of the peptide have Generally Regarded As Safe (GRAS) status. The NP is completely
biodegradable. Encapsulation of Pt (II) and CA4 will reduce systemic toxicity and allow us to explore the use of
effectively higher dosages than currently feasible. Upon the NP’s accumulation in the tumor interstitium, via
enhanced permeability and retention (EPR) effects, the cellular NPs uptake will be enhanced via receptor-
mediated endocytosis. The effect of the cytotoxic activity of Pt (II) and CA4 towards cancer cells and the
tumor’s vasculature, will be measured through therapeutic outcomes. A small percentage of near infrared
fluorophore (NIRF) will be incorporated into the NP’s coating to enable noninvasive optical imaging. The
combination of therapeutic and diagnostic features will transform the NP into a “theranostic” platform. In vitro
studies will include evaluation of NPs targeting to cancer cells, their biological activity, and compatibility with
the immune system. In vivo studies will focus on the assessment of NPs pharmacologic parameters, tumor
targeting, tolerability, and, finally, therapeutic efficacy. Combined in vitro and in vivo studies will employ
microscopy, immunochemistry, and histology, to define the best NP-based treatment regimen resulting in
therapeutic outcomes rivaling free drug routines currently used in the clinic. Thus, the proposed specific aims
are:
Aim 1: Synthesize and characterize an RGDFFF-coated NP platform for targeting, visualizing and treating
ovarian cancer. Aim 2: Test targeting efficacy and therapeutic potential of CA4-NPs and Pt-NPs in vitro.
Aim 3:
Study the biodistribution and targeted ‘trapping’ of NPs in a preclinical OC mouse model via in vivo imaging.
Aim 4: Conduct a therapy study wherein CA4-NPs and Pt-NPs, are applied to a preclinical OC mouse model.
卵巢癌(OC)在所有女性生殖系统癌症中死亡率最高,
在过去的40年里,结果没有改变。今年,超过20,000名妇女将被诊断出患有
在美国,超过14,000名妇女将死于这种疾病。以铂为基础的疗法是
OC患者的主要治疗选择,最终,全身毒性限制了给予的剂量,这在
部分,限制了它的有效性。为了克服这一治疗障碍,替代给药途径有
一直在寻求,包括实际上困难的腹膜内注射,以及最近出现的
铂(II)化疗与肿瘤血管靶向药物联合的策略。的首要目标是
这项研究旨在开发一种基于纳米颗粒(NP)的治疗方法,用于靶向传递高剂量的铂(II)和
血管干扰剂直接作用于癌细胞和血管内皮细胞,提高治疗效果。作为证据-
原则上,我们选择了康泰素CA4作为血管靶向剂。我们的建议探索了一个
第二代缓释聚合物NP平台,以聚(乳酸-乙醇酸)(PLGA)为核心
包覆铂(II)和钙离子。NP的涂层由稳定NP的RGDFFF肽和
同时通过其RGD端作为αvβ3整合素的靶向配体。PLGA是FDA批准的
而氨基酸一般被认为是安全的(GRAS)状态。NP完全是
可生物降解的。包裹铂(II)和钙离子将减少全身毒性,并使我们能够探索使用
有效地比目前可行的剂量更高。根据NP在肿瘤间质中的积聚,通过
增强通透性和滞留(EPR)效应,细胞对NPs的摄取将通过受体-
介导的内吞作用。铂(II)和钙离子对癌细胞的细胞毒作用及其机制
肿瘤的血管系统,将通过治疗结果进行测量。一小部分近红外
荧光体(NIRF)将被结合到NP的涂层中,以实现非侵入性光学成像。这个
治疗和诊断功能的结合将把NP转变为一个“治疗”平台。离体
研究将包括评估以癌细胞为靶点的纳米粒,它们的生物活性,以及与
免疫系统。体内研究将集中在评估NPs的药理参数、肿瘤
靶向性、耐受性,最后是治疗效果。体外和体内相结合的研究将使用
显微镜、免疫化学和组织学,以确定基于NP的最佳治疗方案,从而导致
治疗效果可与目前临床上使用的免费药物相媲美。因此,拟议的具体目标
包括:
目的1:合成和表征一种靶向、可视化和治疗用的RGDFFF包衣NP平台
卵巢癌。目的2:检测钙纳米粒和铂纳米粒的体外靶向效应和治疗潜力。
目标3:
通过活体成像研究NPs在临床前期OC小鼠模型中的生物分布和靶向‘捕获’。
目的:将Ca4纳米粒子和铂纳米粒子应用于临床前OC小鼠模型,进行治疗研究。
项目成果
期刊论文数量(0)
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JOHN A MARTIGNETTI其他文献
JOHN A MARTIGNETTI的其他文献
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{{ truncateString('JOHN A MARTIGNETTI', 18)}}的其他基金
Anti-vascular and cytotoxic nanoparticle formulations for ovarian cancer therapy
用于卵巢癌治疗的抗血管和细胞毒性纳米颗粒制剂
- 批准号:
10411413 - 财政年份:2019
- 资助金额:
$ 33.06万 - 项目类别:
Anti-vascular and cytotoxic nanoparticle formulations for ovarian cancer therapy
用于卵巢癌治疗的抗血管和细胞毒性纳米颗粒制剂
- 批准号:
9980812 - 财政年份:2019
- 资助金额:
$ 33.06万 - 项目类别:
Anti-vascular and cytotoxic nanoparticle formulations for ovarian cancer therapy
用于卵巢癌治疗的抗血管和细胞毒性纳米颗粒制剂
- 批准号:
10672982 - 财政年份:2019
- 资助金额:
$ 33.06万 - 项目类别:
Anti-vascular and cytotoxic nanoparticle formulations for ovarian cancer therapy
用于卵巢癌治疗的抗血管和细胞毒性纳米颗粒制剂
- 批准号:
10475624 - 财政年份:2019
- 资助金额:
$ 33.06万 - 项目类别:
Anti-vascular and cytotoxic nanoparticle formulations for ovarian cancer therapy
用于卵巢癌治疗的抗血管和细胞毒性纳米颗粒制剂
- 批准号:
10469185 - 财政年份:2019
- 资助金额:
$ 33.06万 - 项目类别:
Anti-vascular and cytotoxic nanoparticle formulations for ovarian cancer therapy
用于卵巢癌治疗的抗血管和细胞毒性纳米颗粒制剂
- 批准号:
10524135 - 财政年份:2019
- 资助金额:
$ 33.06万 - 项目类别:
Role of the tumor suppressor KLF6 in prostate cancer
肿瘤抑制因子 KLF6 在前列腺癌中的作用
- 批准号:
7439162 - 财政年份:2007
- 资助金额:
$ 33.06万 - 项目类别:
Role of the tumor suppressor KLF6 in prostate cancer
肿瘤抑制因子 KLF6 在前列腺癌中的作用
- 批准号:
7798240 - 财政年份:2007
- 资助金额:
$ 33.06万 - 项目类别:
Role of the tumor suppressor KLF6 in prostate cancer
肿瘤抑制因子 KLF6 在前列腺癌中的作用
- 批准号:
8051725 - 财政年份:2007
- 资助金额:
$ 33.06万 - 项目类别:
Role of the tumor suppressor KLF6 in prostate cancer
肿瘤抑制因子 KLF6 在前列腺癌中的作用
- 批准号:
7262066 - 财政年份:2007
- 资助金额:
$ 33.06万 - 项目类别:
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