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A multiplexed approach to improve tumoral targeting and chemotherapeutic treatment

A multiplexed approach to improve tumoral targeting and chemotherapeutic treatment
改善肿瘤靶向和化疗的多重方法
批准号:
10443575
负责人:
Benedict Shek Hang Law
金额:
$42.6万
依托单位国家:
美国
项目类别:
财政年份:
2018
资助国家:
美国
项目状态:
已结题
起止时间:
2018-07-03 至 2024-06-30
关键词:
AbraxaneAffectAnimalsAnthracyclineBehaviorBiodistributionBiological ModelsBreast Cancer ModelBreast Cancer TreatmentBypassCharacteristicsChargeChemicalsClinical TrialsCombined Modality TherapyCustomDataDevelopmentDiseaseDoxorubicinDoxorubicin Hydrochloride LiposomeDrug CarriersDrug CombinationsDrug DesignDrug KineticsERBB2 geneEffectivenessEnvironmentEnzymesExcisionExhibitsFDA approvedFormulationGoalsHeterogeneityHormonalIn SituIncidenceKineticsLabelLengthLiposomesLymphatic SystemMalignant NeoplasmsMedicalModificationMolecularMolecular TargetMorbidity - disease rateNeoplasm MetastasisNormal CellOutcomePET/CT scanPatientsPenetrationPeptide HydrolasesPeptidesPharmaceutical PreparationsPhysiologicalPlayPolyethylene GlycolsPrognosisPropertyRadioisotopesRecurrenceRegimenReticuloendothelial SystemRiskRoleSafetyShapesSiteSurfaceSystemTestingTherapeuticThickTimeTissuesToxic effectTreatment EfficacyTreatment outcomeVertebral columnX-Ray Computed Tomographyanaloganti-cancerbasebiomaterial compatibilitycancer clinical trialchemotherapeutic agentchemotherapycontrolled releasedesigndosagedrug release profileeffective therapyefficacy evaluationflexibilityfluorophoreimprovedimproved outcomein vivomalignant breast neoplasmmortalitynanocarriernanofibernanomedicinenanoparticleneoplastic cellnoveloptical imagingreceptorsalinomycinside effectstem cellstargeted agenttargeted deliverytargeted treatmenttaxanetherapeutic evaluationtherapeutically effectivetriple-negative invasive breast carcinomatumortumor growthtumor heterogeneityuptake

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英文摘要
Project Summary/Abstract Triple-negative breast cancer (TNBC) accounts for 15-20% of breast cancer cases. The lack of targeted therapies and poor prognosis have resulted in a major effort to discover molecular targets to improve outcomes. While there is increasing understanding of the molecular heterogeneity of tumors, clinical trials of targeted agents have thus far been disappointing. Chemotherapeutic agents such as anthracycline and taxanes remain the backbone of medical management for both early and metastatic TNBC. This approach is toxic to normal in addition to tumor cells, leading to treatment burden and undesired side effects. These drugs are given to the patients in hope of the benefits to outweigh the risks. One significant approach to improve outcomes is the development of nanocarriers to achieve targeted delivery to tumors and reducing toxicity. To date, antitumor activities of the current FDA-approved nanomedicines (Doxil and Abraxane) have been moderate compared to the free drugs. There is an unmet need for an approach that can overcome different physiological barriers to deliver higher concentration of drugs in a more specific manner. Our long-term goal is to develop a platform to improve chemotherapeutics for achieving safer and more effective treatments. The objective is to develop a platform to overcome multiple barriers in tumor-specific delivery. We propose a biocompatible, non- immunogenic, self-assembling peptide-based nanofiber precursor (NFP). The factors that are essential in effective therapies are (a) co-delivering an optimal drug ratio of a combination therapy, (b) shape-controlled promotion of drug uptake, (c) charge-assisted tumor penetration, (d) enzyme-induced tumor retention (ETR), and (e) pH-activated controlled drug release approaches to be utilized by NFP. High PEG content of NFP minimizes its capture by the RES. Our overarching hypothesis is that such a multiplexed platform will significantly improve therapeutic efficacy and safety when used as a drug carrier. Our preliminary data have shown that NFP incorporated with doxorubicin has a superior therapeutic efficacy with minimal host toxicity compared to the free drug and Doxil. Our rationale is to maximize the delivery of NFP to the tumor, which requires us understand the contribution of NFP’s physicochemical properties (such as size and surface charges, ETR kinetics, and drug release profiles) in their biodistribution and uptake, penetration, and retention. Our specific aims will focus on the (Aim1) Refinement of different physicochemical properties, including size, shape, charge, and functional domains, affecting the in vivo behavior of NFP; and (Aim 2) Evaluation of the therapeutic efficacy of controlled- release NFP as a carrier of chemotherapy. This information will be critical for optimal formulation of multi-drug combinations in the most effective drug ratio to significantly improve the treatment outcomes. While we will utilize TNBC to develop the optimal characteristics of NFP, this information will be instrumental in designing drug combination involving NFP for other malignancies.
期刊论文(4)
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会议论文
DOI: 10.1158/0008-5472.can-21-2897
发表时间: 2022-04-01
期刊: Cancer research
影响因子: 11.2
作者: [Bellat V, Michel AO, Thomas C, Stokol T, Choi BB, Law B]
通讯作者: Law B
An urinary drug disposing approach for treatment of bladder Cancer
  • 批准号:
    10737090
  • 项目类别:
  • 资助金额:
    $66.59万
  • 财政年份:
    2023
  • 负责人:
    Benedict Shek Hang Law
  • 依托单位:
A multiplexed approach to improve tumoral targeting and chemotherapeutic treatment
  • 批准号:
    10190846
  • 项目类别:
  • 资助金额:
    $45.48万
  • 财政年份:
    2018
  • 负责人:
    Benedict Shek Hang Law
  • 依托单位:
海外基金