Smart and self-reporting clinical nano carriers for drug delivery

用于药物输送的智能和自我报告的临床纳米载体

• 批准号: 9302146
• 负责人: Jan Grimm
• 金额: $ 71.4万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-03-01 至 2022-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9302146
• 关键词: Address; Adverse effects; Animal Model; Biological Availability; Cessation of life; Chelating Agents; Clinic; Clinical; Complement; Contrast Media; Coupled; Data; Dextrans; Disease; Dose; Drug Delivery Systems; Drug Exposure; Drug Modelings; Drug Monitoring; Electrostatics; Ensure; Environment; Failure; Formulation; Future; Gadolinium; Heat-Shock Proteins 90; Hydrophobicity; Image; Injectable; Iron; Kinetics; Label; Link; Liver; Magnetic Resonance Imaging; Malignant Neoplasms; Mediating; Methods; Modeling; Molecular Weight; Monitor; Mus; Patient Self-Report; Patients; Peptides; Permeability; Pharmaceutical Preparations; Pharmacotherapy; Physicians; Positron-Emission Tomography; Property; Public Health; Quality of life; Radiolabeled; Reporting; Signal Transduction; System; Systemic Therapy; Testing; Therapeutic Index; Time; Toxic effect; Translating; Treatment Efficacy; Tumor Tissue; Validation; Work; base; blind; cancer therapy; clinical translation; controlled release; cost; cytotoxic; dosage; drug development; drug efficacy; experimental study; imaging modality; improved; in vivo; individual patient; inhibitor/antagonist; insight; iron oxide; killings; nanocarrier; nanoparticle; neoplastic cell; novel strategies; particle; predicting response; response; systemic toxicity; targeted treatment; theranostics; therapy development; treatment strategy; tumor; tumor microenvironment

Abstract: The problem: Most cancers kill patients because of metastatic disease, which requires systemic therapy. However, systemic therapy approaches suffer from dosing limitations – due to reaching unacceptable cytotoxic side effects before complete tumor death. To address this deficiency, nanoparticles are particularly promising – to deliver more drug to tumor cells while sparing non-tumor cells from drug exposure. An “ideal” nanoparticle carrier would (i) be a clinically approved agent able to carry clinically approved drugs for facile clinical translation, (ii) deliver drugs preferentially to tumors to attain highly efficacious concentrations without systemic toxicity, (iii) have a drug release mechanism for controlled release, and (iv) provide confirmation of drug delivery so physicians will know if efficacious quantities of drug were delivered, e.g. to adapt dosing or predict response. Yet, more often than not, particles are not clinically approved; drugs are covalently coupled to particles and require cleavage for release (altering approved formulations of both); there is no defined release mechanism; or there is no way to monitor actual drug release and thus delivery of active drug in patients. Proposed solution: We have developed a drug delivery method with potential “ideal” delivery features. This method is based on clinically approved nanoparticles and is characterized by improved therapy efficacy, a release mechanism triggered by the tumor, and the ability to self-report the release of the drug in the tumor through magnetic resonance imaging (MRI). Our nanocarriers are the clinically approved iron oxide nanoparticle Feraheme and clinically used high molecular weight dextran. Both retain small hydrophobic drugs through electrostatic interactions (i.e. without change in compositions) and release them in a tumor environment. Our hypothesis is that the nanocarriers will deliver higher amounts of drugs selectively to tumors as compared to free-drug and that imaging will be effective at monitoring drug delivery and release. In addition to MRI multiplexed PET (mPET) will allow us to simultaneously image and quantify radiolabeled drug and radiolabeled nanocarrier. In Aim 1, we will use mPET/MRI to quantitatively monitor delivery, release and fate of drug and nanocarrier within orthotopic tumor models. In Aim 2, we will apply mPET/MRI to evaluate if targeted therapy results in higher drug delivery compared to passive, non-targeted delivery, and in Aim 3, we will explore if MRI of drug release can predict the therapy response by probing the tumors microenvironment and receptiveness for nanocarrier-mediated therapy, tailoring nanocarrier-based therapy personally to each patient. This approach will provide valuable insight into the in vivo kinetics of nanocarrier and drug that cannot be obtained otherwise. We will obtain essential data for in vivo drug delivery and therapy response with high potential to improve cancer therapy. This work can be easily translated into clinic. Patients undergoing cancer therapy could be in the near future imaged with drug-loaded nanocarrier to evaluate if their tumors will be suitable for such a therapy - essentially to realize much of the promise provided by nanoparticles.

摘要：问题：大多数癌症患者死于转移性疾病，这需要全身性 心理治疗。然而，系统治疗方法受到剂量限制--由于达到不可接受的程度。 肿瘤完全死亡前的细胞毒性副作用。为了解决这一不足，纳米颗粒尤其 承诺-将更多的药物输送到肿瘤细胞，同时避免非肿瘤细胞接触药物。一个“理想” 纳米粒载体将(I)是一种临床批准的试剂，能够携带临床批准的药物 临床翻译，(Ii)优先向肿瘤递送药物，以获得高效浓度，而不 全身毒性，(3)具有受控释放的药物释放机制，和(4)提供确认 药物输送，以便医生知道是否输送了有效数量的药物，例如调整剂量或 预测响应。然而，通常情况下，微粒并未获得临床批准；药物是共价偶联的。 到颗粒并需要裂解才能释放(改变两者的批准配方)；没有定义 释放机制；或没有办法监测实际药物释放，从而有效药物在 病人。建议的解决方案：我们已经开发出一种潜在的“理想”药物输送方法 功能。这种方法是基于临床批准的纳米颗粒，其特点是改进了治疗方法。 疗效，一种由肿瘤触发的释放机制，以及自我报告药物在 通过磁共振成像(MRI)检查肿瘤。我们的纳米载体是临床批准的氧化铁 纳米亚铁血红素和临床使用的高分子量葡聚糖。两者都保留了小分子疏水药物 通过静电相互作用(即不改变成分)并在肿瘤中释放它们 环境。我们的假设是，纳米载体将选择性地向肿瘤输送更多的药物。 与免费药物相比，这种成像将有效地监测药物的输送和释放。此外 到MRI，多路传输的PET(MPET)将使我们能够同时成像和量化放射性标记的药物和 放射性标记的纳米载体。在目标1中，我们将使用mpet/mri来定量监测药物的投放、释放和命运。 药物和纳米载体在原位肿瘤模型中的应用。在目标2中，我们将应用mpET/mri来评估是否具有靶向性。 与被动的、非靶向的给药相比，治疗导致更高的药物释放，在目标3中，我们将 通过对肿瘤微环境的探测，探讨药物释放的MRI能否预测治疗效果 接受纳米载体介导的治疗，为每个患者量身定做基于纳米载体的治疗。 这一方法将为了解纳米载体和药物的体内动力学提供有价值的见解 以其他方式获得的。我们将获得体内给药和治疗反应的基本数据 改善癌症治疗的潜力。这项工作可以很容易地转化为临床。接受癌症治疗的病人 治疗可能在不久的将来用载药的纳米载体进行成像，以评估他们的肿瘤是否会 适用于这样的疗法--本质上是为了实现纳米颗粒提供的大部分希望。