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：大多数癌症因转移性疾病而导致患者死亡，这需要全身治疗 然而，全身治疗方法由于剂量达到不可接受的程度而受到限制。 为了解决这一缺陷，纳米颗粒特别适合在肿瘤完全死亡之前产生细胞毒性副作用。 – 向有希望的肿瘤细胞输送更多药物，同时使非肿瘤细胞免受药物暴露的“理想”。 纳米颗粒载体将（i）是一种临床批准的试剂，能够携带临床批准的药物以方便地使用 临床转化，（ii）优先将药物递送至肿瘤以获得高效浓度，而无需 全身毒性，(iii) 具有控释药物释放机制，以及 (iv) 提供以下确认： 药物输送，以便医生知道是否输送了有效量的药物，例如调整剂量或 然而，粒子通常是未经临床批准的共价偶联药物； 颗粒并需要裂解释放（改变两者的批准配方）； 释放机制；或者没有办法监测实际的药物释放，从而监测活性药物的输送。 建议的解决方案：我们开发了一种具有潜在“理想”输送的药物输送方法。 该方法基于临床批准的纳米颗粒，其特点是改进的治疗方法。 功效、肿瘤触发的释放机制以及自我报告药物释放的能力 我们的纳米载体是经过临床批准的氧化铁。 纳米颗粒Feraheme和临床上使用的高分子量右旋糖酐都保留了小的疏水性药物。 通过静电相互作用（即不改变成分）并将它们释放到肿瘤中 我们的假设是纳米载体将选择性地向肿瘤递送更多的药物。 与游离药物相比，成像还可以有效监测药物的输送和释放。 MRI 多重 PET (mPET) 将使我们能够同时对放射性标记药物和 在目标 1 中，我们将使用 mPET/MRI 定量监测放射性标记纳米载体的递送、释放和命运。 在目标 2 中，我们将应用 mPET/MRI 来评估原位肿瘤模型中的药物和纳米载体是否具有靶向性。 与被动、非靶向递送相比，治疗可产生更高的药物递送，在目标 3 中，我们将 探索药物释放的 MRI 是否可以通过探测肿瘤微环境来预测治疗反应 对纳米载体介导的治疗的接受度，为每位患者量身定制基于纳米载体的治疗。 这种方法将为纳米载体和药物的体内动力学提供有价值的见解，而这是无法 我们将通过其他方式获得体内药物递送和治疗反应的重要数据。 这项工作可以很容易地转化为癌症患者的临床治疗。 在不久的将来，治疗可能会用载药纳米载体进行成像，以评估他们的肿瘤是否会被治愈。 适合这种疗法——本质上是为了实现纳米颗粒所提供的大部分希望。