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杀死患者，这需要全身性 治疗。但是，由于达到无法接受的，全身治疗方法受到给药的限制 完全肿瘤死亡之前的细胞毒性副作用。为了解决这种缺陷，纳米颗粒尤其是 有希望的 - 向肿瘤细胞提供更多药物，同时免于暴露于药物的非肿瘤细胞。 “理想” 纳米颗粒载体（i）将成为临床认可的药物，能够携带临床认可的药物 临床翻译，（ii）优先向肿瘤输送药物，以达到高效浓度而没有 全身毒性，（iii）具有用于控制释放的药物释放机制，（iv）提供了证实 药物递送，因此医生会知道是否递送了有效量的药物，例如适应给药或 预测响应。然而，粒子经常在临床上批准。药物共价耦合 到颗粒并需要裂解以释放（两者的批准公式更改）；没有定义 释放机制；或者没有办法监测实际的药物释放，从而在 患者。建议的解决方案：我们已经开发了一种具有潜在“理想”输送的药物输送方法 特征。该方法基于临床批准的纳米颗粒，其特征是改善治疗 功效，肿瘤触发的释放机制以及自我报告药物释放的能力 通过磁共振成像（MRI）的肿瘤。我们的纳米载体是经临床认可的氧化铁 纳米颗粒Feraheme和临床使用的高分子量葡萄糖。两者都保留小型疏水药物 通过静电相互作用（即成分没有变化）并将其释放到肿瘤中 环境。我们的假设是，纳米载体将有选择地为肿瘤提供更高量的药物 与自由药物相比，该成像将有效监测药物输送和释放。此外 到MRI多路复用PET（MPET）将使我们同时形象并量化放射性标记的药物，并且 放射标记的纳米载体。在AIM 1中，我们将使用MPET/MRI定量监控交付，释放和命运 原位肿瘤模型中的药物和纳米载体。在AIM 2中，我们将应用MPET/MRI来评估是否针对 与被动，非靶向输送相比，治疗会导致较高的药物输送，而在AIM 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和 纳米载体介导的疗法的接受度，对每个患者量身定制基于纳米载体的疗法。 这种方法将为纳米载体和药物的体内动力学提供宝贵的见解 否则获得。我们将获得体内药物输送和治疗反应的基本数据 改善癌症治疗的潜力。这项工作可以轻松地转化为诊所。患癌症的患者 治疗可能是在不久的将来用载有药物的纳米载体成像的，以评估其肿瘤是否会 适用于这种治疗 - 本质上是实现纳米颗粒提供的许多诺言。