Smart and self-reporting clinical nano carriers for drug delivery

翻译后摘要：问题：大多数癌症杀死病人，因为转移性疾病，这需要全身 疗法然而，全身治疗方法受到剂量限制-由于达到不可接受的剂量， 在肿瘤完全死亡之前产生细胞毒性副作用。为了解决这一缺陷，纳米颗粒特别适用于 有前途的-提供更多的药物给肿瘤细胞，同时保护非肿瘤细胞免受药物暴露。一个“理想” 纳米颗粒载体将（i）是能够携带临床上批准的药物的临床上批准的药剂， 临床转化，（ii）优先将药物递送至肿瘤以达到高效浓度， 全身毒性，（iii）具有控制释放药物释放机制，和（iv）证实 药物输送，因此医生将知道是否输送了有效量的药物，例如调整剂量或 预测响应。然而，更多的时候，颗粒并没有得到临床批准;药物是共价偶联的 颗粒，需要裂解释放（改变两者的批准制剂）;没有定义 释放机制;或者没有办法监测实际的药物释放，从而监测活性药物在体内的递送。 患者建议的解决方案：我们已经开发出一种具有潜在“理想”递送的药物递送方法 功能.这种方法是基于临床批准的纳米粒子，其特点是改善治疗 有效性，由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）检查肿瘤。我们的纳米载体是临床批准的氧化铁 纳米颗粒Feraheme和临床使用的高分子量葡聚糖。两者都保留了小的疏水药物 通过静电相互作用（即组成不变）并在肿瘤中释放 环境我们的假设是纳米载体将选择性地向肿瘤输送更高数量的药物 并且成像将有效地监测药物递送和释放。此外 MRI多重PET（mPET）将使我们能够同时成像和定量放射性标记的药物， 放射性标记的纳米载体。在目标1中，我们将使用mPET/MRI来定量监测药物的输送、释放和命运 原位肿瘤模型中的药物和纳米载体。在目标2中，我们将应用mPET/MRI评估是否靶向 与被动、非靶向递送相比，治疗可实现更高的药物递送，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， 接受纳米载体介导的治疗，定制基于纳米载体的治疗，每个病人个人。 该方法将提供对纳米载体和药物的体内动力学的有价值的洞察，所述纳米载体和药物不能被微生物学方法或生物学方法所识别。 否则获得。我们将获得体内药物输送和治疗反应的重要数据， 改善癌症治疗的潜力。这项工作可以很容易地转化为临床。癌症患者 治疗可以在不久的将来与载药纳米载体成像，以评估他们的肿瘤是否会 适用于这种治疗-基本上实现了纳米颗粒提供的大部分承诺。

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.