NANOTEMPLATE ENGINEERING OF A STEALTH MRI CONTRAST AGENT

描述(由申请人提供)：治疗成本的增加和通过早期发现改善治疗效果所证明的好处是开发更具特异性和敏感性的肿瘤诊断试剂的重要动机。顺磁性Gd络合物被广泛用作磁共振成像(MRI)造影剂，以提高MRI检查的灵敏度和/或特异性，从而能够获得高分辨率的图像。由于固有的体积稀释效应，目前大多数造影剂仅限于它们可能在血液中积累高浓度的靶点。下一代磁共振造影剂需要具有更高的弛豫度和特定的靶向特性，以克服体积稀释效应。肯塔基大学的NanoMed制药公司及其合作者将准备一种用于核磁共振成像的纳米颗粒对比剂。微乳前体将被用来通过一种容易扩展的工艺，使用已经被FDA批准用于人体的材料来制造这些纳米颗粒。表面修饰将被用来赋予隐形和靶向特性，这样纳米颗粒就可以避免清除，并优先被肿瘤吸收。这项第一阶段提案的具体目标是利用纳米模板工程方法制备由FDA批准的平均直径为100-150 nm的材料组成的聚乙二醇化可生物降解纳米颗粒，制备包被转化生长因子-a用于肿瘤靶向的纳米颗粒，证明聚乙二醇化/靶向纳米颗粒的给药剂量在静脉注射后8小时和24小时分别保留在血液中的60%和30%。给药，生产一批放大的聚乙二醇化/靶向纳米颗粒，并在给荷瘤小鼠注射聚乙二醇化/靶向Gd-纳米颗粒后，在体内显示出足够的对比度。聚乙二醇化纳米颗粒和靶向纳米颗粒将通过核磁共振波谱技术在不同介质中测量其物理和磁性。这些测量将有助于评估在磁共振图像中提供足够对比度所需的含Gd纳米颗粒的剂量。我们还将制备将紫杉醇包裹在纳米颗粒基质中的Gd纳米颗粒，这将使这些纳米颗粒成为双重治疗/成像纳米载体。这些可用于临床前模型和临床研究，以检验纳米药物输送与肿瘤反应相关的假设。最终目标是引入一种新的造影剂，提供优质的磁共振图像，使肿瘤的早期诊断和疾病治疗的快速干预成为可能。不断增加的治疗成本和通过早期发现改善治疗效果所证明的好处，是开发更具特异性和敏感性的肿瘤诊断试剂的重要动机。NanoMed制药公司与肯塔基大学的研究人员合作，提议使用一种新的方法来生产隐形纳米颗粒，这种纳米颗粒可以提供卓越的核磁共振图像，从而能够早期发现癌症。

DESCRIPTION (provided by applicant): The increasing costs of therapy and the demonstrated benefits of improved treatment efficacy with early detection are important incentives to develop tumor diagnostic agents of greater specificity and sensitivity. Paramagnetic gadolinium complexes are widely used as MRI (magnetic resonance imaging) contrast agents to improve sensitivity and/or specificity during MRI examinations which enable the acquisition of high resolution images. Due to the inherent volume dilution effect, most current contrast agents are limited to targeting sites where they can be expected to accumulate in high concentration, such as in the blood stream. The next generation agents of MRI contrast agents need to have higher relaxivities and specific targeting properties to overcome the volume dilution effect. NanoMed Pharmaceuticals, Inc. and its collaborators at the University of Kentucky will prepare a nanoparticle contrast enhancement agent for use in MRI. A microemulsion precursor will be employed to manufacture these nanoparticles by a readily scalable process using materials already approved for use in humans by the FDA. Surface modification will be used to impart stealth and targeting properties so that the nanoparticles can avoid clearance and be taken up preferentially by tumors. The Specific Aims of this Phase I proposal are to prepare pegylated biodegradable nanoparticles composed of FDA-approved materials that have an average diameter of 100-150 nm using a Nanotemplate Engineering method, prepare nanoparticles coated with Transforming Growth Factor-a for tumor targeting, demonstrate that 60% of the administered dose of pegylated/targeted nanoparticles are retained in the blood at 8 hr, and 30% at 24 hr after i.v. administration, produce a scaled-up batch of pegylated/targeted nanoparticles, and demonstrate sufficient contrast in vivo tumor MR images following administration of pegylated/targeted Gd- nanoparticles to tumor-bearing mice. The physical and magnetic properties pegylated and targeted nanoparticles will be measured in various media by NMR spectroscopic techniques. These measurements will aid in assessing the dose of Gd-containing nanoparticles required to provide sufficient contrast in MR images. We will also prepare Gd nanoparticles that have paclitaxel entrapped within the nanoparticle matrix that would allow these nanoparticles to serve as dual therapeutic/imaging nanovectors. These may be used in preclinical models and in clinical studies to test the hypothesis that nanoparticle drug delivery correlates with tumor response. The ultimate goal is to introduce a new contrast agent that provides superior MR images that allow for the early diagnosis of tumors and rapid intervention in the treatment of the disease. The increasing costs of therapy and the demonstrated benefits of improved treatment efficacy with early detection are important incentives to develop tumor diagnostic agents of greater specificity and sensitivity. NanoMed Pharmaceuticals, Inc., in collaboration with investigators at the University of Kentucky, proposes to use a novel method to produce stealth nanoparticles that provide superior MRI images that allow for the early detection of cancer.