Magnetic Drug Delivery for Cancer

癌症磁性药物输送

• 批准号: 8349399
• 负责人: Michael Emmert-Buck
• 金额: $ 34.99万
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8349399
• 关键词: Anatomic structures; Anatomy; Antineoplastic Agents; Appearance; Autopsy; Blood Vessels; Body Regions; Body part; Clinical; Drug Delivery Systems; Drug usage; Engineering; Feedback; Goals; Human; Image; Implant; Iron; Lesion; Light Microscope; Link; Location; Magnetism; Malignant Neoplasms; Maryland; Mechanics; Metastatic Lesion; Methods; Microfluidics; Molecular; Movement; Natural History; Neoplasm Metastasis; Patients; Pharmaceutical Preparations; Primary Neoplasm; Rest; Site; Skin; Steel; Stents; Surface; System; Therapeutic; Therapeutic Agents; Time; Tissues; Toxic effect; Tumor Burden; Tumor Pathology; Tumor Tissue; Universities; Vascular blood supply; base; cancer type; clinically significant; experience; improved; magnetic field; molecular pathology; nanoparticle; neoplastic cell; novel strategies; particle; tumor

Magnetic drug delivery refers to linking therapeutic or imaging agents with magnetically responsive objects, iron nano-particles for example, and using magnetic fields to focus the agents to a specific site within the body. For cancer, this approach may be therapeutically useful by creating a locally high concentration of drug at a tumor location. At present, the state-of-the-art in magnetic drug delivery utilizes stationary magnets placed outside the skin to attract particles. However, this method is effective to only a limited tissue depth, thus drug targeting is restricted to tumors that are near the skin surface. Alternatively, magnets or objects that concentrate the magnetic field (e.g. stents that contain steel or iron) can sometimes be implanted deep inside the body and enable focusing of drug near deep tumors; however, surgically implanting such objects in a patient is undesirable and not always possible in the clinical setting. To overcome the problems with current magnetic drug delivery methods, we are developing a dynamic feedback control system that uses magnetic fields to focus drugs to deep targets by using a set of externally-applied magnetic fields and controlling them one against another. Although this is a promising approach, there are several technical challenges involved that may be difficult to overcome, such as the need to radiologically image and then target each tumor focus, a difficult task that requires real-time sensing of particle location. A simpler approach for magnetic drug delivery is based on relevant observations of gross and molecular tumor pathology. The observations and implications for tumor therapy are: 1) That clinically significant tumor burden is often localized only to specific anatomic zones of the body, even though the tumor may be widely metastatic. Thus, delivery of drug to specific and defined anatomic regions may provide optimal clinical benefit with minimal toxicity. The target zones will be based on the natural history of each cancer type, the deleterious effect of tumor cells on anatomic structures within the zone, and the efficacy-toxicity ratio of delivering high levels of drug to a particular region of the body. 2) That the blood supply to a subset of metastases in a patient is particularly compromised. This is evidenced by the firm, white, nodular gross appearance of these lesions at autopsy, and the incomplete vasculature as seen at the light microscope level. These lesions are often distinctly different from the primary tumors from which they arose, as well as from other metastases in different parts of the body. This vascular compromise likely results in poor delivery of therapeutic agents to this subset of metastatic lesions, rendering them non-responsive to systemically applied chemotherapeutics, and clinically problematic. Thus, effective drug delivery strategies for these tumor foci likely will require exceptionally high local concentrations of drug, and/or, the ability to magnetically drive the therapeutic into them using the drug reservoir that is present in adjacent normal, well-vascularized tissue, and/or in sub-regions of well-vascularized tumor tissue. Both of the observations and related implications above can be overcome using a modified and simpler version of a magnetic drug delivery system. Moreover, since the technical challenges involved in focusing and holding drug in anatomic zones of the body are less involved than a one-by-one tumor targeting approach, the new system will be easier to develop. In summary, the goal of the project is to subject anatomic regions of the body that harbor a clinically significant tumor burden to high concentrations of a therapeutic agent while sparing the rest of the body from these high drug levels and associated toxicity.

磁性药物输送是指将治疗或成像剂与磁响应的物体，铁纳米粒子的链接联系，并使用磁场将其聚焦到体内的特定位点。对于癌症，通过在肿瘤位置创建局部高浓度的药物，这种方法在治疗上可能很有用。目前，磁性药物输送的最新技术利用放置在皮肤外的固定磁铁吸引颗粒。但是，该方法仅对有限的组织深度有效，因此药物靶向仅限于皮肤表面附近的肿瘤。或者，有时可以将磁场浓缩的磁体或物体（例如，含有钢或铁的支架）植入体内的深处，并能够将药物聚焦在深肿瘤附近。但是，将这种物体植入患者是不可取的，在临床环境中并非总是可能的。为了克服当前磁性药物输送方法的问题，我们正在开发一个动态反馈控制系统，该系统使用磁场将药物聚焦于深层目标，通过使用一组外部应用的磁场并将它们控制在彼此之间。尽管这是一种有前途的方法，但涉及的一些技术挑战可能难以克服，例如需要放射学图像然后瞄准每个肿瘤焦点，这是一项艰巨的任务，需要对粒子位置进行实时感知。磁性药物输送的更简单的方法是基于对总体和分子肿瘤病理学的相关观察结果。对肿瘤疗法的观察结果和影响是：1）即使肿瘤可能广泛转移，临床上显着的肿瘤负担通常仅定位于人体的特定解剖区域。因此，将药物递送到特定和定义的解剖区域可能会以最小的毒性提供最佳的临床益处。目标区域将基于每种癌症类型的自然病史，肿瘤细胞对区域内解剖结构的有害作用，以及将高水平的药物提供给人体特定区域的疗效毒性比。 2）特别损害了患者转移的子集的血液供应。这些病变在尸检时的牢固，白色的，结节性的总外观以及在光显微镜水平上看到的不完全脉管系统证明了这一点。这些病变通常与它们产生的原发性肿瘤以及体内不同部位的其他转移酶明显不同。这种血管折衷可能导致治疗剂递送到转移性病变的子集，从而使它们无反应到系统地应用化学治疗疗法，并且在临床上有问题。因此，这些肿瘤灶的有效药物输送策略可能需要极高的局部浓度的药物，并且/或使用在邻近的正常，血管性良好的组织中和/或在血管血管肿瘤组织的亚地区中存在的药物储层将治疗性驱动到它们的能力。 上面的观察结果和相关含义都可以使用磁性药物输送系统的修改，更简单的版本来克服。此外，由于在人体解剖区域中涉及的专注和持有药物所涉及的技术挑战少于一种逐一肿瘤靶向方法，因此新系统将更容易开发。 总而言之，该项目的目的是使身体的解剖区域对临床上显着的肿瘤负担置于高浓度的治疗剂，同时从这些高药物水平和相关毒性中保留其余的身体。