Magnetothermally-Triggered Drug Release from Block Copolymer Micelles

描述（由申请人提供）：提出了一种触发递送治疗剂的新方法，该方法将利用某些磁性纳米颗粒在暴露于AC磁场时的独特加热性质。磁性纳米颗粒（MNP）产生的热量触发了宿主载体的相变，从而允许开发具有外部触发机制的药物递送系统。虽然磁加热（和磁热疗）不是新的主题，但这些材料与温度响应胶束的结合是一种使用磁场触发释放的创新方式。该提案的大部分内容都集中在开发和仔细检查热响应系统，这些系统可以通过温度从37摄氏度增加到大约45摄氏度来激活。通过减缓（或停止）药物释放直到施加外部磁场，所提出的胶束包封的MNP系统可以在递送药物之前定位到体内的靶向区域或细胞类型。这种方法将实现比传统策略更高的每药物剂量的疗效，并且可以很容易地与磁流体热疗结合用于癌症治疗。它为肿瘤学家提供了前所未有的控制癌症治疗的空间，通过细胞水平的靶向，和时间，通过选择时间和持续时间的磁触发。 药物载体系统是基于聚（环氧乙烷-共-5-己内酯）的二嵌段共聚物的自组装的胶束结构，其具有在40-42 oC左右熔化的结晶核。通过施加脉冲磁场，在胶束中产生热量，并且随着核心熔化，胶束不稳定，导致化疗药物的快速递送。该系统设计允许在施加磁场时释放;因此，该器械可由置于患者体外的场触发。将研究不同载体参数的释放速度和持续时间。为了评估这些用于靶向和治疗癌症的系统，我们将在纳米载体表面附着靶向配体，并对癌症和健康细胞系进行体外实验。 该项目汇集了工程师，科学家和医学研究人员，并将由化学和生物工程副教授Christopher Brazel博士领导，他是聚合物系统专家，化学教授大卫Nikles博士，他在磁性纳米材料的设计和表征方面拥有丰富的经验。UAB心血管疾病和人类基因治疗助理教授Joel格拉斯哥博士将领导癌细胞系靶向和体外试验的实验。Maaike Everts博士是UAB的一名助理教授，具有靶向载体的背景，他将担任靶向实验研究小组的顾问。该项目的顾问Jacqueline Nikles博士将专注于嵌段共聚物的开发和表征胶束的形成和破坏。 公共卫生相关性：通过开发磁触发输送系统，可以开发更有效的治疗方法。例如，携带磁性纳米颗粒的胶束可以靶向癌症或其他细胞，并通过施加在体外的交变磁场触发药物的递送。这将减少每次治疗所需的药物量，同时最大限度地减少强效药物的副作用。该系统可能会对许多人的生活产生重要影响，这些人正在寻求更好的治疗方法来治疗一系列癌症和潜在的许多其他疾病。

DESCRIPTION (provided by applicant): A novel approach to triggered delivery of therapeutics is proposed that will take advantage of the unique heating properties of certain magnetic nanoparticles when exposed to an AC magnetic field. The heat generated by the magnetic nanoparticles (MNPs) triggers a phase change in the host carrier, allowing the development of drug delivery systems with an external triggering mechanism. While magnetic heating (and magnetic hyperthermia) are not new subjects, the combination of these materials with temperature-responsive micelles is an innovative way to use a magnetic field to trigger release. Much of this proposal is focused on the development and careful examination of thermally-responsive systems that can be activated by a temperature increase from 37 to approximately 45 oC. By slowing (or halting) drug release until the external magnetic field is applied, the micelle-encapsulated MNP systems proposed can localize to a targeted region or cell type within the body prior to delivery of medication. This method would achieve significantly higher efficacy per drug dose than conventional strategies, and could easily be combined with magnetic fluid hyperthermia for use in cancer therapies. It provides the oncologist unprecedented control of the cancer therapy with both spatial, through cellular-level targeting, and temporal, by selecting the time and duration of the magnetic trigger. The drug carrier system is a micelle structure based on the self-assembly of diblock copolymers based on poly (ethylene oxide-co-5-caprolactone), which has a crystalline core that melts around 40-42 oC. By application of a pulsed magnetic field, heat is generated in the micelles, and as the core melts, the micelle is destabilized, causing rapid delivery of chemotherapeutic drugs. The system design allows release as the magnetic field is applied; thus, the device can be triggered by a field placed external to the patient's body. The speed and duration of the release will be investigated for different carrier parameters. To evaluate these systems for targeting and treating cancer, we will attach targeting ligands to the surface of the nano-carriers and carry out in vitro experiments on cancer and healthy cell lines. The project brings together engineers, scientists and medical researchers, and will be led by Dr. Christopher Brazel, an associate professor of chemical and biological engineering who is an expert on polymeric systems, and Dr. David Nikles, a professor of chemistry, who has significant experience with the design and characterization of magnetic nanomaterials. Dr. Joel Glasgow, an assistant professor of cardiovascular disease and human gene therapy at UAB, will lead experiments on targeting and in vitro tests in cancer cell lines. Dr. Maaike Everts, an Assistant Professor with a background in targeting vectors at UAB, will be a consultant to the research team for the targeting experiments. Dr. Jacqueline Nikles, a consultant on the project, will focus on development of block copolymers and characterizing micelle formation and disruption. PUBLIC HEALTH RELEVANCE: By developing a magnetically-triggered delivery system, more efficient therapeutic treatments can be developed. For example, micelles carrying magnetic nanoparticles can be targeted to cancer or other cells with delivery of medicine triggered by an alternating magnetic field applied outside the body. This would reduce the amount of drug required per treatment while minimizing the side effects of potent drugs. This system could have an important impact on the lives of many people seeking better treatments for a range of cancers and potentially many other medical conditions.