Multifunctional and tunable lipid-nanoparticle assemblies

多功能纳米疗法代表着疾病治疗的一个变革性的新前沿。脂质体为包裹具有不同表面化学性质的功能性无机纳米粒提供了一个通用和动态的平台，从而达到多种治疗目的。该项目采用独创的方法，用无机纳米颗粒选择性地修饰工程脂质体，并研究纳米颗粒的大小、电荷和疏水性如何影响脂质体的结构和功能。这种复合材料组件将在需要空间和时间靶向递送的治疗应用中发挥重要作用。表面功能化的超顺磁性氧化铁(SPIO)将被用作模型纳米颗粒，因为它们已经成功地用作MRI造影剂和体内热疗，其中加热是使用在射频工作的外部磁场来实现的。磁脂质体的程序化射频刺激将提供一种简单而稳健的方法来控制脂质体的结构和稳定性。通过目标1，将形成静电和疏水组装的修饰磁脂质体，并对其结构、形态和胶体稳定性进行表征。在目标2中，将研究选择性修饰、SPIO纳米颗粒脂类相互作用以及射频加热对脂相行为的影响。在目标3中，包裹在磁性脂质体中的分子的选择性跨双层渗透性将通过控制释放或通过编程射频加热的新的突发释放机制来展示。在软胶体纳米系统中选择性地控制相行为、热和传质的能力对于形成下一代多功能疗法、纳米颗粒、纳米材料和纳米器件是非常必要的。双层中的局域射频加热是一个原始的概念，有望提供对双层相行为的选择性控制，进而实现扩散。该项目将为杂化纳米颗粒/脂质组装体的合成和表征提供新的实验方法。因此，无机纳米粒子和生物分子系统的集成将扩展到包括这类独特的活性纳米材料。表征热力学和传输性质将提供组件的完整图景，这将是确定其作为多功能治疗剂的潜力所必需的。例如，修饰的磁性脂质体可以通过提供外部触发和产生时间和剂量依赖的扩散来增强药物输送。通过反转问题，我们还发现了一种将磁性脂质体用作潜在的纳米级温度传感器的方法。鉴于射频加热的微创性质和对组织的穿透，这些新型载体将非常有效地操纵体内治疗剂的输送。正在与URI药学院的教职员工一起寻找机会，以确定有前途的申请。此外，这些新结构为研究纳米粒子与细胞膜的相互作用提供了合适的模型系统，包括它们在摄取和潜在毒性方面的作用。该项目还将作为高中、本科生和研究生的教育工具。联合PI Bose组织了一个暑期高中实习生计划，两位PI已经与新英格兰LSAMP计划联系，并将与他们合作指导学生。在我们不同的实验室小组中，我们打算将高中生和本科生与研究生导师配对，以开展与混合脂质体直接相关的独立项目。这项活动将扩大项目的影响，使其超越传统的和预期的研究参与。该项目背后的概念和取得的成果将作为春季学期开设的一门新的跨学科研究生水平生物农学课程的教材，并通过一个合作网站免费传播。

Multifunctional nano scale therapeutics represents a transformative new frontier in disease treatment. Liposomes provide a versatile and dynamic platform for encapsulating functional inorganic nanoparticles with different surface chemistries to achieve multiple therapeutic objectives. This project employs original approaches to selectively decorate engineered liposomes with inorganic nanoparticles, and examine how nanoparticle size, charge and hydrophobicity affect liposome structure and function. Such composite assemblies will play an important role in therapeutic applications where spatially as well as temporally targeted delivery is required. Surface functionalized superparamagnetic iron oxide (SPIO) will be used as model nanoparticles, as they have been successfully employed as MRI contrast agents and for in vivo hyperthermia, where heating is achieved using external magnetic fields operating at radio frequencies. Programmed RF stimulation of the magnetoliposomes will provide a simple yet robust way to control liposome structure and stability. Through Aim 1, electrostatically and hydrophobically assembled decorated magnetoliposomes will be formed and their structure, morphology, and colloidal stability characterized. In Aim 2, the effect of selective decoration, SPIO nanoparticle lipid interactions, and RF-heating on lipid phase behavior will be studied. In Aim 3, selective transbilayer permeability of a molecule encapsulated within the magnetoliposomes will be demonstrated via controlled-release or a novel burst-release mechanism through programmed RF heating.Intellectual Merit. The ability to selectively control phase behavior, heat, and mass transfer in soft colloidal nanoscale systems is highly desirable for the formation of next generation multifunctional therapies, nanoparticles, nanomaterials, and nanodevices. Localized RF heating in bilayers is an original concept that is expected to provide selective control over bilayer phase behavior, and in turn diffusion. This project will provide new experimental methods for the synthesis and characterization of hybrid nanoparticle/lipid assemblies. Hence, the integration of inorganic nanoparticles and biomolecular systems will be extended to include this unique class of active nanomaterials. Characterizing thermodynamic and transport properties will provide a complete picture of the assemblies, which will be needed to determine their potential as multifunctional therapeutic agents. For instance, the decorated magnetoliposomes may enhance drug delivery by providing an external trigger and yielding time and dose dependent diffusion. By inverting the problem, we also have identified a way to use the magnetoliposomes as a potential nanoscale temperature sensor.Broader Impacts. Given the minimally invasive nature and tissue penetration of RF-heating, these novel carriers would be very effective for manipulating the delivery of therapeutic agents in vivo. Opportunities are being pursued with faculty from the College of Pharmacy at URI to identify promising applications. In addition, these new structures provide suitable model systems for studying nanoparticle interactions with cellular membranes, including their role in uptake and potential toxicity. This project will also serve as an educational tool for high school, undergraduate, and graduate students. Co-PI Bose organizes a summer high school intern program and both PIs have been contacted by and will work with the New England LSAMP program to mentor students. Within our diverse laboratory groups, we intend to pair high school and undergraduate students with graduate student mentors to conduct independent projects directly related to hybrid liposomes. This activity will expand the impact of the project to beyond the traditional and expected research participation. The concepts behind this project and the results obtained will be used as teaching material in a new interdisciplinary graduate level Bionanotechnology course offered in the spring semester, and disseminated freely through a collaborative website.