Multifunctional and tunable lipid-nanoparticle assemblies

多功能纳米尺度疗法代表了疾病治疗的变革性新前沿。脂质体为封装具有不同表面化学性质的功能性无机纳米颗粒提供了一个通用和动态的平台，以实现多种治疗目标。该项目采用新颖的方法，选择性地用无机纳米颗粒修饰工程脂质体，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。这种复合组件将在需要空间以及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）将被用作模型纳米粒子，因为它们已被成功地用作MRI造影剂和体内热疗，其中加热是使用在射频下操作的外部磁场实现的。磁性脂质体的程序化RF刺激将提供控制脂质体结构和稳定性的简单而稳健的方式。通过目标1，将形成静电和疏水组装修饰的磁性脂质体，并表征其结构、形态和胶体稳定性。在目标2中，将研究选择性装饰、SPIO纳米颗粒脂质相互作用和RF加热对脂质相行为的影响。在目标3中，磁性脂质体中包裹的分子的选择性跨双层渗透性将通过程序化射频加热的控释或新型突释机制来证明。在软胶体纳米级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期望的。双层中的局部RF加热是一个原始概念，预计将提供对双层相行为的选择性控制，进而控制扩散。该项目将为混合纳米颗粒/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整合将扩展到包括这一类独特的活性纳米材料。表征热力学和运输性能将提供一个完整的图片的组件，这将需要确定其作为多功能治疗剂的潜力。例如，修饰的磁性脂质体可以通过提供外部触发并产生时间和剂量依赖性扩散来增强药物递送。 通过反转这个问题，我们也找到了一种方法，可以将磁性脂质体用作潜在的纳米级温度传感器。考虑到射频加热的微创性质和组织穿透性，这些新型载体将非常有效地用于操纵体内治疗剂的递送。机会正在追求与从药剂学院在URI的教师，以确定有前途的应用程序。此外，这些新结构为研究纳米颗粒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中的作用。这个项目也将作为高中，本科和研究生的教育工具。共同PI Bose组织了一个暑期高中实习生项目，两个PI都已经与新英格兰LSAMP项目联系并将与该项目合作，指导学生。在我们多样化的实验室团队中，我们打算将高中生和本科生与研究生导师配对，进行与混合脂质体直接相关的独立项目。这一活动将扩大项目的影响，超越传统和预期的研究参与。该项目背后的概念和所获得的结果将被用作春季学期提供的新的跨学科研究生水平生物纳米技术课程的教材，并通过合作网站免费传播。

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.