Encapsulating Hydrophobic Solutes in Self-Assembled Nanoparticles Formed by Decompressing Near Critical Micellar Solutions of Block Copolymers

1034530Radosz纳米颗粒将药物输送到癌症组织的有效性随着其载药量的增加而增加。传统的在水溶液中制备纳米粒子时，纳米粒子具有选择性和稳定性，但其包封率和效率往往较低。这是因为最有效的抗癌药物是疏水性的，这限制了它们在水中的溶解度，从而限制了胶囊的可用性。虽然这一点很好理解，但在非水近临界流体中胶束化和包埋的替代方法却鲜为人知。在这种可压缩的溶剂中进行胶束包裹，然后进行固体沉淀，可以通过减压来完成。然而，目前尚不清楚胶束包封率和沉淀固体纳米结构如何依赖于减压路径的选择、药物沉淀压力和共聚物溶剂对的选择。PI的长期研究目标是通过解压嵌段共聚物的近临界胶束溶液来发展支持将疏水溶质包裹在纳米颗粒中的方法的基础知识。这项建议的主要目标是具体了解加工条件如何影响固体沉淀物的包埋效果和纳米结构，这是以前从未尝试过的。这项研究建立在初步数据的基础上，表明从可压缩的近临界溶剂中获得的纳米颗粒的载药量比从传统液体溶剂中获得的纳米颗粒的载药量要高得多。中心假设是，适当的减压路径跨越胶束化、药物沉淀和共聚物沉淀压力可以产生均匀的纳米颗粒，与不可压缩的液体溶剂相比，该纳米颗粒具有更高的包封率和包封率。这一中心假设是三个特定目标和工作假设的组织原则：(1)了解解压缩路径如何影响沉淀固体结构为了产生由窄分布的球形纳米粒子组成的沉淀，解压缩路径应该从高压下的随机分子溶液开始，穿过胶束化区域。(2)了解解压路径对溶质包埋的影响。药物沉淀压力应在共聚物胶束化区域内，即低于胶束化压力，方向上不能离共聚物沉淀压力太远。(3)了解如何选择优化药物包封率的聚合物溶剂对？对于给定的嵌段共聚物类型，存在最佳嵌段比范围和相对于每个嵌段的最佳溶剂选择性，从而使药物包封率最大化。PI为开展这一项目做好了充分的准备，因为除了证实这些目标和假设的可行性的强有力的初步数据外，该实验室还拥有将尖端聚合物合成和超临界流体物理相结合的记录，旨在开发适用于药物和基因输送的受控聚合物纳米颗粒。智力优势：拟议的工作旨在开发一个知识库，使药物和基因输送的新型纳米颗粒具有显著提高的封装能力和效率。高容量将能够使用较少的药物输送材料选择性地输送相同或更大剂量的药物，因此具有更好的疗效和更低的毒性。高包封率将使非常昂贵的抗癌药物的加工损失大大降低。更重要的是，这项拟议的工作将为在可压缩溶剂中通过聚合物胶束封装难溶疏水固体的物理和工程打开新的机会。更广泛的影响：具有高载药量的纳米颗粒毒性较小，治疗效果将更高。拟议的研究将使参与该项目的两名博士生能够继续教育，并为现有的针对年轻女性、少数民族和高中生的外展和招聘计划做出独特贡献。例如，作为主要由休利特基金会资助的中学女孩计划的一部分，中学年龄的女孩和男孩将有机会进行为期一周的体验，重点是对尖端工程主题的亲身探索，例如基于纳米技术的药物输送。

1034530RadoszThe effectiveness of nanoparticles to deliver drugs to cancer tissue increases with their drug loading. When conventionally prepared in aqueous solvents, nano particles can be selective and stable, but their encapsulation content and efficiency tend to be low. This is because the most effective cancer drugs are hydrophobic, which limits their solubility in water and hence encapsu- lation availability. While this is well understood, alternative approaches to micellization and encapsulation in non-aqueous near critical fluids are poorly understood. Micellar encapsulation in such compressible solvents, followed by solid precipitation, can be accomplished by decompression. However, it is not known how the micelle encapsulation efficiency and the precipitated solid nanostructure depend on the choice of the decompression path, on the drug precipitation pressure, and on the choice of the copolymer solvent pair.The PI's long term research goal is to develop the fundamental knowledge that underpins methods for encapsulating hydrophobic solutes in nanoparticles by decompressing near critical micellar solutions of block copolymers. The overarching objective in this proposal is to understand specifically how the processing conditions impact the encapsulation effectiveness and the nano- structure of the solid precipitate, which has not been attempted before. This research builds on preliminary data suggesting much higher drug loading content for nanoparticles obtained from compressible near critical solvents than those from conventional liquid solvents. The central hypothesis is that a suitable decompression path crossing the micellization, drug precipitation, and copolymer precipitation pressures can produce uniform nanoparticles that exhibit much higher encapsulation capacities and efficiencies than those obtained from incompressible liquid solvents. This central hypothesis is an organizing principle for three specific aims and working hypotheses: (1) Understand how the decompression path affects the precipitated solid structure in order to produce a precipitate composed of narrowly distributed spherical nanoparticles, the decompression path should start from a random molecular solution at high pressures and cross the micellization region. (2) Understand how the decompression path affects solute encapsulation the drugprecipitation pressure should be within the copolymer micellization region, that is, below the micellization pressure and, directionally, not too far from the copolymer precipitation pressure. (3) Understand how to select polymer solvent pairs that optimize drug encapsulation ? for a given block copolymer type, there is an optimum block ratio range and optimum solvent selectivity with respect to each block that maximize drug encapsulation. The PI is well prepared to undertake this project because, in addition to strong preliminary data that confirm the feasibility of these aims and hypotheses, the laboratory has a record of combining cutting-edge polymer synthesis and supercritical fluid physics aimed at well controlled polymeric nanoparticles applicable to drug and gene delivery.Intellectual Merit:The proposed work aims to develop a knowledge base that will allow novel nanoparticles for drug and gene delivery with drastically improved encapsulation capacities and efficiencies. The high capacity will enable a selective delivery of the same or greater dose of the drug using a smaller amount of the drug delivery material, and hence a better efficacy and lower toxicity. The high encapsulation efficiency will enable much lower processing losses of the very expensive cancer drugs. Even more importantly, the proposed work will open up new opportunities for physics and engineering of encapsulating hard to dissolve hydrophobic solids by polymeric micelles in compressible solvents, which is virgin territory.Broader Impact:The nanoparticles with high drug loading will be less toxic and will have much higher therapeutic effectiveness. The proposed research will enable the continuing education of two doctoral students working on this project and uniquely contribute to existing outreach and recruiting programs for young women, minority, and high school students. For example, middle school age girls and boys will have the opportunity for a one-week experience highlighted by hands on exploration of cutting edge engineering topics, including nanotechnology based drug delivery, for example, as part of the Middle School Girls program, funded primarily by the Hewlett Foundation.