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

1034530Radosz纳米颗粒将药物递送至癌症组织的有效性随着其载药量而增加。当常规地在水性溶剂中制备时，纳米颗粒可以是选择性的和稳定的，但是它们的包封含量和效率往往较低。这是因为最有效的癌症药物是疏水性的，这限制了它们在水中的溶解度，因此限制了它们的可利用性。虽然这是很好地理解，但在非水近临界流体中胶束化和包封的替代方法知之甚少。在这种可压缩溶剂中的胶束包封，随后固体沉淀，可以通过减压来完成。 然而，目前还不知道胶束包封效率和沉淀的固体纳米结构如何取决于减压路径的选择，药物沉淀压力，以及共聚物溶剂对的选择。PI的长期研究目标是开发基础知识，通过对嵌段共聚物的近临界胶束溶液进行减压，将疏水性溶质包封在纳米颗粒中。该提案的首要目标是具体了解加工条件如何影响固体沉淀物的包封有效性和纳米结构，这在以前还没有尝试过。这项研究建立在初步的数据表明，从可压缩的近临界溶剂比从传统的液体溶剂中获得的纳米颗粒更高的载药含量。中心假设是，穿过胶束化、药物沉淀和共聚物沉淀压力的合适的减压路径可以产生均匀的纳米颗粒，其表现出比从不可压缩的液体溶剂获得的那些高得多的包封能力和效率。这个中心假设是三个具体目标和工作假设的组织原则：（1）了解减压路径如何影响沉淀的固体结构，以产生由窄分布的球形纳米颗粒组成的沉淀物，减压路径应该从高压下的随机分子溶液开始并穿过胶束化区域。(2)了解减压路径如何影响溶质包封，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，并且方向上不太远离共聚物沉淀压力。(3)了解如何选择优化药物包封的聚合物溶剂对？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，其最大化药物包封。主要研究者已经做好了充分的准备来开展这个项目，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，实验室还拥有将尖端聚合物合成和超临界流体物理学相结合的记录，旨在控制适用于药物和基因递送的聚合物纳米颗粒。拟议的工作旨在开发一个知识库，使新的纳米粒子的药物和基因的交付与大大改善封装能力和效率。高容量将使得能够使用较少量的药物递送材料选择性地递送相同或更大剂量的药物，并且因此具有更好的功效和更低的毒性。高包封效率将使得非常昂贵的癌症药物的加工损失低得多。更重要的是，这项工作将为物理学和工程学开辟新的机会，即在可压缩溶剂中通过聚合物胶束封装难以溶解的疏水性固体，这是一个处女地。更广泛的影响：具有高载药量的纳米颗粒将具有更低的毒性和更高的治疗效果。拟议的研究将使两名博士生在这个项目上工作的继续教育，并独特地有助于现有的外展和招聘计划的年轻女性，少数民族和高中生。例如，中学年龄的女孩和男孩将有机会获得为期一周的经验，重点是探索尖端工程主题，包括基于纳米技术的药物输送，例如，作为中学女孩计划的一部分，主要由休利特基金会资助。

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.