The 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.
