Browsing by Subject "Flash nanoprecipitation"

Now showing 1 - 2 of 2
  • Thumbnail Image
    Item
    Diblock copolymer stabilized nanoparticles for drug delivery via flash nanoprecipitation
    (2014-10) Han, Jing
    Cancer is one of the most challenge diseases to treat around the world. Drug delivery system, as one of the chemotherapeutic treatments has received enorrmous attention from researchers. This thesis is to develop amphiphilic diblock copolymer protected nanoparticles loaded with anti-cancer drug, with small size and high drug loading, to achieve selective drug delivery using EPR effect. Chapter 1 briefly describes the motivation and novelties of this research pursuit. Chapter 2 introduces a modified confined impingement jets mixer with dilution (CIJ-D mixer), using flash nanoprecipitation to produce nanoparticles made of hydrophobic drugs. The CIJ-D mixer was evaluated by the sizes of β-carotene nanoparticles at varied flow conditions compared to these made by multi-inlet vortex mixer. The CIJ-D mixer provides higher efficiency and easiness of handling for nanoparticle preparation. That is why CIJ-D mixer was used for all the work presented in the following chapters. In Chapter 3, we made the first attempt to produce PEG-b-PLGA protected paclitaxel loaded nanoparticles but failed, because paclitaxel is too hydrophilic to be captured in particles. Thus, a series of silicate ester derivatized paclitaxel were synthesized by Hoye research group and successfully encapsulated into nanoparticles. Several nanoparticle post-treatments, such as filtration, hollow fiber diafiltration, and ultracentrifugation were used and assessed, in order to purify nanoparticles. Lyophilization was found to induce nanoparticle aggregation due to the freezing process. The addition of sucrose as cryoprotectant was studied to prevent aggregation and recover nanoparticle. Chapter 4 focuses on developing in vitro drug release protocols, for more accurate quantification of highly hydrophobic paclitaxel prodrugs. Different dialysis devices were used such as dialysis tubes, dialysis cassettes, and dialysis mini capsules. Infinite sink and limited sink conditions were compared as well to provide sufficient concentration gradient across dialysis semi-permeable membrane. At last, a reverse drug release experimental protocol was customized to determine the remaining drug left in dialysis mini capsules while the sink condition was maintained by frequently refreshing buffer solution during in vitro drug release study. Chapter 5 mainly presents the pharmacokinetics of paclitaxel prodrug nanoparticles loaded with different silicate ester derivatives, at different pH, both inside nanoparticles and in buffer solution. Chapter 6 includes a series of Cryo-TEM images of nanoparticles collected at different time, such as fresh nanoparticles immediately after being prepared by CIJ-D mixer, nanoparticles after ultracentrifugation, after lyophilization, 0hr, and 24 hr during drug release study. These images not only showed a reverse liner relation of average particle size and hydrophobicity of the loaded drug, but also displayed a core-shell internal structure of nanoparticles prepared via flash nanoprecipitation and potential particle disassembly after 24hr drug release. Finally, Chapter 7 summarizes the key results and conclusions obtained from previous chapters, lessons learned from mistakes and failures, and future directions for this project, in order to prepare nanoparticles with better controlled size and drug release kinetics and to understand deeply on nanoparticle formation and release mechanisms.
  • Thumbnail Image
    Item
    Synthesis and characterization of silicate ester prodrugs and poly(ethylene glycol)-b-poly(lactic-co-glycolic acid) block copolymers for formulation into prodrug-loaded nanoparticles
    (2012-09) Wohl, Adam Richard
    Fine control of the physical and chemical properties of customized materials is a field that is rapidly advancing. This is especially critical in pursuits to develop and optimize novel nanoparticle drug delivery. Specifically, I aim to apply chemistry concepts to test the hypothesis "Silicate ester prodrugs of paclitaxel, customized to have the proper hydrophobicity and hydrolytic lability, can be formulated with well-defined, biocompatible, amphiphilic block copolymers into nanoparticles that are effective drugs." Chapter 1 briefly describes the context and motivation of the scientific pursuits described in this thesis. In Chapter 2, a family of model silicate esters is synthesized, the hydrolysis rate of each compound is benchmarked, and trends are established based upon the steric bulk and leaving group ability of the silicate substituents. These trends are then applied to the synthesis of labile silicate ester prodrugs in Chapter 3. The bulk of this chapter focuses on the synthesis, hydrolysis, and cytotoxicity of prodrugs based on paclitaxel, a widely used chemotherapeutic agent. In Chapter 4, a new methodology for the synthesis of narrowly dispersed, "random" poly(lactic-co-glycolic acid) polymers by a constant infusion of the glycolide monomer is detailed. Using poly(ethylene glycol) as a macroinitiator, amphiphilic block copolymers were synthesized. Co-formulating a paclitaxel silicate and an amphiphilic block copolymer via flash nanoprecipitation led to highly prodrug-loaded, kinetically trapped nanoparticles. Studies to determine the structure, morphology, behavior, and efficacy of these nanoparticles are described in Chapter 5. Efforts to develop a general strategy for the selective end-functionalization of the polyether block of these amphiphilic block copolymers are discussed in Chapter 6. Examples of this strategy include functionalization of the polyether with an azide or a maleimide. Finally, Chapter 7 provides an outlook for future development of the strategies described in this thesis and summarizes the results and conclusions of the experimental results that led to the development of the therapeutic, paclitaxel silicate-loaded, polymeric nanoparticles.