¬Controlled Release of Therapeutic Agents from Polymeric Particles

Drug delivery technologies have been emerging for decades for its potential in increasing drug circulation time and bioavailability, targeting specific diseased sites and in the meanwhile decreasing side effects. In this report, I will present three research aspects about polymeric micelles, polymer-lipid-peptide hybrid nanoparticles, and toroidal-spiral particles (TSPs), to promote polymeric particles for delivering therapeutics. Polymeric nanoparticles have attracted a lot of attentions as drug delivery vehicles because of their superior stability and wide range of choices for various functionalities. Unlike the lipid vesicles, formation of the polymeric micelles and drug-loaded nanoparticles is controlled by a competitive kinetics. Without knowing the details of the kinetics, which is difficult to measure due to their multi-scale nature, rational design and optimization of the process is almost not possible. In this thesis, micellization kinetics of a diblock copolymer, poly(ethylene-glycol)-b-poly(caprolactone) (PEG-b-PCL) was measured in situ with millisecond temporal and micrometer spatial resolution, utilizing synchrotron small-angle X-ray scattering (SAXS) integrated with a microfluidic device. The five-inlet microfluidic device provided steady continuous mixing of the polymer solution and the antisolvent. Solvent replacement was mainly dominated by lateral diffusion across the hydrodynamically focused central layer, whose thickness could be precisely designed and manipulated from mass balance of the partitioning streams. The evolutionary regimes of polymer micellization – nucleation, fusion, and insertion were directly observed. Knowing the micellization kinetics of the polymers is essential for design and optimization of self-assembled polymeric nanostructures. The technique of integrating SAXS with microfluidic devices can be translatable to other systems for a breadth of applications. Another nanoparticle system for drug delivery reported in this thesis is hybrid nanoparticles of polymer-lipid encapsulating an anticoagulant peptide amphiphiles Myr-M3mP6. The focus of the study was to correlate the molecular packing structures with the morphology of the nanoparticles, which may be essential in determining the efficacy and cell uptake of the peptide, and finally to build a scale-up process for mass productions of the micelle formulation. A micelle morphology phase diagram in a lipid, PEG, peptide ternary system was proposed to reveal the relation between micelle morphologies and compositions. The methodology reported could possibly generalize to be a directional guide for searching for the desired nanoparticle morphology in lipid, lipid-PEG, peptide ternary systems and realize mass production. Finally, a platform for delivery of therapeutic cells was investigated by encapsulating T cells into toroidal spiral particles (TSPs), previously developed in our group. Immunotherapy broke the stone in combating with cancers. Chimeric antigen receptor T (CAR-T) cells has achieved remarkable therapeutic efficacy in treating B-cell malignancies in the past decade. However, due to a series of reasons such as immunosuppressive microenvironment in solid tumors and lack of trafficking and infiltration of T cells, therapeutic efficacy of CAR-T therapy in solid tumors has been very limited. In order to overcome the difficulties of delivering and constant releasing CAR-T cells in solid tumors, we proposed to co-encapsulate T cells and compounds supporting the expansion of the cells (such as interleukin-2) into different parts of the TSPs and designed the heterogeneous structures and functionalities of the TSPs for constant activation, proliferation and release of T cells. Primary data showed maintained cell viability, vigorous cell expansion, and sustained cell release from the particles, as the in vivo efficacy is to be optimized.