PRINT® nanoparticle parameters to improve docetaxel PK/PD

Nanomedicines currently approved for oncology improve certain properties of the reformulated small molecule, such as toxicity, but do not always enhance efficacy or pharmacokinetics. Further research to advance the understanding of how nanoparticle design can affect in vivo performance will aid in the rational design of nanomedicines. Particle Replication in Non-wetting Templates (PRINT®) is a particle fabrication technique capable of making precisely controlled formulations which allows for the systematic evaluation of single formulation variables. In this dissertation, three formulation variables were evaluated: particle size of non spherical particles, drug loading and release kinetics. The findings of this research indicate that reduced particle size decreases particle accumulation in the liver, spleen and lungs while enhancing plasma and tumor exposure. Reducing the drug loading of the particles had a similar effect, potentially due to blockading the mononuclear phagocyte system (MPS). Decreasing the release rate of docetaxel from the particles also improved the plasma exposure in addition to improving the maximum tolerated dose of drug. The improved tolerability through use of a prodrug strategy allowed a higher dose of docetaxel to be delivered to achieve improved tumor growth inhibition. Controlling the released docetaxel concentration within the plasma may be a key parameter to improve the safety and therapeutic profile of docetaxel.Doctor of Philosoph