| Micelles formed through the self-assembly of block copolymers have been widely used to encapsulate highly hydrophobic drugs to increase their effective solubility. However, this emerging nanoparticle technology faces fabrication challenges that call for better understanding of the underlying principles that result in effective micelle-based drug delivery systems. Among the challenges, for example, are how to consistently prepare micelles with a narrow, predictable size-distribution and a high drug loading content, which remain stable upon dilution but dissociate upon reaching the target. For example, micelles of hydrophilic-hydrophobic block polymers, such as poly(ethylene glycol)- block-poly(epsilon-caprolactone) (PEG-b-PCL) have been shown to improve the pharmacokinetics and therapeutic efficacy of hydrophobic cancer drugs, such as paclitaxel. However, conventional drug encapsulation methods using incompressible aqueous and organic solvents are limited by lack of control over the micellization process, which results in drug loading around 3 wt% and encapsulation efficiencies of around 30%. An alternative is to use near-critical fluid solvents, such as trifluoromethane and dimethyl ether, to prepare drug loaded micelles under high pressure conditions, then release the solvent, which evaporates almost instantaneously, and rediperse the resulting nanoparticles in water. By controlling the drug precipitation within the micellar solution region of the near-critical solvent, the loading of paclitaxel in PEG-b-PCL can reach over 12 wt% with encapsulation efficiencies approaching 100%. Additionally, nanoparticles have also been prepared that slow down the burst release of encapsulated drug, commonly observed upon dilution: for one particular case the release of paclitaxel upon dilution from is reduced from 19% to 2% at one hour and 50% to 39% at five hours. This new near-critical fluid micellization (NCFM) method will enable the preparation of drug-loaded nanoparticles that promise not only a lower exposure of the body to the copolymer at the same treatment drug-rate, due to the high drug loading, but also for less waste of the expensive drug, due to the high efficiency, enabling the efficient fabrication of stable, well-defined nanoparticles for revolutionary new cancer treatments. |
