No abstract

Paclitaxel, an expensive first-line anticancer drug, is known to have better pharmacokinetics and therapeutic efficacy if encapsulated in polymeric micelles. However, the conventional encapsulation methods using incompressible aqueous solutions are limited to low drug loading, less than 3% of micelle weight, and low efficiency, more than two-thirds of the drug in solution remains unencapsulated, and hence wasted, not to mention the burst release problems. This work demonstrates that expansion of near-critical fluid solutions, for example in compressible dimethyl ether and trifluoromethane not too far from their critical region, can lead to a much higher drug loading, for example in micelles formed from poly(ethylene glycol)-block-poly(ε-caprolactone) (PEG-b-PCL). By controlling the drug precipitation within the micellar solution region, the loading of paclitaxel in PEG-b-PCL can reach over 12% with a loading efficiency of 87%, which is unattainable by conventional methods. Moreover, the burst release fraction of the drug can be reduced despite the higher drug loading. This means that the new near-critical fluid micellization (NCFM) method will allow not only for 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.

Micelles of hydrophilic−hydrophobic block polymers, such as poly(ethylene glycol)−block-poly(ϵ-caprolactone) (PEG−b-PCL), used as drug-delivery carriers, are generally fabricated via solvent displacement or dialysis, which is time-consuming, requires freeze drying, and can leave toxic traces of the residual organic solvents. An alternative is presented in this paper: form micellar PEG−b-PCL nanoparticles in a supercritical fluid solvent and then disperse them in water toward a water-dispensable formulation. This method is illustrated with pressure−temperature phase diagrams for PEG−b-PCL in supercritical trifluoromethane, which is selective enough for the PCL and PEG blocks to induce micellization. When subjected to decompression to remove trifluoromethane, dry and organic solvent-free nanoparticles are readily obtained. Their micellar structure is immediately reestablished in water, as confirmed by laser light scattering. Neither has been demonstrated previously.

Near-critical micellization (NCM), allowing for precise pressure-tuned control of sequential block collapse and micelle formation, can be synchronized with cancer-drug encapsulation with virtually no drug losses. NCM is demonstrated to produce benign, stable nanoparticles made of PEG-b-PLLA-b-PCL triblock copolymers that are not only solvent-free and paclitaxel-rich, which reduces the body exposure to the excipients, but also nearly burst-release-free, which reduces if not eliminates its toxic side effects while enhancing its therapeutic efficacy.

Micelles of hydrophilic−hydrophobic block copolymers, such as poly(ethylene glycol)-block-poly(caprolactone) (PEG-b-PCL), are useful for delivery of hydrophobic drugs. Such micelles can be formed by liquid solvent displacement or dialysis. A more recent approach is to use supercritical fluids as solvents, but the selection criteria for solvents are not well understood. The compressible solvents studied in this work can induce pressure-tunable micellization of PEG-b-PCL. Their capacity and selectivity, and hence their ability to form micelles, depends on their density, polarity, and hydrogen bonding potential. By mixing two solvent components, such as dimethyl ether (good solvent) and trifluoromethane (selective antisolvent), one can control not only the micellization temperature and pressure, but also the bulk separation pressure (cloud pressure), crystallization temperature, and melting temperature. This can be utilized to develop efficient ways to prepare micellar precursors for drug-loaded nanoparticles.