Poly(ethylene glycol)-block-poly(epsilon-caprolactone) micelles for the delivery of drugs with limited aqueous solubility.

摘要

Amphiphilic block copolymer (ABC) micelles are a unique and effective drug delivery vehicle for poorly water-soluble drugs. This work focuses ABC micelles based on poly(ethylene glycol)-block-poly(epsilon-caprolactone) (PEG-b-PCL). Due to the highly hydrophobic core-forming block, PEG-b-PCL micelles can potentially incorporate high levels of poorly water-soluble drugs. However, the existing drug loading procedures have limited the maximization of drug loading using this polymer. The utility of PEG-b-PCL micelles as a drug delivery vehicle for poorly water-soluble drugs was shown in this thesis to be enhanced through the use of alternative PEG-b-PCL micelle assembly and drug loading conditions. The main objective of this research was to study the assembly, stability, and drug loading of PEG-b-PCL micelles. PEG- b-PCI, unimers assemble into micelles with narrow size distributions after dissolution in acetonitrile (ACN), followed with gradual addition of water, and subsequent evaporation of a negative ACN-water azeotrope. The assembly of PEG-b-PCL micelles in ACN-water mixtures was studied and was shown to be dependent on PEG-b-PCL concentration, PCL block size, and the presence of fenofibrate, a poorly water-soluble drug. During PEG-b-PCL assembly, it was possible for PEG- b-PCL micelles to incorporate poorly water-soluble drugs, such as fenofibrate and paclitaxel, depending on the PEG-b-PCL concentration, PCL block size, and the initial drug level. The PCL block was found to largely influence the kinetic stability of PEG-b-PCL micelles. In addition, both paclitaxel and fenofibrate were shown to be associated with intact PEG-b-PCL micelles upon dilution, indicating encapsulation and retention of the drug. In the solid-state, drug stability may be enhanced and drug loss from the ABC micelle avoided, however, PEG-b-PCL micelles freeze-dried without lyoprotectants resulted in large PEG- b-PCL aggregates following reconstitution. When freeze-dried in the presence of sugars, especially sucrose, PEG-b-PCL micelles were obtained following reconstitution. The resulting PEG-b-PCL micelles retained their original micelle dimensions and drug content, depending on PCL block length and initial drug levels. Although Increasing the PCL length can potentially result in higher drug loading levels, this thesis work has shown that increasing the PCL block length presents PEG-b-PCL micelle preparation and reconstitution challenges.