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Injectable drug delivery systems (DDS) such as particulate carriers and water-soluble polymers are being used and developed for a wide variety of therapeutic applications. However, a number of immunological risks with serious clinical implications are associated with administration of DDS. These immunological events can compromise the efficacy and safety of these systems by changing the pharmacokinetics, biodistribution and targeting capability of DDS, and by inducing hypersensitivity reactions. Antibodies induced by administration of DDS can be directed against the carrier material, the drug and/or targeting ligands associated with the DDS. Complement activation and opsonization of DDS, which may or may not be associated with antibody formation, may lead to accelerated clearance, hypersensitivity reactions and formation of membrane attack complexes resulting in premature release of the drug. Also platelets have been reported to play a role in DDS immunogenicity. Despite our curtailed understanding of the relationships between physicochemical characteristics and immunogenicity of DDS, several risk factors have been identified. Insight into these factors should be employed in the development of novel DDS with low immunological risk.

Purpose. To study the in vitro photocytotoxicity and cellular uptake of biodegradable polymeric micelles loaded with the photosensitizer mTHPC, including the effect of lipase-catalyzed micelle degradation. Methods. Micelles of mPEG750-b-oligo(ε-caprolactone)5 (mPEG750-b-OCL5) with a hydroxyl (OH),benzoyl (Bz) or naphthoyl (Np) end group were formed and loaded with mTHPC by the film hydration method. The cellular uptake of the loaded micelles, and their photocytotoxicity on human neck squamous carcinoma cells in the absence and presence of lipase were compared with free and liposomal mTHPC (Fospeg®). Results. Micelles composed of mPEG750-b-OCL5 with benzoyl and naphtoyl end groups had the highest loading capacity up to 30% (w/w), likely due to π-π interactions between the aromatic end group and the photosensitizer. MTHPC-loaded benzoylated micelles (0.5 mg/mL polymer) did not display photocytotoxicity or any mTHPC-uptake by the cells, in contrast to free and liposomal mTHPC. After dilution of the micelles below the critical aggregation concentration (CAC), or after micelle degradation by lipase, photocytotoxicity and cellular uptake of mTHPC were restored. Conclusion. The high loading capacity of the micelles, the high stability of mTHPC-loaded micelles above the CAC, and the lipase-induced release of the photosensitizer makes these micelles very promising carriers for photodynamic therapy in vivo.

Drug carrier systems can be used to overcome problems related to the proper formulation of a promising drug candidate, or to improve its efficacy and safety in vivo. In particular self-assembled nanosized polymeric vesicles and micelles are interesting for the (targeted) delivery of hydrophilic and hydrophobic drugs, respectively. Their small size and hydrophilic surface are attractive features to achieve long circulatory behaviour after intravenous admininstration, enabling extravasation and accumulation at tumour sites. Other favourable characteristics of these systems are their ease of preparation and their tailorability, as the use of (semi-)synthetic polymers offers the possibility to modulate the carriers properties and to control the release of the loaded drug. In this thesis the self-assembling properties of well-defined low molecular weight poly(ethylene glycol) (PEG)-b-oligoesters were studied in detail, and their suitability to design novel nanosized drug carriers was evaluated. It was demonstrated that mPEG-b-oligo(L-lactate)s (OLA) with monodisperse hydrophobic blocks formed nanoparticles with a hydrodynamic radius of 130-300 nm, whereas polydisperse mPEG-b-OLAs formed large aggregates. Further characterisation of the nanoparticles by static light scattering (SLS) indicated that they were highly hydrated nanoaggregates. When mPEG-b-OLAs are applied for the solubilisation of therapeutic proteins and drugs for intravenous administration, their relatively high critical aggregation concentration (CAC) necessitates the use of high amounts of mPEG-b-OLA, and systems with a lower CAC would be more attractive. Therefore the self-assembly of block oligomers with a more hydrophobic oligoester, mPEG-b-oligo(epsilon-caprolactone) (OCL), was investigated, which had much lower CACs than the mPEG-b-OLAs. Moreover, in water mPEG-b-OCL formed small and almost monodisperse oligomeric micelles with a hydrodynamic diameter of 8-15 nm, which may have attractive properties for drug delivery applications in terms of biodistribution and tumour penetration. Importantly, it was found that modification of the OCL block with an aromatic end group substantially improved the physical stability of these micelles, by an extensive reduction of the CAC and by improving their temperature sensitivity profile. Degradation studies revealed an estimated half-life of the hydrolytic cleavage of the ester bonds in these mPEG-b-OCL based micelles at physiological pH and temperature of several years. However, the presence of lipase accelerated the degradation and destabilisation of the mPEG-b-OCL micelles to half-lives of a few days to hours, indicating that degradation induced destabilisation and subsequent drug release from these mPEG-b-OCL micelles is feasible by the action of enzymes in vivo. The loading of these micelles with paclitaxel and docetaxel was evaluated, demonstrating that the presence of an aromatic end group is essential for the formation stable small-sized mPEG-b-OCL micelles loaded with 10% (w/w) of taxane, and their integrity of the was not affected by the presence of albumin. Their cytotoxic effect on C26 cells was comparable to that of the commercial formulations Taxol and Taxotere whereas the empty micelles, in contrast to Cremophor EL, were not toxic in the concentration range tested. In conclusion, the PEG-b-oligoesters studied in this thesis represent an interesting class of amphiphilic molecules, which possess attractive properties for pharmaceutical applications.