Tuneable & degradable polymeric micelles for drug delivery: from synthesis to feasibility in vivo (2007)

In recent years, colloidal systems (e.g. liposomes, nanoparticles and micelles) are increasingly applied as vehicles for controlled drug delivery purposes. Ideally, the encapsulation of hydrophobic drugs in a micellar core prolongs the systemic circulation and drug-loaded micelles selectively accumulate in diseased tissues as a result of the enhanced permeation and retention (EPR) effect. Furthermore, it is aimed for that the micelles dissociate only at the target site to allow the drug to exert a local therapeutic effect. Block copolymers comprising a hydrophilic part (e.g. mPEG) and a thermosensitive block (e.g. side-chain derivatised (meth)acrylamide backbone) self-assembled in water above their critical micelle temperature (CMT) into spherical micelles (60 - 80 nm). The hydrophobic side chains were cleaved off under physiological conditions, thereby increasing the hydrophilicity of the polymer. Ultimately, the CMT exceeded 37 C, and the polymer dissolved in water which led to micelle dissociation. The time required for micellar disassembly depended on the type of methacrylamide backbone and was 5 or 210 hours for N-(2-hydroxyethyl)methacrylamide (HEMAm) or N-(2-hydroxypropyl)methacrylamide (HPMAm), respectively. HPMAm-based micelles encapsulated a very hydrophobic photosensitiser (PS, used in the photodynamic therapy of localised tumours) up to a final concentration of ~ 2 mg/mL. In B16F10 and 14C cells, the PS-loaded micelles displayed a high photocytotoxicity, i.e. an IC50 of 3.0 +/- 0.2 nM in the presence of 10 % serum. Highly loaded micelles displayed a very good stability, also in the presence of 50 % serum, and the encapsulated PS was only released upon hydrolysis-induced micellar disassembly. Cellular uptake of rhodamine-labelled micelles by B16F10 or 14C cells demonstrated that micelles were only taken up to a very low extent (0.1 %). The stability of polymeric micelles was drastically enhanced by covalently crosslinking the micellar cores while retaining their biodegradability. After intravenous administration in mice, these stabilised micelles demonstrated a 6-fold higher tumour accumulation than non crosslinked particles. Moreover, the liver and spleen uptake was low, indicating that the small stabilised micelles successfully avoided macrophage uptake and extravasated via the EPR effect. However, administration of paclitaxel-loaded CCL micelles revealed that the drug was rapidly released and/or extracted from the stabilised micelles. Finally, the surface of fluorescently labelled and crosslinked micelles was decorated with thiol-reactive groups. These multifunctional particles can be used for the attachment of various targeting ligands to promote for instance cellular internalisation. In conclusion, the type of biodegradable thermosensitive micelles presented in this thesis can be used not only as a biocompatible and easy-to-load nanosized drug carrier with a high drug-loading capacity, but also embeds a controlled degradation mechanism. Especially the core crosslinked micelles display favourable characteristics in terms of circulation kinetics and tumour accumulation. Together with the potential targetability, these unique characteristics make biodegradable thermosensitive micelles very attractive as targeted drug delivery devices.