Poly(polyethylene glycol methyl ether methacrylate-co-methacrylic acid)-block-poly(methyl methacrylate) P(PEGMEMA-co-MAA)-b-PMMA block copolymer were prepared via RAFT (reversible addition-fragmentation chain transfer) polymerization and subsequently self-assembled into micelles as a drug delivery carrier for albendazole (ABZ). For comparison, the micelles were additionally cross-linked to study the effect of shell-cross-linking on the biological activity. The hydrodynamic diameter of cross-linked and un-cross-linked micelles was approximately 40 nm in both cases. While the cross-linked micelle was stable even in good solvents for both blocks, the un-cross-linked micelle was found to lose its integrity in cell growth media. Crosslinking had a major effect on the rate of drug release reducing it dramatically from 50% (uncrosslinked) to around 20% (crosslinked) over a 30 h incubation period. Both drug delivery systems were tested on human prostate cancer cells (PC-3, DU-145) and human ovarian cancer cells (OVCAR-3, A-2780). No toxic effects were measured with the unloaded micelle while the ABZ loaded un-cross-linked micelle lead to IC(50) values between 0.2 and 0.9 μM depending on the cell line. The IC(50) dropped to values between 0.006 and 0.06 μM, depending on cell line, once the micelles were stabilized by cross-linking. Three treatment cycles with ABZ for one day, followed by two days incubation in media using ABZ-loaded drug carriers led to complete cell death even at low concentrations in the case of the cross-linked micelle only. Cellular uptake has been studied using fluorescently labeled micelles and Nile red as model drug, showing cell uptake above the CMC but no micelle uptake below the CMC. Additional biological studies, such as colony formation assay and tubulin disorganization tests, were also performed to gain more insight into the effect of cross-linking of the shell of the micelle. In conclusion, shell-cross-linking is highly recommended, even for glassy micelles, for an efficient cellular uptake at low concentrations.

Block copolymers were prepared via RAFT polymerization with P(PEGMEMA) as the hydrophilic block to form micelles for the controlled delivery of ABZ. The group contribution method was used to estimate the partial solubility parameters for ABZ and various polymers as potential core-forming block to achieve optimum compatibility. Different ratios between MMA and LMA, a non-compatible monomer, were prepared. Cytotoxicity tests revealed a high toxicity of the ABZ-loaded micelle resulting in 80% cell deaths at a micelle concentration of 10 µg · mL(-1) . Cellular uptake of micelles has been studied using fluorescently labeled micelles, showing that a large fraction of micelles is readily taken up by OVCAR-3 cells. RGD-conjugated micelles were prepared and showed an increased cellular uptake.