Hydrolysable core-crosslinked thermosensitive polymeric micelles: synthesis, characterisation and in vivo studies

In this study, core-crosslinked (CCL) biodegradable thermosensitive micelles based on mPEG(5000) and N-(2-hydroxyethyl)methacrylamide)-oligolactates (mPEG-b-p(HEMAm-Lac(n))) were synthesised and their properties investigated. Rapidly heating aqueous solutions of partially methacrylated block copolymers to above their critical micelle temperature (CMT), followed by illumination in presence of a photoinitiator yielded almost monodisperse CCL micelles with a size of 68+/-7 nm. Either below the CMT or after addition of sodium dodecyl sulphate, the non-crosslinked (NCL) micelles rapidly disintegrated whereas the CCL micelles kept their integrity. NCL micelles fell apart after 5h in pH 7.4 at 37 degrees C as a result of the hydrolysis of lactate side chains, whereas the CCL micelles had a much higher stability and only degraded after cleavage of the ester bonds in the crosslinks. The circulation kinetics and biodistribution of CCL micelles were considerably better than those of NCL micelles, i.e., 58% of the injected dose (ID) of CCL versus 6% of NCL micelles was recovered in the circulation 4h post-injection. Furthermore, the liver uptake of the CCL micelles (10% ID) was much lower than that of the NCL micelles (24% ID) 4h after administration, while tumour accumulation was almost 6 times higher for the CCL micelles. Likely, NCL micelles dissociated after i.v. administration and/or were opsonised and captured by macrophages while the dense PEG shell of CCL micelles made them less prone towards opsonisation. The excellent physical stability of these degradable CCL micelles and very favourable biodistribution profile renders them very suitable for drug targeting purposes.