Influence of molar mass, dispersity, and type and location of hydrophobic side chain moieties on the critical micellar concentration and stability of amphiphilic HPMA-based polymer drug carriers

In the present paper, we address the question to which extent the critical micellar concentration (cmc) value can be varied for clinically related drug delivery carriers if all crucial parameters needed for successful drug delivery are already preset. For this purpose, the cmc values of an amphiphilic polymer carrier based on N-(2-hydroxypropyl) methacrylamide (HPMA) with cholesterol side groups, differing in a variety of parameters, such as molar mass, dispersity, architecture (statistical vs. diblock copolymer), and spacer structure, were studied in detail. At this, we chose physiological conditions (phosphate buffered saline at pH 7.4) and investigated the formation of micelles using fluorescence correlation spectroscopy in dependence on polymer concentration. Moreover, conjugates where the cholesterol moieties are attached to the HPMA backbone by a pH-cleavable hydrazone bond were investigated in dependence on time with respect to their long-term stability at pH 7.4, and it was found that the nanoparticles change size in the course of a few weeks. After a pH change from 7.4 to 5.0 (typical for tumor cells), the nanoparticles grow during the first few hours, then shrink. A weak correlation between the cmc value and the content of the hydrophobic group was found for HPMA-based polymers, regardless their architecture, polydispersity, and spacer structure. A much stronger correlation was observed between the cmc value and the dispersity. This finding could be explained by the higher absolute number of hydrophobic groups located on the higher molar mass fractions of the HPMA copolymers, which initiate the micelle formation.