High-loading nanosized micelles of copoly(styrene–maleic acid)–zinc protoporphyrin for targeted delivery of a potent heme oxygenase inhibitor

Amphiphilic styrene–maleic acid (SMA) copolymer efficiently formed micelles with a potent heme oxygenase inhibitor–zinc protoporphyrin (ZnPP). The micelles were constructed by subtle pH adjustments to form non-covalent interaction between the hydrophobic ZnPP and amphiphilic SMA. The micelles (SMA–ZnPP) thus formed were nanoparticles with narrow size distribution in water (mean diameter 176.5 nm), having tunable loading (from 15% to 60% w/w of ZnPP) with remarkable aqueous solubility. SMA–ZnPP had an average molecular size of 144 kDa as determined by size-exclusion chromatography (SEC), this size is a marked increase from the molecular weight of free ZnPP (626.03 Da), suggesting the formation of micellar structure. The micelles showed a constant ZnPP release rate of about 0.5%/day in vitro at neutral pH. SMA–ZnPP micelles inhibited splenic microsomal HO-1 activity, in a competitive and dose-dependent manner, with an apparent inhibitory constant (Ki) of 0.12 μm, comparable to free ZnPP and also exhibited marked cytotoxic effect on KYSE-510 human esophageal cancer cells. The unique features of SMA–ZnPP micelles are that they are nanoparticles in aqueous solution having high water solubility and loading, yet macromolecular in nature, which can be beneficial in targeted release of a potent HO-1 inhibitor.