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 176.5nm), having tunable loading (from 15% to 60% w/w of ZnPP) with remarkable aqueous solubility. SMA-ZnPP had an average molecular size of 144kDa as determined by size-exclusion chromatography (SEC), this size is a marked increase from the molecular weight of free ZnPP (626.03Da), 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 (K-i) of 0.12 mu m, 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. (c) 2006 Elsevier Ltd. All rights reserved.