PEGylation for drug delivery to ischemic myocardium: pharmacokinetics and cardiac distribution of poly(ethylene glycol)s in mice with normal and ischemic myocardium.

PEGylation now plays an important role in drug delivery and is considered as the method of choice for improving the pharmacokinetics and stability of parenteral agents. However, its application in treating cardiac diseases is still limited. To guide the design of PEGylation for drug delivery to ischemic myocardium, the effects of the molecular weight of PEG and the myocardial ischemic conditions on PEG levels in plasma and myocardium were studied in this work following intravenous administration of fluorescein isothiocyanate-labeled 20- and 40-kDa mPEGs to mice with normal and ischemic myocardium. The results show that myocardial ischemia caused some consistent changes in pharmacokinetic parameters of mPEGs. Due to the enhanced permeability and retention (EPR) effect caused by ischemia, the distribution of 20- and 40-kDa mPEGs in ischemic hearts was approximately 1.47- and 1.92-fold higher than that in normal hearts, respectively. Under the same heart condition (either normal or ischemic), the cardiac AUC(0.5-24h)s of the two mPEGs were comparable, although their plasma AUCs differed by nearly 4-fold; however, a smoother cardiac level-time profile was achieved by 40-kDa mPEG. This study addressed the relative importance of the EPR effect of ischemic zones and the molecular size of PEG in cardiac drug delivery, which is believed to be helpful for macromolecular drug design.