Distribution of KAI-9803, a Novel δ-Protein Kinase C Inhibitor, after Intravenous Administration to Rats

KAI-9803 is composed of a selective δ-protein kinase C (δPKC) inhibitor peptide derived from the δV1-1 portion of δPKC (termed “cargo peptide”), conjugated reversibly to the cell-penetrating peptide 11-amino acid, arginine-rich sequence of the HIV type 1 transactivator protein (TAT47–57; termed “carrier peptide”) via a disulfide bond. KAI-9803 administration at the end of ischemia has been found to reduce cardiac damage caused by ischemia-reperfusion in a rat model of acute myocardial infarction. In the study presented here, we examined the TAT47–57-mediated distribution of KAI-9803 in rats after a single intravenous bolus administration (1 mg/kg). 14C-KAI-9803 was rapidly delivered to many tissues, including the heart (1.21 μg eq/g tissue), while being quickly cleared from the systemic circulation. The microautoradiography analysis showed that 14C-KAI-9803 was effectively delivered into various cells, including cardiac myocytes and cardiac endothelial cells within 1 min after dosing. The tissue distribution of 125I-labeled KAI-9803 was compared to that of 125I-labeled cargo peptide; this comparison demonstrated that the distribution of KAI-9803 to tissues such as the liver, kidney, and heart was facilitated by the reversible conjugation to TAT47–57. In an in vitro cardiomyocyte study, the extent of 125I-KAI-9803 internalization was greater at 37°C than that at 4°C, whereas the internalization of the 125I-cargo peptide at 37°C was not observed, indicating that the uptake of 125I-KAI-9803 into the cardiomyocytes was mediated by the TAT47–57 carrier. Our studies demonstrated that after a single intravenous administration, KAI-9803 can be delivered into the target cells in the liver, kidney, and heart by a TAT47–57-mediated mechanism.