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.