Tanshinone IIA-loaded reconstituted high density lipoproteins: Atherosclerotic plaque targeting mechanism in a foam cell model and pharmacokinetics in rabbits.

Spherical and discoidal tanshinone IIA-loaded reconstituted high density lipoproteins (TA-rHDL) with different formulations and techniques were prepared and characterized. The targeting mechanism was investigated using a foam cell model. Pharmacokinetics of four TA-rHDL formulations with or without apolipoproteins (apos) after a single dose intravenous injection to rabbits has been studied. The results showed that the sizes of spherical and discoidal TA-rHDL increased after coupling with apos from 55.38 nm to 157.26 nm, 61.03 nm to 166.19 nm, and zeta potential decreased from -29.2 mV to -35.4 mV, -5.2 mV to -11.82 mV, respectively. The results of circular dichroic spectroscopy indicated variations of apos in protein secondary structure after binding with lipids. Phagocytosis tests demonstrated that the spherical TA-rHDL had a targeting effect for foam cells through the scavenger receptor-BI and CE-TG interchange with TG-rich lipoproteins pathway under cholesteryl ester transfer protein. Discoidal TA-rHDL could reconstruct to spheres and target via a similar route as TA-rHDL spheres, showing a higher targeting efficiency. In vivo experiments showed that areas under the plasma level-time curve (AUC) of TA increased as a function of spherical and discoidal rHDL, which were 4 and 13 times more than that of TA suspensions, respectively. Spherical and discoidal TA-rHDL had long circulating times in blood with mean residence time (MRT) of 15.874 and 18.956h, respectively, compared to 1.802h of TA suspensions, 14.190h of spherical TA-rHDL without apos and 15.071 of discoidal TA-rHDL without apos. The distribution volume of spherical TA-rHDL was 2.143 and 1.552 times as that of discoidal TA-rHDL and TA suspensions, respectively. In conclusion, TA-rHDL may be a long-circulating, healthy and potentially targeted carrier for delivering lipophilic cardiovascular drugs.