Pharmacokinetics and atherosclerotic lesions targeting effects of tanshinone IIA discoidal and spherical biomimetic high density lipoproteins.
High density lipoproteins (HDL) have been successfully reconstructed to deliver a large number of lipophilic drugs. Here, discoidal and spherical recombinant HDL loaded with cardiovascular drug tanshinone IIA (TA) were constructed (TA-d-rHDL and TA-s-rHDL), respectively. And next their in vitro physiochemical and biomimetic properties were characterized. Furthermore, pharmacokinetics, atherosclerotic lesions targeting effects and antiatherogenic efficacies were elaborately performed and compared in atherosclerotic New Zealand White (NZW) rabbits. In vitro characterizations results showed that both TA-d-rHDL and TA-s-rHDL had nano-size diameter, high entrapment efficiency (EE) and drug-loading capacity (DL). Additionally, similar to their native counterparts, TA-d-rHDL maintained remodeling behaviors induced by lecithin cholesterol acyltransferase (LCAT), and TA leaked during remodeling behaviors. Pharmacokinetic studies manifested that both TA-d-rHDL and TA-s-rHDL markedly improved pharmacokinetic behaviors of TA in vivo. Ex vivo imaging demonstrated that both d-rHDL and s-rHDL bound more avidly to atherosclerotic lesions than to normal vessel walls, and s-rHDL had better targeting effect than d-rHDL. Pharmacodynamic tests illustrated that both TA-d-rHDL and TA-s-rHDL had much stronger antiatherogenic efficacies than conventional TA nanostructured lipid carriers (TA-NLC), TA liposomes (TA-L) and commercially available preparation Sulfotanshinone Sodium Injection (SSI). Moreover, TA-s-rHDL had more potent antiatherogenic efficacies than TA-d-rHDL. Collectively our studies indicated that rHDL could be exploited as potential delivery vehicles of TA targeting atherosclerotic lesions as well as synergistically improving efficacies, especially for s-rHDL.
Department of Pharmaceutics, China Pharmaceutical University, Nanjing 210009, PR China.
Wenli
W
Zhang
Hongliang
H
He
Jianping
J
Liu
Ji
J
Wang
Suyang
S
Zhang
Shuangshuang
S
Zhang
Zimei
Z
Wu
D045784:Abietanes / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D050197:Atherosclerosis / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D001391:Azo Compounds / Q000378:metabolism; D040761:Biomimetic Materials / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D059168:Carotid Intima-Media Thickness; D002784:Cholesterol / Q000378:metabolism; D003094:Collagen / Q000378:metabolism; D004195:Disease Models, Animal; D008074:Lipoproteins / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D008075:Lipoproteins, HDL / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use* / Q000648:ultrastructure; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D007862:Phosphatidylcholine-Sterol O-Acyltransferase / Q000378:metabolism; D011817:Rabbits; D011994:Recombinant Proteins / Q000494:pharmacology / Q000627:therapeutic use; D055672:Static Electricity; D051996:Transcription Factor RelA / Q000378:metabolism
D045784:Abietanes; D001391:Azo Compounds; D008074:Lipoproteins; D008075:Lipoproteins, HDL; D011994:Recombinant Proteins; D051996:Transcription Factor RelA; C034366:discoidal lipoproteins; C021751:tanshinone; D003094:Collagen; D002784:Cholesterol; D007862:Phosphatidylcholine-Sterol O-Acyltransferase; C011049:oil red O