Cell-specific expression of uptake transporters--a potential approach for cardiovascular drug delivery devices.
Enhanced proliferation of human coronary artery smooth muscle cells (HCASMCs) and thereby formation of neointima is one of the factors contributing to failure of coronary stents. Even if the use of drug eluting stents (DES) and thereby the local delivery of cytotoxic compounds has significantly improved the clinical outcome, unselective cytotoxic effects are assumed to hamper clinical success. Novel pharmacological approaches are required to enhance cellular selectivity of locally delivered drugs. Cell specific overexpression of a drug transporter could be used to enhance cellular accumulation and therefore cell specificity. In the herein reported study we tested the possibility of cell specific transporter expression to enhance drug effects in HCASMCs. We generated adenoviral constructs to overexpress the organic cation transporter 1 (OCT1) under control of the promoter of SM22α, which had been previously reported as muscle cell specific gene. First the activity of the SM22α-promoter was assessed in various cell types supporting the notion of muscle cell specificity. Subsequently, the activity of the transporter was compared in infected HCAECs and HCASMCs revealing enhanced accumulation of substrate drugs in HCASMCs in presence of the SM22α-promoter. Testing the hypothesis that this kind of targeting might serve as a mechanism for cell-specific drug effects, we investigated the impact on paclitaxel treatment in HCASMC and HCAECs, showing significantly increased antiproliferative activity of this substrate drug on muscle cells. Taken together, our findings suggest that cell-specific expression of transport proteins serves as mechanism governing the uptake of cytotoxic compounds for a selective impact on targeted cells.
['Meyer Zu Schwabedissen|Henriette E|HE|', 'Begunk|Robert|R|', 'Hussner|Janine|J|', 'Juhnke|B Ole|BO|', 'Gliesche|Daniel|D|', 'Böttcher|Kerstin|K|', 'Sternberg|Katrin|K|', 'Schmitz|Klaus-Peter|KP|', 'Kroemer|Heyo K|HK|']
D000256:Adenoviridae D000818:Animals D000972:Antineoplastic Agents, Phytogenic D015153:Blotting, Western D002317:Cardiovascular Agents D049109:Cell Proliferation D002478:Cells, Cultured D003331:Coronary Vessels D004285:Dogs D016503:Drug Delivery Systems D004730:Endothelium, Vascular D049452:Green Fluorescent Proteins D006801:Humans D061985:Madin Darby Canine Kidney Cells D051379:Mice D008840:Microfilament Proteins D009124:Muscle Proteins D009131:Muscle, Smooth, Vascular D032383:Myocytes, Cardiac D027702:Organic Cation Transporter 1 D017239:Paclitaxel D011401:Promoter Regions, Genetic D012333:RNA, Messenger D060888:Real-Time Polymerase Chain Reaction D020133:Reverse Transcriptase Polymerase Chain Reaction
drug delivery paclitaxel SM22 organic cation transporter1 (OCT1) pharmacokinetics vascular smooth muscle cells