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.
Biopharmacy, Department of Pharmaceutical Sciences, Klingelbergstrasse 50, 4056 Basel, Switzerland.
Henriette E
HE
Meyer Zu Schwabedissen
Robert
R
Begunk
Janine
J
Hussner
B Ole
BO
Juhnke
Daniel
D
Gliesche
Kerstin
K
Böttcher
Katrin
K
Sternberg
Klaus-Peter
KP
Schmitz
Heyo K
HK
Kroemer
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D015153:Blotting, Western; D002317:Cardiovascular Agents / Q000494:pharmacology; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D003331:Coronary Vessels / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D004285:Dogs; D016503:Drug Delivery Systems; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D061985:Madin Darby Canine Kidney Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D008840:Microfilament Proteins / Q000235:genetics*; D009124:Muscle Proteins / Q000235:genetics*; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D027702:Organic Cation Transporter 1 / Q000235:genetics / Q000378:metabolism*; D017239:Paclitaxel / Q000494:pharmacology; D011401:Promoter Regions, Genetic / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction
D000972:Antineoplastic Agents, Phytogenic; D002317:Cardiovascular Agents; D008840:Microfilament Proteins; D009124:Muscle Proteins; D027702:Organic Cation Transporter 1; D012333:RNA, Messenger; C485184:enhanced green fluorescent protein; C051615:transgelin; D049452:Green Fluorescent Proteins; D017239:Paclitaxel
SM22; drug delivery; organic cation transporter1 (OCT1); paclitaxel; pharmacokinetics; vascular smooth muscle cells