Cell-Specific Expression of Uptake Transporters—A Potential Approach for Cardiovascular Drug Delivery Devices

Abstract

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.

Secreted Matrix Metalloproteinase-9 of Proliferating Smooth Muscle Cells as a Trigger for Drug Release from Stent Surface Polymers in Coronary Arteries

“…In this regard, we recently reported a proof-of-concept study, showing that adenoviral driven overexpression of an uptake transporter changes pharmacokinetics in the microcompartment of the vascular wall, thereby enhancing pharmacological efficacy of substrate drugs in SMCs. 17 A third option would be a release of cytotoxic compounds triggered by proliferation of SMCs. This concept is inspired by the so-called prodrug concept 18 with bioactivation in close vicinity of the targeted organ or cell.…”

“…Second, cellular differences in pharmacokinetics could be used to enhance accumulation in SMCs, thereby increasing the specificity of a drug with an intracellular drug target. In this regard, we recently reported a proof-of-concept study, showing that adenoviral driven overexpression of an uptake transporter changes pharmacokinetics in the microcompartment of the vascular wall, thereby enhancing pharmacological efficacy of substrate drugs in SMCs . A third option would be a release of cytotoxic compounds triggered by proliferation of SMCs.…”

Mechanisms of Sorafenib Resistance in HCC Culture Relate to the Impaired Membrane Expression of Organic Cation Transporter 1 (OCT1)

“…Recombinant adenovirus with cytomegalovirus (CMV) promoter-driven expression of OCT1 and LacZ was obtained from Henriette E. Meyer Zu Schwabe Dissen, Basel, Switzerland. 30 The recombinant adenovirus was propagated in HEK293A cells and the virus titer was determined using a standard protocol.…”

“…The expression of OCT1 and OCT3 was performed using paraffin fixed tissue section of HCC cases available from a previous study in the Department of Pathology. 30 This does not involve any patient contact therefore ethical clearance is not required. Five-micron tissue sections were prepared from paraffin-embedded HCC tissues.…”

The Transporter-Mediated Cellular Uptake and Efflux of Pharmaceutical Drugs and Biotechnology Products: How and Why Phospholipid Bilayer Transport Is Negligible in Real Biomembranes

“…Given the need for transporters if drugs are to cross cell membranes, one can make a virtue of necessity [ 284 ] by seeking either to exploit their natural expression profiles [ 291 , 292 , 293 ] or to vary them explicitly [ 294 ], so as to target them to particular tissues [ 295 ]. The latter has obvious benefits in oncology [ 296 , 297 , 298 , 299 , 300 ], where the necessary cytotoxicity of many drugs, such as nucleoside analogues, is rather non-specific.…”