Specific binding to intracellular proteins determines arterial transport properties for rapamycin and paclitaxel

Abstract

Endovascular drug-eluting stents have changed the practice of medicine, and yet it is unclear how they so dramatically reduce restenosis and how to distinguish between the different formulations available. Biological drug potency is not the sole determinant of biological effect. Physicochemical drug properties also play important roles. Historically, two classes of therapeutic compounds emerged: hydrophobic drugs, which are retained within tissue and have dramatic effects, and hydrophilic drugs, which are rapidly cleared and ineffective. Researchers are now questioning whether individual properties of different drugs beyond lipid avidity can further distinguish arterial transport and distribution. In bovine internal carotid segments, tissue-loading profiles for hydrophobic paclitaxel and rapamycin are indistinguishable, reaching load steady state after 2 days. Hydrophilic dextran reaches equilibrium in several hours at levels no higher than surrounding solution concentrations. Both paclitaxel and rapamycin bind to the artery at 30 -40 times bulk concentration. Competitive binding assays confirm binding to specific tissue elements. Most importantly, transmural drug distribution profiles are markedly different for the two compounds, reflecting, perhaps, different modes of binding. Rapamycin, which binds specifically to FKBP12 binding protein, distributes evenly through the artery, whereas paclitaxel, which binds specifically to microtubules, remains primarily in the subintimal space. The data demonstrate that binding of rapamycin and paclitaxel to specific intracellular proteins plays an essential role in determining arterial transport and distribution and in distinguishing one compound from another. These results offer further insight into the mechanism of local drug delivery and the specific use of existing drug-eluting stent formulations.

Downstream coronary effects of drug-eluting stents

“…The current theory of abluminal diffusion directly into the endothelium has taken root as a de facto mechanism of stentbased drug delivery after a variety of animal studies demonstrating high local intravascular concentrations. 36 This mechanism surely contributes to the prevention of restenosis. However, recent literature has described the mathematical relationships of drug delivery into the Kaplan-Meier analysis of new lesion development in control and target vessels for both the entire (A) and the propensity-matched (B) cohorts.…”

Acoustic Cluster Therapy (ACT) enhances the therapeutic efficacy of paclitaxel and Abraxane® for treatment of human prostate adenocarcinoma in mice

“…However, solid tumors show an increased interstitial fluid pressure (IFP), which forms a barrier to transcapillary transport [1,37] and represents a significant obstacle in tumor treatment. Modification of the tumor interstitium might influence the IFP and facilitate the penetration of drugs into tumors [38][39][40][41].…”

Towards a Complex Automata Multiscale Model of In-Stent Restenosis

“…To solve the diffusion equation numerically we use a Finite Differences (FD) approach, solved by a Propagation-Collision loop, which complies with the CxA modeling language. According to [16], the time scale to reach the steady state is of the order of minutes. Therefore, when coupling DD and SMC, we are largely interested in the steady drug concentration (the time step for the SMC model, which uses as input the drug concentration, is of the order of 1 hour).…”

“…The diffusion tensor is chosen such that the diffusion along the artery axis or tangentially to a cross section is at least 10 times higher than the diffusion in the radial direction [15,16]. To solve the diffusion equation numerically we use a Finite Differences (FD) approach, solved by a Propagation-Collision loop, which complies with the CxA modeling language.…”