Abstract
Vascular endothelium selectively controls the transport of plasma contents across the blood vessel wall. The principal objective of our preliminary study was to quantify the electroporation-induced increase in permeability of blood vessel wall for macromolecules, which do not normally extravasate from blood into skin interstitium in homeostatic conditions. Our study combines mathematical modeling (by employing pharmacokinetic and finite element modeling approach) with in vivo measurements (by intravital fluorescence microscopy). Extravasation of fluorescently labeled dextran molecules of two different sizes (70 kDa and 2000 kDa) following the application of electroporation pulses was investigated in order to simulate extravasation of therapeutic macromolecules with molecular weights comparable to molecular weight of particles such as antibodies and plasmid DNA. The increase in blood vessel permeability due to electroporation and corresponding transvascular transport was quantified by calculating the apparent diffusion coefficients for skin microvessel wall (D [μm2/s]) for both molecular sizes. The calculated apparent diffusion coefficients were D = 0.0086 μm2/s and D = 0.0045 μm2/s for 70 kDa and 2000 kDa dextran molecules, respectively. The results of our preliminary study have important implications in development of realistic mathematical models for prediction of extravasation and delivery of large therapeutic molecules to target tissues by means of electroporation.
Highlights
Electroporation (EP) is a physical method used for controlled increase of cell membrane permeability for large extracellular molecules which otherwise cannot enter the cytosol in homeostatic conditions [1,2]
The image acquired 20s before the delivery of EP pulses shows that the fluorescent dextrans (FD) molecules within non-electroporated skin remain mainly confined to the intravascular compartment while the image acquired 40 min after the delivery of EP pulses shows that the FD molecules within the electroporated skin extravasate into the extravascular compartment
In vivo extravasation of two different sizes of FDs (70 kDa and 2000 kDa) was investigated for an electroporation protocol used in clinical electrochemotherapy and clinical electrogene therapy of skin tumors: 8 square-wave electric pulses, voltage-to-distance ratio of
Summary
Electroporation (EP) is a physical method used for controlled increase of cell membrane permeability for large extracellular molecules which otherwise cannot enter the cytosol in homeostatic conditions [1,2]. Numerous clinical and preclinical studies demonstrated efficacy of electrochemotherapy for treatment of tumors of different histologies with both local and systemic administration of anticancer drugs [7,8,9,10]. Recent clinical trials of gene therapy using electroporation for gene electrotransfer demonstrated encouraging results for therapeutic DNA delivery to different types of tissues, including skin, muscle, liver and tumor [11,12,13]. Clinical trials of electroporation-based DNA vaccination have shown promising results for DNA delivery in different tissues [14,15]. For effective DNA vaccine delivery skin and muscle have been proposed as tissues of choice [16]
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