Currently one of the greatest obstacles facing effective anticancer molecular therapies is efficient drug delivery. Advanced methods such as carriers, liposomes, ultrasound, and viruses have generated modest results with unresolved technical, economical, and regulatory problems. Conventional therapies such as radiation and chemotherapy carry a host of undesirable side effects. Electroporation therapy (EPT) is a promising new modality of drug delivery that exploits the physical process of inducing transient permeability in biological membranes in vivo by short pulses of electric fields. The EPT procedure involves injecting a low dose of drug into cancerous tissue followed by inserting a small needle array that delivers a series of short electrical pulses to induce cellular uptake. In clinical studies EPT has been effective in the treatment of subcutaneous solid tumors of the head and neck, as well as other types of solid tumors when applied with the cytotoxin bleomycin. The utility of EPT has not yet been demonstrated as an adjunct to surgical resection as a potential treatment of wound margins with the aim of reducing tumor recurrence rates. To determine the compatibility of bleomycin-EPT with healing of the surgical wound we studied myocutaneous wound healing in a healthy (noncancerous) porcine model. A series of longitudinal incisions were made along the dorsum of pigs to a depth of 5 mm into the muscle. The margins of each incision were either injected with bleomycin, vehicle (saline), or nothing and two groups received bleomycin or saline, respectively, followed by electroporation (EP). One group received transverse incisions, which were treated with bleomycin-EPT. Wounds were allowed to heal for 2, 7, 14, or 21 days prior to sacrifice and specimens of the incision sites, including skin and muscle, were excised for histological examination. Separate full-thickness skin specimens from across the incision sites were excised and tested for mechanical strength. EP alone showed no significant effect on the mechanical strength of healing porcine skin at any time point. Bleomycin, regardless of use of EP, inhibited the early (< 7 days) development of wound strength; this was most likely due to interference in chemotaxis and/or proliferation of cells involved in early wound healing. However, after 14 days, breaking strength was comparable to saline injected controls. Wound strength after treatment with bleomycin-EPT was higher for longitudinal incisions than for transverse incisions. Histological data documenting the healing process for skin and muscle during the 3 weeks following incision and treatment will be presented.

The effectiveness of potentially powerful therapeutics, including DNA, is often limited by their inability to permeate the cell membrane efficiently. Electroporation (EP) also referred to as `electropermeabilization' of the outer cell membrane renders this barrier temporarily permeable by inducing `pores' across the lipid bilayer. For in vivo EP, the drug or DNA is delivered into the interstitial space of the target tissue by conventional means, followed by local EP. EP pulses of micro- to millisecond duration and field strengths of 100–1500 V cm−1 generally enhance the delivery of certain chemotherapeutic drugs by three to four orders of magnitude and intracellular delivery of DNA several hundred-fold. We have used EP in clinical studies for human cancer therapy and in animals for gene therapy and DNA vaccination. Late stage squamous cell carcinomas of the head and neck were treated with intratumoural injection of bleomycin and subsequent EP. Of the 69 tumours treated, 25% disappeared completely and another 32% were reduced in volume by more than half. Residence time of bleomycin in electroporated tumours was significantly greater than in non-electroporated lesions. Histological findings and gene expression patterns after bleomycin-EP treatment indicated rapid apoptosis of the majority of tumour cells. In animals, we demonstrated the usefulness of EP for enhanced DNA delivery by achieving normalization of blood clotting times in haemophilic dogs, and by substantially increasing transgene expression in smooth muscle cells of arterial walls using a novel porous balloon EP catheter. Finally, we have found in animal experiments that the immune response to DNA vaccines can be dramatically enhanced and accelerated by EP and co-injection of micron-sized particles. We conclude that EP represents an effective, economical and safe approach to enhance the intracellular delivery, and thus potency, of important drugs and genes for therapeutic purposes. The safety and pharmaco-economic profile of EP compares favourably with other drug and DNA delivery methods.

Current methods of local drug delivery frequently fail to achieve a prolonged therapeutically effective tissue drug level without producing vascular trauma. A novel double-balloon catheter system, incorporating electroporation technology, has been designed and tested to deliver heparin into rabbit carotid arteries in an overstretch balloon injury model in vivo. Following arterial injury, fluoresceinated heparin was delivered into the volume between the two inflated balloons, and the artery was subjected to an electrical pulse. Catheter deployment and endovascular electrical pulsing were well-tolerated in all animals (N = 21) without adverse hemodynamic and histological changes. Periodic arterial blood samples revealed no abnormalities in the clotting profile or any gross morphological changes in the blood cells up to 8 hr after treatment. Much stronger heparin fluorescence was detected throughout the vessel layers for at least 12 hr in the pulsed samples compared to the control. Histochemical staining of the tissue showed intracellular localization of heparin. Endovascular electroporation may provide better retention and higher therapeutic efficacy than can be achieved by conventional systemic delivery of heparin at clinically safe concentrations.