Limits...
Electrochemotherapy of tumors as in situ vaccination boosted by immunogene electrotransfer.

Sersa G, Teissie J, Cemazar M, Signori E, Kamensek U, Marshall G, Miklavcic D - Cancer Immunol. Immunother. (2015)

Bottom Line: The therapeutic effectiveness of delivered chemotherapeutics or nucleic acids depends greatly on their successful and efficient delivery to the target tissue.In an attempt to increase systemic antitumor effectiveness of electrochemotherapy, electrotransfer of genes with immunomodulatory effect (immunogene electrotransfer) could be used as adjuvant treatment.Since electrochemotherapy can induce immunogenic cell death, adjuvant immunogene electrotransfer to peritumoral tissue could lead to locoregional effect as well as the abscopal effect on distant untreated metastases.

View Article: PubMed Central - PubMed

Affiliation: Department of Experimental Oncology, Institute of Oncology Ljubljana, Zaloska 2, 1000, Ljubljana, Slovenia, gsersa@onko-i.si.

ABSTRACT
Electroporation is a platform technology for drug and gene delivery. When applied to cell in vitro or tissues in vivo, it leads to an increase in membrane permeability for molecules which otherwise cannot enter the cell (e.g., siRNA, plasmid DNA, and some chemotherapeutic drugs). The therapeutic effectiveness of delivered chemotherapeutics or nucleic acids depends greatly on their successful and efficient delivery to the target tissue. Therefore, the understanding of different principles of drug and gene delivery is necessary and needs to be taken into account according to the specificity of their delivery to tumors and/or normal tissues. Based on the current knowledge, electrochemotherapy (a combination of drug and electric pulses) is used for tumor treatment and has shown great potential. Its local effectiveness is up to 80 % of local tumor control, however, without noticeable effect on metastases. In an attempt to increase systemic antitumor effectiveness of electrochemotherapy, electrotransfer of genes with immunomodulatory effect (immunogene electrotransfer) could be used as adjuvant treatment. Since electrochemotherapy can induce immunogenic cell death, adjuvant immunogene electrotransfer to peritumoral tissue could lead to locoregional effect as well as the abscopal effect on distant untreated metastases. Therefore, we propose a combination of electrochemotherapy with peritumoral IL-12 electrotransfer, as a proof of principle, using electrochemotherapy boosted with immunogene electrotransfer as in situ vaccination for successful tumor treatment.

Show MeSH

Related in: MedlinePlus

Electric field distribution in and around the tumor tissue during the application of electric pulses for plate (left) and hexagonal needle electrodes—cross section through the mid-plane of the electrodes (right). The electric field distribution is indicated with the rainbow color scale
© Copyright Policy - OpenAccess
Related In: Results  -  Collection


getmorefigures.php?uid=PMC4554735&req=5

Fig2: Electric field distribution in and around the tumor tissue during the application of electric pulses for plate (left) and hexagonal needle electrodes—cross section through the mid-plane of the electrodes (right). The electric field distribution is indicated with the rainbow color scale

Mentions: The behavior of cells when exposed to electric fields (pulses) cannot be translated directly from cells in vitro to tissues in vivo. Cells in tissue are embedded in a matrix, they are of several types in a certain organ (heterogeneous population), and they form electrical connections between themselves mediated by cell-to-cell junctions [41]. So the values of critical electric field at which cell membrane becomes permeabilized cannot be determined in vitro and then used in in vivo experiments. Furthermore, different tissue properties such as perfusion (better perfusion is usually associated with higher electric conductivity), cell density and cell volume fraction, preferential orientation like in muscle, all affect the electric conductivity of the tissue. Skin has a considerably lower conductivity than any other tissue; muscle conductivity along muscle fibers is higher than in perpendicular direction and tumor tissues generally have higher conductivity than tissue in which they are embedded—even in the liver, which is highly conductive tissue [42]. As a consequence, when we deliver electric pulses using electrodes (either penetrating needles type or nonpenetrating, e.g., surface plate electrodes or pins), the electric current distributes according to the electrode and tissue geometry and tissue conductivity; current and electric field are dual and are connected in place and time through Ohm’s law (Fig. 2). In principle at the same current, higher conductivity will result in lower electric field and vice versa. This means that if electric pulses are applied across the skin, the highest electric field will be in the skin [43]. As electroporation of cell membrane is a consequence of induced transmembrane voltage on the cell membrane [15], cells in high electric field will get permeabilized first. Once they are permeabilized, the conductivity changes and electric field distribution changes as well [44].Fig. 2


Electrochemotherapy of tumors as in situ vaccination boosted by immunogene electrotransfer.

Sersa G, Teissie J, Cemazar M, Signori E, Kamensek U, Marshall G, Miklavcic D - Cancer Immunol. Immunother. (2015)

Electric field distribution in and around the tumor tissue during the application of electric pulses for plate (left) and hexagonal needle electrodes—cross section through the mid-plane of the electrodes (right). The electric field distribution is indicated with the rainbow color scale
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4554735&req=5

Fig2: Electric field distribution in and around the tumor tissue during the application of electric pulses for plate (left) and hexagonal needle electrodes—cross section through the mid-plane of the electrodes (right). The electric field distribution is indicated with the rainbow color scale
Mentions: The behavior of cells when exposed to electric fields (pulses) cannot be translated directly from cells in vitro to tissues in vivo. Cells in tissue are embedded in a matrix, they are of several types in a certain organ (heterogeneous population), and they form electrical connections between themselves mediated by cell-to-cell junctions [41]. So the values of critical electric field at which cell membrane becomes permeabilized cannot be determined in vitro and then used in in vivo experiments. Furthermore, different tissue properties such as perfusion (better perfusion is usually associated with higher electric conductivity), cell density and cell volume fraction, preferential orientation like in muscle, all affect the electric conductivity of the tissue. Skin has a considerably lower conductivity than any other tissue; muscle conductivity along muscle fibers is higher than in perpendicular direction and tumor tissues generally have higher conductivity than tissue in which they are embedded—even in the liver, which is highly conductive tissue [42]. As a consequence, when we deliver electric pulses using electrodes (either penetrating needles type or nonpenetrating, e.g., surface plate electrodes or pins), the electric current distributes according to the electrode and tissue geometry and tissue conductivity; current and electric field are dual and are connected in place and time through Ohm’s law (Fig. 2). In principle at the same current, higher conductivity will result in lower electric field and vice versa. This means that if electric pulses are applied across the skin, the highest electric field will be in the skin [43]. As electroporation of cell membrane is a consequence of induced transmembrane voltage on the cell membrane [15], cells in high electric field will get permeabilized first. Once they are permeabilized, the conductivity changes and electric field distribution changes as well [44].Fig. 2

Bottom Line: The therapeutic effectiveness of delivered chemotherapeutics or nucleic acids depends greatly on their successful and efficient delivery to the target tissue.In an attempt to increase systemic antitumor effectiveness of electrochemotherapy, electrotransfer of genes with immunomodulatory effect (immunogene electrotransfer) could be used as adjuvant treatment.Since electrochemotherapy can induce immunogenic cell death, adjuvant immunogene electrotransfer to peritumoral tissue could lead to locoregional effect as well as the abscopal effect on distant untreated metastases.

View Article: PubMed Central - PubMed

Affiliation: Department of Experimental Oncology, Institute of Oncology Ljubljana, Zaloska 2, 1000, Ljubljana, Slovenia, gsersa@onko-i.si.

ABSTRACT
Electroporation is a platform technology for drug and gene delivery. When applied to cell in vitro or tissues in vivo, it leads to an increase in membrane permeability for molecules which otherwise cannot enter the cell (e.g., siRNA, plasmid DNA, and some chemotherapeutic drugs). The therapeutic effectiveness of delivered chemotherapeutics or nucleic acids depends greatly on their successful and efficient delivery to the target tissue. Therefore, the understanding of different principles of drug and gene delivery is necessary and needs to be taken into account according to the specificity of their delivery to tumors and/or normal tissues. Based on the current knowledge, electrochemotherapy (a combination of drug and electric pulses) is used for tumor treatment and has shown great potential. Its local effectiveness is up to 80 % of local tumor control, however, without noticeable effect on metastases. In an attempt to increase systemic antitumor effectiveness of electrochemotherapy, electrotransfer of genes with immunomodulatory effect (immunogene electrotransfer) could be used as adjuvant treatment. Since electrochemotherapy can induce immunogenic cell death, adjuvant immunogene electrotransfer to peritumoral tissue could lead to locoregional effect as well as the abscopal effect on distant untreated metastases. Therefore, we propose a combination of electrochemotherapy with peritumoral IL-12 electrotransfer, as a proof of principle, using electrochemotherapy boosted with immunogene electrotransfer as in situ vaccination for successful tumor treatment.

Show MeSH
Related in: MedlinePlus