It was found in 1970s that, electric fields can produce some pores on cells without causing permanent damages to the cells. This discovery made it possible for molecules to enter into the cytoplasm. People know that by means of the so-called electroporation, genes and other molecules such as drug compounds, are capable to be introduced into living cells. Genes or drugs as well as living cells are mixed in a buffer medium, and then applied with short pulses of a strong electric field. In this way, cell membranes transiently become porous, and then genes or molecules enter the cells. They can improve the genomes of the cells in there.
Drug compounds and genes are delivered into cells in vivo by electroporation therapy (EPT) utilizing the electric field, the electroporation therapy may also be referred as cell perforation therapy (CPT) or electrochemotherapy (ECT). Using cell perforation therapy for the treatment provides a way to avoid side effects usually accompanying with the use of anticancer drugs or cytotoxic agents. This treatment allows people to introduce these agents to selectively damage or kill the undesired cells, and meanwhile to avoid damaging or killing the surrounding healthy cells or tissues.
A therapeutic application of the electroporation is used in the treatment of cancers. Experiments have been carried out utilizing experimental mammals, and published reports are as follows: Okino, M., E. Kensuke, “The Effects of a Single High Voltage Electrical Stimulation with an Anticancer Drug on in vivo Growing Malignant Tumors”, Jap. Journal of Surgery, vol. 20: 197-204, 1990. Mir, L. M., S. Orlowski, J. Belehradek Jr., and C. Paoletti, “Electrochernotherapy Potentiation of Antitumor Effect of Bleomycin by Local Electric pulses”, Eur. J. Cancer, vol. 27: 68-72, 1991. Mir, L. M., M. Belehradek, C. Domengem, S. Orlowski, B. Poddevin, et al., have conducted clinical trials and published the report “Electrochemotherapy, a novel antitumor treatment: first clinical trial”, C. R. Acad. Sci. Paris., vol 313: 613-618, 1991.
Electroporation in vivo is generally restricted to be applied on the tissues or cells near the skin of a living body, on which parts the electrode can be placed. Therefore, the electrode for electroporation generally cannot approach to tissues such as tumors which can be treated by the systemic drug delivery or chemotherapy. In the treatment of certain types of cancers by chemotherapy, it is needed to use a sufficient dose of drug to kill cancer cells on the premise of not killing too many normal cells. This purpose can be achieved if the chemotherapeutic drugs can be directly injected into the cancer cells. Some anticancer drugs, such as bleomycin, usually cannot effectively penetrate through cell membranes of some types of cancer cells. However, bleomycin can be injected into cells by electroporation.
The treatment method usually is, directly injecting an anticancer drug into the tumor, and then applying an electric field to the tumor between a pair of electrodes. The electric field intensity must be adjusted in appropriate accuracy so as to conduct electroporation on the tumor cells under the premise of not damaging the normal or healthy cells, or at least minimizing damages to the normal or healthy cells. For the tumor of the body surface, a pair of electrodes usually may be applied on two sides of the tumor to generate an electric field between the pair of electrodes, and thereby electroporation can be easily implemented. In the case of that the electric field is a uniform electric field, the distance between the electrodes is firstly measured, and then according to the formula E=V/d (E=electric field intensity in volts/centimeter; V=voltage in volts; d=distance in centimeter), an appropriate voltage is applied to the electrodes. When treating large tumors or tumors inside the body, it is difficult to properly place the electrodes and measure the distance between the electrodes. The above mentioned reports disclose an electrode system for electroporation in vivo, wherein the electrodes can be inserted into the tumor.
This therapeutic method is to directly penetrate an anticancer drug into the tumor, and to apply an electric field to the tumor located between the pair of electrodes. The electric field intensity must be adjusted reasonably and accurately, in order to achieve electroporation on tumor cells, without any damage to normal cells, i.e. healthy cells. This therapy usually is easy to implement for external tumors, and specific method is to place electrodes on two sides of the tumor so as to generate an electric field d between the electrodes. Then, the distance d between the electrodes is measured, and a suitable voltage is applied to the electrodes according to the formula E=V/d.
Researches have shown that large nucleotide sequences (up to 630 kb) can be introduced into mammalian cells by electroporation, and in this way, a gene therapeutic method is provided.
In a relevant U.S. Pat. No. 5,273,525, the injector for injecting molecules and macromolecules by electroporation is injection needle, and meanwhile, the injection needle plays the role of electrodes. This structure enables the electrode to work at the subcutaneous area. It is desired that an electrode device has an electrode capable of inserting into the tumor or getting close to the tumor, such that a predefined electric field required by electroporation on tumor cells can be generated in the tissue.
However, due to that the electric field generated by the electrode always is difficult to adjust during electroporation using the injector, and the nonuniform of the electric field intensity results in damages to a large amount of normal cells. Greater defects are, during actual operation, very difficult to operate an injector with an electrode, high requirement on operator, low drug utilization efficiency, and increased sufferings of the patients during treatment.
In order to overcome the above-mentioned disadvantages, the technical problems mainly solved by the present invention is to provide an electroporating drug-delivering device capable of entering human body with no damage or minimal damage, capable of monitoring in real time and accurately positioning, accurately controlling the administration dosage and depth, and capable of accurately adjust the electric field intensity. This device is a drug-delivering device for electroporation in vivo with a wide universality, a good electroporating effect and no chemical pollution, reducing damages to the normal cells, enhancing the drug utilization efficiency, reducing the treatment time and mitigating the sufferings of patients during treatment.
USPTO Backgrounds
USPTO Backgrounds