BACKGROUND

Field of the Invention

Embodiments of the present invention relate to a combination therapy using an interventional drug delivery system and radiotherapy, and more particularly, to a system and method for facilitating delivery of various cargos, such as, for example, therapeutic agents, to target sites of internal body tissue in vivo, in combination with radiotherapy.

Description of Related Art

Many techniques exist for the treatment of diseased tissues, including therapeutic drugs (e.g., chemotherapy) and radiotherapy. Additionally, many techniques exist for the delivery of drugs, therapeutic agents, and radiotherapy to the body. Traditional drug delivery methods include, for example, oral administration, topical administration, intravenous administration, and intramuscular, intradermal, and subcutaneous injections. With the exception of topical administration which permits more localized delivery of therapeutic agents to particular area of the body, the aforementioned drug delivery methods generally result in systemic delivery of the therapeutic agent throughout the body. Accordingly, these delivery methods are not optimal for localized targeting of drugs and therapeutic agents to specific internal body tissues.

Both traditional drug delivery and traditional radiotherapy techniques may suffer from limited efficacy in treating perfusion limited tissues, such as solid tumors. Dense stromal environments and poor vascularization impede diffusion, reducing drug exposure to the primary tumor. Radiotherapy typically subjects the target tissue, either directly or indirectly, to ionizing radiation, which disrupts the growth of the tissue. In some instances, radiotherapy forms free radicals from oxygen in the tissue to destroy the target cells; however, solid tumors that lack sufficient vascularization are often hypoxic and cannot produce the free radicals necessary to treat the tumor. Radiotherapy may be used in combination with radiosensitizers, which increase the susceptibility of tissue to ionizing radiation; however, because of the abovementioned diffusion limitations, it is often difficult to administer radiosensitizers to solid tumors while also avoiding harm to the body caused by systemic toxicity.

Accordingly, it would be desirable to provide an improved system and method for treating body tissues that overcomes the aforementioned limitations by selectively and locally targeting delivery of various drugs and therapeutic agents in combination with radiotherapy to synergistically improve the effectiveness of both the local drug treatment and radiotherapies.

SUMMARY

The above and other needs are met by aspects of the present invention which provide, in one instance, a delivery system, and in particular, a delivery system for local drug delivery to a target site of body tissue in combination with radiotherapy applied to the target site. Some embodiments of the present invention may be directed to a method of delivering a cargo to a target site of body tissue in combination with radiotherapy. In some embodiments the method may include disposing a source electrode proximate to a target site of body tissue in vivo; disposing a counter electrode in electrical communication with the source electrode, the counter electrode being configured to cooperate with the source electrode to form a localized electric field proximate to the target site; disposing a cargo proximate the electric field and capable of being delivered to the target site when exposed to the localized electric field formed between the source electrode and the counter electrode; applying a voltage potential across the source and counter electrodes to form an electric field, thereby delivering at least a portion of the cargo to the target site; and/or applying a radiation to the target site.

In some embodiments the method may include disposing the cargo in a reservoir such that the reservoir is configured to place the cargo in the localized electric field. The method may include disposing the reservoir at least partially about the source electrode, such that upon activation of the electric field the cargo diffuses out of the reservoir and toward the counter electrode. The method may additionally or alternatively include disposing a cellulose membrane across an opening of the reservoir such that the membrane partially seals the reservoir while allowing the cargo to diffuse out of the reservoir toward the counter electrode. In some embodiments, the method includes disposing an inlet and an outlet in the reservoir such that cargo is configured to flow continuously across the source electrode.

In some embodiments, the cargo may include at least one radiosensitizer. The at least one radiosensitizer may include one of 1,2,4-benzotriazin-3-amine 1,4-dioxide (SR 4889) and 1,2,4-benzotriazine-7-amine 1,4-dioxide (WIN 59075), gemcitabine, cisplatin, carboplatin, oxaliplatin, 5-fluorouracil, or fluorodeoxyuridine. In some embodiments, the cargo includes at least one cytotoxic agent.

In some embodiments of the method, the radiation is applied to the target site from an external source. The radiation may be applied by an external beam irradiator. The radiation may additionally or alternatively be applied by brachytherapy. In some embodiments, the radiation may be applied by disposing a radiation source proximate the target site. In some embodiments, the radiation may be applied by disposing at least one radiation source on a reservoir. The radiation may be applied by disposing a radiation source within the target site. Some embodiments of the method may apply the radiation after the cargo is delivered to the target site. Additionally or alternatively, the radiation may be applied substantially concurrently with the delivery of the cargo to the target site.

Some embodiments of the method may provide intravenous delivery of a second cargo. In some embodiments, the cargo comprises at least one of small ionic molecules, nucleic acids, proteins, organic nanoparticles, therapeutic agents, and imaging agents. In some embodiments of the method, disposing a source electrode and a counter electrode further comprises disposing a source electrode and a counter electrode comprised of one of a metallic material, a conductive polymer material, and combinations thereof. Disposing a counter electrode may further comprise disposing a counter electrode such that the counter electrode contacts the target site so as to promote directional transport of the cargo toward the target site. In some embodiments, the body tissue comprises a solid tumor.

In another embodiment of the present invention, a system for treating a target site of body tissue may be provided. The system may include a source electrode proximate to a target site of body tissue in vivo; a counter electrode in electrical communication with the source electrode, the counter electrode being configured to cooperate with the source electrode to form a localized electric field proximate to the target site; wherein the localized electric field is configured to deliver at least a portion of a cargo to the target site by applying a voltage potential across the source and counter electrodes to form the localized electric field; and/or a radiation source configured to apply a radiation to the target site. Some embodiments of the system include a reservoir such that the reservoir is configured to place the cargo in the localized electric field. The reservoir may be disposed at least partially about the source electrode, such that upon activation of the electric field the cargo diffuses out of the reservoir and toward the counter electrode. In some embodiments, the system may include a cellulose membrane configured to be disposed across an opening of the reservoir such that the membrane is configured to partially seal the reservoir while allowing the cargo to diffuse out of the reservoir toward the counter electrode. Some embodiments of the system include an inlet and an outlet defined in the reservoir such that cargo is configured to flow continuously across the source electrode.

In some embodiments, the cargo includes at least one radiosensitizer. The at least one radiosensitizer may include one of 1,2,4-benzotriazin-3-amine 1,4-dioxide (SR 4889) and 1,2,4-benzotriazine-7-amine 1,4-dioxide (WIN 59075), gemcitabine, cisplatin, carboplatin, oxaliplatin, 5-fluorouracil, or fluorodeoxyuridine. In some embodiments, the cargo includes at least one cytotoxic agent.

Some embodiments of the radiation source are configured to apply the radiation from an external position. In some embodiments, the radiation source is an external beam irradiator. Additionally or alternatively, the radiation source may be a brachytherapeutic device. The radiation source may be configured to be disposed proximate the target site. In some embodiments, the radiation source may be configured to be disposed on a reservoir. The radiation source may additionally or alternatively be configured to be disposed within the target site. In some embodiments, the radiation may be configured to be applied after the cargo is delivered to the target site. In some embodiments of the system, the radiation may be configured to be applied substantially concurrently with the delivery of the cargo to the target site. Embodiments of the system may include a second cargo configured to be introduced to the target site intravenously. In some embodiments, the cargo comprises at least one of small ionic molecules, nucleic acids, proteins, organic nanoparticles, therapeutic agents, and imaging agents.

In some embodiments, each of the source electrode and the counter electrode may comprise one of a metallic material, a conductive polymer material, and combinations thereof. The counter electrode may be configured to contact the target site so as to promote directional transport of the cargo toward the target site. In some embodiments of the system, the body tissue may comprise a solid tumor.

As such, embodiments of the present invention are provided to enable highly targeted and efficient delivery of various cargos to predetermined target sites in combination with radiotherapy. In this regard, aspects of the present invention provide significant advantages as otherwise detailed herein.

