WO2023186923A1

WO2023186923A1 - Implanted agent delivery system

Info

Publication number: WO2023186923A1
Application number: PCT/EP2023/058040
Authority: WO
Inventors: Maria KOUTSOUPIDOU; Panagiotis KOSMAS; Maria THANOU; Efthymios Kallos; Ioannis SOTIRIOU
Original assignee: Meta Materials Inc.
Priority date: 2022-03-30
Filing date: 2023-03-28
Publication date: 2023-10-05

Abstract

The present disclosure is directed to an externally controlled, implantable, agent delivery device (310), a system including such a device, and methods for treating an internal disorder or disease, diagnosing, and/or imaging an organ or tissue, in a mammalian subject with such device and system.

Description

IMPLANTED AGENT DELIVERY SYSTEM

FIELD OF THE DISCLOSURE

[0001] The present disclosure is in the field of medicine. More particularly, the disclosure relates to externally controlled, implantable, agent delivery devices, systems, and methods for delivering agents for treatment of medical disorders and for internal body imaging.

BACKGROUND OF THE DISCLOSURE

[0002] Treatment of medical disorders includes the delivery of drugs and other treatment agents to the patient locally or systemically. Drug delivery is generally accomplished, but is not limited to, by oral administration, intravenous (IV), systemic provision of drugs, endoscopic dru [0003] g application, and delivery using implantable devices. Systemic drug delivery via oral administration or intravenous delivery lacks organ or tissue specificity. As one example, epidemiological data show that pancreatic cancer is a medical disorder, e.g., disease, with high mortality. Radiation therapy and chemotherapy are typically used to treat pancreatic cancer, while surgical operation for tumor resection offers an increased chance for cure (e.g., the cancer goes away with treatment, no more treatment is needed, and the cancer is not expected to come back). However, only 10% of patients are eligible for surgery because pancreatic cancer is typically in advanced phases when diagnosed.

[0004] Standard care of resectable tumours involves surgery. For advanced and unresectable tumours, neoadjuvant protocols and chemotherapy can be used although some may be associated with severe side effects, such as neutropenia, leukopenia, fatigue and peripheral neuropathy.

[0005] For example, prognosis of patients with pancreatic cancer can still be poor, while treatments such as immunotherapy have yet to show therapeutic results for this type of cancer. The disease poses challenges towards the advancement of effective treatments, including molecular heterogeneity and the tumour microenvironment, which typically includes inflammatory components and limited blood vessels that affect signalling pathways and drug accessibility.

[0006] Endoscopic drug application directly to an affected organ or a tumor has been used. For example, endoscopic ultrasound-guided (EUS) injection has been applied on pancreatic cysts, and has been used to treat pancreatic cancer with chemotherapy and/or immunotherapy treatments. However, the effectiveness of these techniques for treating advanced diseases and disorders, e.g., stage III pancreatic cancer, has not been proven and, in some cases, the treatments involve an invasive and uncomfortable procedure each therapeutic session.

[0007] Alternative drug delivery systems such as biodegradable implants, including the use of hydrogels and liposomes, have also been used for treatment of pancreatic cancers. However, in such systems, the release rate can be different for each drug and may change over time, such as, for example, being fast initially (the first hours or day) and slowing during the following duration. [0008] In addition, there are barriers for cancer treatment, which can include: blockage by the affected organ or tumor microenvironment for drug delivery to the organ or tumor by intravenous methods; side effects of intravenous delivery of chemotherapy drugs, including sideeffects to other tissues targeted by the drugs; reduced effectiveness of radiotherapy and immune therapy; and reduced stability of targeted drug delivery through hydrogel and liposomes [0009] Thus, what is needed is a safe and effective solution that overcome these barriers for imaging and treating disorders, in particular although not exclusively those affecting organs including locally advanced life-threatening malignant solid cancers.

SUMMARY OF THE DISCLOSURE

[0010] It has been discovered that disorders affecting organs, including, but not limited to, solid cancers, are treatable with the use of an implantable device containing a targeted therapeutic agent, where release of the therapeutic agent is controlled, for example externally, by microwave radiation.

[OOH] This discovery has been exploited to develop the devices and systems described in the present disclosure, which, in part, is directed to an implantable device for the imaging of internal organs and tissues and /or the treatment of disorders affecting organs or tissues, such as, but not limited to, solid cancers. The device may be externally controlled and the disclosure extends to a system including such an externally controlled device.

[0012] In a first aspect, disclosed herein is an implantable device for targeted agent release, the device comprising a vessel defining a volume for containing an agent within the vessel and having a port to an external environment; one or more antennae; a gate arranged to seal the port against liquid flow, wherein the gate is variable between an open state and a closed state; a controller configured to communicate with an external device via the one or more antennae in a first frequency band and to actuate the gate to be in the open state in response to a signal received from the external device; and a power source to provide power to the controller and the gate. [0013] Examples can include the following features. The controller can be configured to sense a sensing signal indicative of a fill level of the agent inside the volume via the one or more antenna. The sensing signal can be in a second frequency band different from the first frequency band. The first and second frequency bands can be non-overlapping. The controller can be configured to determine a change in the fill level of the volume from the sensed signal and to actuate the gate to be in the closed state in response to the change meeting a dosing threshold. The controller can be configured to transmit a signal indicative of the sensing signal or the fill level to the external device and to actuate the gate to be in the closed state in response to a signal received from the external device. The one or more antennae can be disposed on an internal surface of the device, or they may be disposed on an external surface of the device, for example exposed to the environment around the device.

[0014] Further examples can include the following features. The gate can include an ionic polymer metal-composite. The volume can include a plurality of conductive nanoparticles and a plurality of agent nanoparticles. The nanoparticles can include a therapeutic agent, an imaging agent and/or a diagnostic agent. The first frequency band can be in a range from about 2.4 GHz to about 2.5 GHz. The first frequency band can be in a range from about 400 MHz to about 500 MHz. The first frequency band can be in a range from about 13 MHz to about 40 MHz. The first frequency band can be in a range from about 13 MHz to about 500MHz. The gate can be continuously variable between the open state and the closed state.

The device can comprise a chamber, the gate being arranged between the volume and the chamber . The volume can be subdivided into a plurality of chambers, and the gate can be configured to reversibly seal the plurality of chambers against liquid flow individually, and wherein the controller can be further configured to control the gate for each of the plurality of chambers responsive to the received signal. The device can be subdivided into a first and a second chamber, the first chamber and second chamber being arranged at opposing ends of the implantable device and the second chamber having the port to the external environment. The device can further be subdivided into a third chamber and the gate can be arranged between the second and third chamber. The third chamber can include one or more ports to the external environment, the ports arranged circumferentially around a longitudinal axis of the vessel. The gate can include a rotary gate.

[0015] The device can comprise an antenna arranged within the first chamber and configured to transmit and receive signals in a first frequency band and a second frequency band, the second frequency band being higher than the first frequency band, device can comprise an antenna arranged within the first chamber and configured to communicate signals in a first frequency band and monitor changes in the second chamber in a second frequency band, the second frequency band being higher than the first frequency band. [0016] The vessel further can include an anchoring device, wherein the anchoring device can be a mechanical grip anchoring device or a suction anchoring device, The vessel further can include at least one conductive contact configured to contact a tissue of an external environment, and wherein the battery can be further configured to provide power to the at least one conductive contact, and the controller can be further configured to apply a potential to the at least one conductive contact responsive to the received signal.

[0017] The implantable device further can include a rotary dispensing device arranged within second chamber and configured to urge a fluid from the second chamber, and wherein the battery can be further configured to provide power to the rotary dispensing device, and the controller can be further configured to control the rotary dispensing device responsive to the received signal. [0018] Further examples can include the following features. The vessel can have a first dimension measuring less than about 30 mm, and a second dimension less than the first dimension, the second dimension measuring less than about 10 mm. The first frequency band can be in a range from about 2.4 GHz to about 2.5 GHz. The first frequency band can be in a range from about 400 MHz to about 500 MHz. The first frequency band can be in a range from about 13 MHz to about 40 MHz. The second chamber can include a plurality of conductive nanoparticles or a plurality of agent nanoparticles. The conductive nanoparticles can include one or more conductive materials. The conductive material can include a metal-containing conductive material. The conductive material can have an effective conductivity of greater than about 1 S/m at a radiation frequency of greater than about 1 GHz. The agent nanoparticles can be disrupted by heat. For example, the tissue or agent nanoparticles can be heated by microwave radiation, the heat causing the agent nanoparticles to be disrupted. The agent nanoparticles may be disrupted, for example, by melting or breaking down, for example due to the exposure to heat. Disrupting the agent nanoparticles may comprise activating the agent nanoparticles, for example transitioning the agent nanoparticles from an inactive to an active state. The agent nanoparticles can include an agent for treatment of a disease or disorder, an imaging agent, a diagnostic agent, or any combination thereof. The gate can include an ionic polymer metal-composite.

[0019] The vessel further can include an anchoring device, wherein the anchoring device can be a mechanical grip anchoring device or a suction anchoring device. The anchoring mechanism can be a self-locking feature configured to arrest the device on the internal treatment site. The device can be placed by a medical operator with the aid of imaging device. The imaging device can include an endoscope or an echoendoscope. The battery can be further configured to provide power to the anchoring device, and the controller can be further configured to apply a potential to the anchoring device responsive to the received signal. The vessel further can include at least one conductive contact configured to contact a tissue of an external environment in which the implantable device can be implanted, and wherein the battery can be further configured to provide power to the at least one conductive contact, and the controller can be further configured to apply a potential to the at least one conductive contact responsive to the received signal.

[0020] In some examples, the device can comprise one or more resonators disposed on the device so as to be able to heat an environment around the device. For example, the one or more resonators can be disposed on an outer surface of the device, or under and adjacent an outer surface of the device in order to be able to heat the environment. The one or more resonators can be passive and excitable by an external RF field at their resonant frequency to produce heat. The one or more resonators can be active and configured to be controlled and powered by the controller to produce heat.

[0021] In a second aspect, disclosed herein is an external device for controlling an implantable device described above. The external device comprises one or more antennae; and a controller configured to emit a first control signal in the first frequency band via the one or more antenna to cause the controller in the implantable device to actuate the gate to be in the open state.

[0022] In some examples, the controller can be configured to receive a signal indicative of a sensing signal indicative of a fill level or a signal indicative of a fill level from the implantable device; to determine a change in the fill level from the signal; and to emit a second control signal in the first frequency band via the one or more antennae in response to determining that the change has met a dosing threshold. The device can comprise a microwave generator, and the controller can be configured to, subsequent to emitting at least one of the first and second control signals, cause emission of a microwave signal to heat tissue adjacent the implantable device. The controller can be configured to cause emission of the microwave signal at a frequency that is a resonance frequency of conductive nanoparticles dispensed from the implantable device.

[0023] The external device can comprise one or more antenna for receiving and transmitting a signal in the first frequency band; a microwave generator; and a controller configured to transmit a signal within the first frequency band including a command for the implantable device to actuate the gate to a flow-permissive state; receive a signal from the implantable device indicative of a volume change in the second chamber; compare the volume change to a volume change threshold; and transmit, responsive to the volume change exceeding the volume change threshold, a signal including a command for the implantable device to actuate the gate to a closed state.

[0024] In a third aspect, disclosed herein is a system comprising an implantable as described above and an external device as described above. [0025] In a fourth aspect, disclosed herein is a method of delivering an agent to a subject, the method including: implanting a device into the subject in a vicinity of a targeted organ or tissue, the device including a chamber containing the agent to be delivered; directing electromagnetic radiation from a source outside of the subject to the device implanted in the subject, the electromagnetic radiation including a signal which, when received by the device, causes the device to release the particles from the chamber, wherein releasing the particles from the chamber provides the particles to the targeted organ or tissue.

[0026] Examples can include the following features. The signal can have a frequency in a range from about 2.4 GHz to about 2.5 GHz. The agent can be an imaging agent, a diagnostic agent, and/or a therapeutic agent. The device to release the particles can include causing the device to actuate a gate separating the chamber from an external environment. The agents can be contained within particles. The signal can be a first signal and the frequency can be a first frequency. A second signal can have a second frequency in a range above the first frequency. The method further can include directing electromagnetic radiation from the source. The particles releasing the agents can be contained within particles responsive to the second signal. The signal can be further configured to cause the device to anchor the device in the vicinity of the target organ or tissue. The signal can be further configured to release the particles from one or more of a plurality of chambers. The signal can be further configured to cause the device to release the particles according to a pre-determined dosing rate.

[0027] This approach enables the targeted delivery of a selected agent, e.g., the therapeutic agents and/or imaging agents, in small dosages as prescribed by a health care or imaging entity directly to the site of environment of implantation of the delivery device site.

[0028] In one aspect, the disclosure provides an implantable device featuring two chambers, the first chamber housing an antenna, control circuitry, and a power source, and the second chamber housing a suspension of therapeutic agents, imaging agents, or both, and a voltage- regulated gate. The integrated antenna can be designed to receive signals from an external controller and monitor the delivery of the therapeutic and/or imaging agents.

[0029] In some examples, the external controller features one or more antennae to receive signals from the implanted device, transmit commands to the implanted device, and generate signals at a frequency at which device is responsive, e.g., microwave frequencies. In operation, the implantable device receives commands from an external controller to actuate the chamber door and deliver a dose of a treatment or imaging agent at a controlled release rate. The controller sends commands which at least partially opens the gate according to the release rate in the received commands and a suspension fluid carrying the agents flows through the gate into the surrounding tumor area. The agents can include one or more therapeutic agents, e.g., drugs, or encapsulated drugs, imaging agents, e.g., contrast imaging agent, or nanoparticles, e.g., conductive nanoparticle (CNP), or agents encapsulated in nanoparticles. The agents diffuse as the suspension fluid enters the surrounding tissue. Imaging agents facilitate increased imaging contrast compared to the surrounding tissue, facilitating determination of placement and concentration of the CNPs within the pancreas, and determination of quantity and rate of drug delivery.

[0030] The features in the preceding examples can be applied to any of the systems or methods described above.

[0031] In some examples, the external controller can determine when a complete dose of the selected agents have been delivered by receiving signals from the antenna of the implanted device. The external controller can send a command to the implanted device to cause the device to close the door, sealing the device from flow and terminating fluid transmission to the surrounding tissue. Additionally, or alternatively, the external controller can transmit a delivery rate and/or treatment time to the implanted device and the implanted device controls the gate according to the delivery rate and/or treatment time.

[0032] In some examples, the selected agent includes one or more CNPs. The CNPs can be sensitive to radiation at microwave frequencies (e.g., in the about 2.4 GHz to about 2.5 GHz, about 400 MHz to about 500 MHz, or about 13 MHz to about 40 MHz frequency bands). The suspension fluid enters the surrounding tissue and the external controller generates the microwave signal. In such examples, the CNPs respond to the microwave signal. The microwave signal can cause the CNPs to increase in temperature which increases the temperature of the surrounding tissue. The microwave resonance of the CNPs facilitates increasing the temperature locally, e.g., but not limited to, at the diffusion site of the CNPs, without increasing the temperature of the surrounding tissue. In this manner, localized heating of the targeted area can be achieved.

[0033] The agent to be provided can be in any form deliverable by the device. For example, it can be neat, in combination with other agents, drugs, or medicaments, and/or contained within a deliverable vehicle. For example, and in some implementations, the agent is contained in a thermosensitive nanoparticle. In such implementations, the structure of the thermosensitive nanoparticle can be disrupted by increased temperature and the contents contained by the nanoparticle can be released into the surrounding tissue. In this manner, and in such implementations, the gating state, dosing rate, treatment time, tissue temperature, and/or total dose can be controlled by the external controller according to therapeutic limits determined and input by a user. [0034] In some examples, the method comprises reinforcing the delivery of the agent to a target organ or tissue of a subject. The method can comprise directing electromagnetic radiation from a source outside of the subject to the device implanted in the subject, the electromagnetic radiation including a signal which, when received at the device, causes one or more resonators of the device to resonate and heat a target organ or tissue. In some examples, the local heat increase can improve the absorption rate of the agent by the tissue, for example to provide thermal therapy.

[0035] The details of one or more examples are set forth in the accompanying drawings and the description below. Other features and advantages will be apparent from the description and drawings, and from the claims.

DESCRIPTION OF THE DRAWINGS

[0036] The foregoing and other objects of the present disclosure, the various features thereof, as well as the disclosure itself may be more fully understood from the following description, when read together with the accompanying drawings in which:

[0037] FIG. 1 is a diagrammatic representation of an agent delivery system placed in a patient pancreas, and showing functions including communication with the external base, drug release and drug volume sensing in accordance with the disclosure;

[0038] FIG. 2A is a simulated line chart comparing signal loss to incident radiation frequency and showing a shift in the operating bandwidth of the device depending on the volume of suspension fluid in the second chamber in accordance with the disclosure;

[0039] FIG. 2B is a schematic representation of a directional antenna in accordance with the disclosure;

[0040] FIG. 2C is a schematic representation of a split ring resonator assembly in accordance with the disclosure;

[0041] FIG. 2D is a simulated line chart comparing signal loss to incident radiation frequency and showing a decrease in signal loss for antennae including split ring resonator assemblies in accordance with the disclosure; and

[0042] FIG. 3 is a schematic representation of an exemplary agent delivery system in accordance with the disclosure. DESCRIPTION

[0043] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. The initial definition provided for a group or term herein applies to that group or term throughout the present specification individually or as part of another group, unless otherwise indicated.

[0044] As used herein, the articles “a” and “an” refer to one or to more than one (z.e., to at least one) of the grammatical object of the article. By way of example, “an element” means one element or more than one element. Furthermore, use of the term “including” as well as other forms, such as “include,” “includes,” and “included,” is not limiting.

[0045] As used herein, the term “about” will be understood by persons of ordinary skill in the art and will vary to some extent on the context in which it is used. As used herein when referring to a measurable value such as an amount, a temporal duration, and the like, the term “about” is meant to encompass variations of ±20% or ±10%, including ±5%, ±1%, and ±0.1% from the specified value, as such variations are appropriate to perform the value. For example, here 100 megahertz (MHz) includes precisely 100 MHz, approximately 100 MHz, and within ± 10% of 100 MHz.

[0046] For the purposes of explaining the disclosure, well-known features of medicinal and imaging technology known to those skilled in the art of implantable devices have been omitted or simplified in order not to obscure the basic principles of the disclosure. Parts of the following description will be presented using terminology commonly employed by those skilled in the art of implanted devices and metamaterials. It should also be noted that in the following description of the disclosure repeated usage of the phrase “in one example” does not necessarily refer to the same example. The features in the following examples can be applied to any of the systems or methods described herein.

[0047] The present disclosure provides devices, systems, and methods for delivering a selected agent of interest (e.g., a therapeutic agent, an imaging agent, or a diagnostic agent) to a desired tissue or organ in the body of a subject (e.g., a mammalian subject). The present disclosure provides a safe and effective system for delivering one or more therapeutic and/or imaging agents for imaging internal organs or tissues and/or for or treating internal disorders affecting organs, including solid cancers. The system utilizes an externally controlled, implantable device (IMD) for controlled agent delivery.

[0048] Referring to FIG. 1, the disclosure features a microwave (MW)-based system 100 for controlled delivery of one or more agents, e.g., therapeutic drugs, and/or imaging agents into an area of a subject 10 at which the IMD 110 has been implanted, the location of the area could be, but is not limited to being, a cancer, or a tumor 150. Although a MW-based system is described as a specific example, it will be appreciated that the disclosure extends to other electromagnetic frequency bands, for example in the radio-frequency spectrum. The MW-based system 100 includes the IMD 110 configured to carry the selected agents, agents, and release them in a controlled manner. The system 100 includes an external base 130 for communicating with the IMD 110. The base 130 includes one or more internal or external antennae functional to communicate commands to an antenna of the IMD 110. In some cases, the antennae of the base 130 andIMD 110 include an impedance-matching metamaterial surface configured to maximize signal penetration through the subject tissue.

[0049] In non-limiting examples, the IMD 110 is implanted next to an organ, such as, but limited to, the pancreas, surgically or endoscopically with a small incision through the duodenum. The base 130, e.g., an external controller, can be arranged at or adjacent the site of implantation such that a distance between the base 130 and the IMD 110 is within communication distance. For example, the base 130 can be placed, or temporarily affixed (e.g., by an adhesive), on the skin of the subject 10 above the implanted IMD 110.

[0050] The base 130 can control the targeted and local agent delivery to the tumour over a period of time. For example, over a period of time of up to several months (e.g., about 1 week or more, about 2 weeks or more, about three weeks or more, about a month or more, about two months or more, or about three months or more).

[0051] In a specific example of a treatment session, the base 130 initiates the treatment session with a command transmitted on a first frequency to the IMD 110 to release the suspension fluid carrying the agents by emitting (e.g., directionally emitting) MW radiation towards the IMD 110. This provides for spatial and temporal control of the delivery of the agents. In some examples, the base 130 and IMD 110 communicate to release the selected agents into the surrounding tissue, e.g., the tumor 150, or other cancer, organ or tissue, over multiple treatment sessions.

[0052] The first frequency is in a communications band for communication with the IMD 110. In some examples, the communications band is in the ISM band, for example, from about 2.4 GHz to about 2.5 GHz, e.g., about 2.45 GHz. This band is achievable with small antenna sizes (e.g., sub-centimeter structures) and has limited penetration depth in human tissue due to higher losses. Additionally or alternatively, the communications band is in the Med Radio band, e.g., from about 400 MHz to about 500 MHz. This band facilitates a functional tradeoff between antenna size and antenna radiation efficiency and penetration into the tissue. In some implementations, the communications band covers lower ISM bands, e.g., in a range between about 13 MHz to about 41 MHz. This band offers the highest penetration into the tissue. Such examples of the communications band can be applied to any of the systems or methods described herein

[0053] The agent may be contained in thermosensitive agent nanoparticles (TNPs), which release the agent in response to heating, in some examples. To initiate agent delivery to the implantation site, e.g., the affected organ or tumor 150 in these examples, the base 130 transmits microwave radiation at a second frequency to heat the implantation site. The implantation site may be heated directly by the radiation at the second frequency. The second frequency may be different or may be the same as the first frequency. In some examples, the IMD 110 may contain a mixture of TNPs and CNPs. In these examples, the implantation site may be heated by exciting a resonance mode of the CNP to facilitate the heating.. The second frequency can be in a frequency band of higher frequency than the communications band, e.g., higher than about 2.5 GHz, or higher than about 500 MHz. The transmitted microwave radiation induces resonances in the CNPs causing the CNPs to emit thermal radiation, e.g., heat, the surrounding tissue, e.g., tumor 150. Controlling the agent release by heating provides for spatial and temporal control of the release of the agents from the TNPs. Using CNP to mediate the heating enables more selectively heating the tumor 150 containing the CNPs and hence can reduce overheating of the surrounding tissue, whether the goal is to release agent from TNPs or to heat the tissue for thermal therapy or ablation. To avoid interference between the signal to release the suspension fluid and the signal heating the tissue or the CNPs, the one or more antennae can be designed to have the first frequency band unaffected by the CNPs conductivity and dielectric permittivity. [0054] Further details of the system 100 and IMD 110 are described below. Referring to the inset image of the IMD 110 of FIG. 1 as an example configuration, in this example the size of the IMD 110 is 30 mm long or less, and 10 mm wide or less, to facilitate implantation, e. The IMD 110 includes a first chamber 112 and a second chamber 114 separated from the first chamber 112. The first chamber 112 and second chamber 114 define two respective volumes. The antenna 118, control electronics, and a battery are housed within the first chamber 112. The antenna can instead be housed in the second chamber or can be disposed external to the IMD 110, for example disposed on an external surface of the IMD 110. The second chamber 114 includes a voltage regulated gate 116 in communication with the control electronics and separating the second chamber 114 from the external environment of the IMD 110. For example, when implanted, the gate 116 separates the second chamber 114 from the surrounding tissue. The second chamber 114 of the IMD 110 contains a suspension fluid carrying the selected agents. In some implementations, the selected agents include one or more selected therapeutic, imaging, and/or diagnostic drugs. [0055] In some examples, the gate 116 is composed of a material which responds to applied potential from the control electronics or battery by changing shape. For example, the gate 116 is composed of a synthetic composite nanomaterial that changes shape under an applied voltage or electric field. The gate 116 is configured to controllably bend with the application of a low voltage, such as less than 1 V. In some examples, the gate 116 is composed of an ionic polymermetallic composite (IPMC). An IPMC is composed of an ionic polymer, such as, but not limited to, Nafion (Chemours Company, Wilmington, DE) or Flemion (AGC Chemicals Company, Exton, PA) whose surface is chemically plated, or physically coated, with a conductive material, such as a conductive metal or metallic alloy (e.g., but not limited to, platinum or gold). The application of energy to the IPMC and availability make them allowable candidates for the gate 116 sealing the second chamber 114. As the gate 116 material is hydrophilic and pliable in wet environments, the gate 116 is coated, or covered, with a biocompatible polymer (e.g., but not limited to, polyolefin or polydimethylsiloxane) to ensure proper sealing with the second chamber 114 of the IMD 110 when the gate 116 is in a closed state.

[0056] An applied voltage across the gate 116 causes a bending deformation which fluidically connects the second chamber 114 to the external environment. The control electronics transmit the voltage to induce the bending deformation and induce the gate 116 into an at least partially open state. The control electronics can vary the applied voltage continuously across the voltage range and the gate 116 responds according to the applied voltage. As a non-limiting example, electrodes connecting the conductive surfaces of the gate 116 having an applied voltage of about 1.5 V induce an about 20 ° bending angle in the gate 116. Lower voltage (e.g., about 1 V, or about 1.2 V) induces a smaller bending angle (e.g., about 20 ° or less), while higher voltage (about 2 V) induces a higher bending angle (greater than about 20 °). Controlling the applied voltage controls the opening from the second chamber 114 to the external environment.

[0057] Certain examples of the gate 116 include a rotary gate. In such examples, the gate 116 includes a rotary valve in which a gating element rotates around an axis to control the gating state of the gate 116. The rotary gate actuates between an open state to a closed state when an electrical signal is provided to the gate 116. In some examples, the rotary valve of the gate 116 is continuously variable between an open state and a closed state. For example, a micro-dispensing rotating valve can operate as the rotary gate. Dispensing and metering the dosage in high accuracy. This is based on the principle of infinite circulation piston (micro -screw feeder).

[0058] In some examples, the IMD 110 includes a dosing mechanism which controls the release of the suspension fluid. One example of a dosing mechanism is a screw feeder, e.g., a worm- screw micro feeder. The screw feeder includes an augur which drives the suspension fluid out of the IMD 110 when the augur rotates about a longitudinal axis. The IMD 110 controls the rotation rate of the augur which determines the rate at which the suspension fluid is expelled from the IMD 110. The expelling rate and the agent concentration in the suspension fluid determine the dosing rate of the agent to the external environment. In some implementations, the external base 130 controls the augur rotation rate to meet a pre-determined dosing rate of the agent. The screw feeder dispensing mechanism dispenses, e.g., meters, the dosing rate with increased accuracy compared to pumping or diffusing mechanisms. The screw feeder dispensing mechanism can be based on the principle of infinite circulation piston (e.g., a micro-screw feeder).

[0059] In some examples, the IMD 110 includes more than two chambers. For example, the IMD 110 can include three chambers, four chambers, or more. In such examples, the gate 116 can be housed within the IMD 110 and separate the second chamber 114 from other chambers, e.g., a third chamber or a fourth chamber, within the IMD 110. In such examples, the third chamber can be gated from the external environment by a second gate, valve, or valves, or fluidically connected to the external environment via nozzles or apertures connecting the interior volume of the third chamber with the external environment. In one example, a third chamber arranged between the second chamber 114 and the external environment and gated by the gate 116 reduces occurrences in which the gate 116 is affected by or in contact with the external environment, such as by surrounding tissues, and may increase the useable lifespan of the IMD 110.

[0060] In further examples, the IMD 110 includes a switchable gate, or multiple gates. In one example in which the IMD 110 includes multiple chambers, the IMD 110 can include one gate 116 per chamber. The IMD 110 can include a single gate which regulates the exposure of the interior volume of the chambers individually, or in combination. For example, the gate 116 can include one port per chamber, each port individually configurable between an open state and a closed state.

[0061] In some examples, the IMD 110 includes one or more electrical contacts arranged around the surfaces of the IMD 110 to be exposed to the external environment. For example, the electrical contacts can be arranged at one of the distal ends of the IMD 110, or circumferentially around the surface. The electrical contacts are electrically connected to the battery and configured to deliver an electrical signal (e.g., a microcurrent) to the external environment. In one example, the electrical contacts contact biological tissue in the external environment, such as tumor tissue or organ tissue, e.g., the stroma of an organ. The electrical signal is transmitted to the tissue through the electrical contacts thereby energizing the surrounding tissue. In some examples in which the agent is electrically conductive, the agent responds to the energized tissue according to the electrical parameters of the agent, e.g., a charged agent can be attracted to the energized tissue thereby increasing the tissue specificity of agent delivery.

[0062] In some examples, the IMD 110 includes one or more anchoring mechanisms to anchor the IMD 110 within the environment and reduce IMD 110 displacement following implantation of the device within tissue. The anchoring device creates a mechanical grip on surrounding tissue by applying a force to the tissue, e.g., a self-locking feature utilizing suction force or a friction force. The anchoring area is arranged on the distal surface of the IMD 110 and such that the anchoring mechanism is exposed to the exterior environment.

[0063] The attachment of the IMD 110 can be made using tools at the distal end of the endoscope. Note that “distal” refers to the direction along the IMD 110 pathway leading internally to the patient and “proximal” refers to the direction leading externally from the patient. A minimally invasive endoscopic approach is useful to address the attachment and detachment of the device by external operation. The anchoring mechanism can use a self-locking feature (mechanical and/or suction) on the internal treatment site. The endoscopic distal attachment to the internal treatment site can use an anchoring mechanism both mechanical and suction and is performed by the endoscopist using e.g., an endoscope or echoendoscope. The placement of the IMD 110 (e.g., attachment, or detachment) can be performed by a medical operator, e.g., an endoscopist with the aid of imaging techniques.

[0064] The IMD 110 can receive commands from, e.g., is controlled by, the base 130 to deliver the suspension fluid carrying the selected agents in a controlled manner, e.g., at a predetermined duration, rate, or total dose, to initiate a delivery session. The IMD 110 can communicate with the external base 130 to receive commands or parameters for initializing the delivery session and transmitting information based on the suspension fluid volume released. In some examples, the IMD 110 receives one or more commands to modify a gating state of the gate 116 separating the IMD 110 volume from the external environment. Commands to modify the gating state include a command to modify the gate 116 to a gating state, which can include an open state, closed state, or to a state between open and closed. The gate 116 is variable, e.g., continuously variable, between the open and closed states based on a voltage applied to the gate 116. The amount by which the gate 116 is opened determines a rate at which the suspension fluid flows between the second chamber 114 and the external environment.

[0065] Additionally or alternatively, the IMD 110 can receive one or more dosing parameter values for one or more of the selected agents which determine the treatment session. As examples, the IMD 110 receives a total dose value, a dosing rate value, a delivery duration value, a total volume release value, or a volume change rate value. The IMD 110 can receive instructions including the dosing parameter values for a single treatment session, or multiple treatment sessions over an extended duration.

[0066] In a non-limiting example, the IMD 110 receives commands to perform one treatment session on a first day during which a first dose is administered to the tumor. The IMD 110 receives commands to perform a second treatment session on a second day, spaced from the first day in which a second dose is administered to the tumor. In this manner, the total dose available to the IMD 110 is administered in portions to the tumor. Administering the total dose over multiple treatments extends the useable life of the IMD 110 while implanted and reduces the number of endoscopic procedures a patient 10 undergoes to receive the multiple treatments. Such examples of treatment administration can be applied to any of the systems or methods described herein.

[0067] The IMD 110, in some examples, can sense suspension fluid volume changes inside the reservoir by monitoring a change in the resonance bandwidth shift of the antenna 118, for example at a second frequency, higher than the first frequency. The second frequency can be in a frequency band of higher frequency than the communications band, e.g., higher than about 2.5 GHz, higher than about 40 MHz, or higher than about 500 MHz. The second frequency can be the same as or different to the first frequency.

[0068] The release of the suspension fluid containing the selected agents changes the overall dielectric properties (e.g., effective dielectric constant, the effective conductivity, or both) of the volume and contents of the second chamber 114, which results in a shift in the antenna’s resonant frequency, e.g., as calculated by the antenna’s return loss (Si l) . The effective dielectric constant (e.g., permittivity) and conductivity are averaged dielectric and magnetic characteristics of an inhomogeneous medium, such as the suspension fluid contained in the second chamber 114, or the tumor in which the selected agents are released. Effective conductivity represents the ability of the inhomogeneous medium to conduct electric current.

[0069] In some examples, to initiate and/or reinforce the treatment on the implantation site e.g., the affected organ or tumor 150, the base 130 can transmit microwave radiation at a frequency at which the CNPs respond. The transmitted microwave radiation induces resonances in the CNPs causing the CNPs to emit thermal radiation, e.g., heat, the containing tissue, e.g., tumor 150. This can provide for spatial and temporal control of the release of the agents. Selectively heating the tumor 150 containing the CNPs reduces overheating of the surrounding tissue. To avoid interference between the signal to release the suspension fluid and the signal heating the CNPs, the antenna 118 can be designed to have the first frequency band unaffected by the CNPs conductivity and dielectric permittivity. [0070] The theoretical return loss (SI 1) in decibels (dB) of the of the antenna 118 compared to the frequency of radiation in gigahertz (GHz) incident on the antenna 118, is shown in FIG 2A. FIG. 2A includes two vertical lines at exemplary frequencies of 2.4 GHz and 2.5 GHz. The frequency range between the two vertical lines represents a portion of the ISM band. The solid line indicates the theoretical Si l resonance profile when the second chamber 114 contains the total amount of the suspension fluid containing the CNPs and TNPs (e.g., full container). The dashed line indicates the theoretical Si l resonance profile when the second chamber 114 does not contain the suspension fluid, or is empty.

[0071] As the IMD 110 releases a portion of the suspension fluid and agents carried therein, the theoretical resonance profile transitions from the solid line to the dashed line. The change in the resonance profile is measured by the control electronics via the antenna 118 of the IMD 110. The control electronics compare the change in the resonance profiles to a predetermined standard to determine an amount of suspension volume which flowed from the second chamber 114. Monitoring the amount of suspension volume delivered passively by the change in resonance profile provides an indirect measurement of the amount of agent delivered. In some examples, the amount of fluid delivered is monitored passively by measuring a response to a signal applied from the external base. This reduces the electric power needed by the IMD 110 to monitor the amount of fluid delivered as the need to actively drive the antenna 118 is avoided.

[0072] The IMD 110 monitors the volume change of the suspension fluid, and when the one or more dosing parameter values exceed a respective dosing parameter threshold, the IMD 110 actuates the gate 116 to a closed state thereby terminating the dosing. The IMD 110 transmits a signal indicative of the terminated dosing, such as a signal indicative that the suspension fluid volume threshold has been met or exceeded. In some examples, the IMD 110 measures the resonant frequency of return loss of the antenna 118 and transmits the measurement (or a value indicative of the measurement) to the external base. The external base can then perform the monitoring based on the measurement and send a signal causing the IMD to actuate the gate to a closed state to terminate the dosing. In other words, the monitoring and terminating of the dosing may be fully under the control of the IMD 110 or may be controlled by the external base in response to measurement signals received from the IMD 110.

[0073] The suspension fluid containing the selected agents is released from the IMD 110 via actuation of the gate 116. Interstitial fluids in the organ will diffuse the suspension fluid into the surrounding tissue and flow the solution from the IMD 110. The suspension fluid diffuses through the surrounding tissue, such as, for example, into the tumor lesion. The base 130 can receive the signal indicative of the terminated dosing, in some examples. In some implementations, the base 130 antenna is a directional antenna (e.g., a Vivaldi antenna) designed to substantially direct the emitted microwaves in a direction. The base 130 may be arranged such that the directional antenna directs the MW radiation toward the IMD 110. Such examples of the directional antenna can be applied to any of the systems or methods described herein.

[0074] MW radiation for monitoring and initializing the IMD 110 to release the suspension fluid is advantageous because the radiation is functional for the IMD 110 to communicate with the external base 130 and, in some implementations, as a sensing technique. In some implementations, the MW radiation can be uses for heating technique via CNP suspensions. In some implementations, the base 130 antenna emits MW radiation in a frequency band in a range from about 2.4 GHz to about 2.5 GHz (e.g., or about 400 MHz to about 500 MHz, or about 13 MHz to about 40 MHz). As mentioned above, the disclosure is not limited to the MW part of the RF spectrum.

[0075] The system 100 performance depends, at least in part, on the efficiency and size of the base 130 directional antenna and the antennal 18 of the IMD 110. In some implementations, the antenna 118 covers the inner (or, in some examples, outer) surface of the IMD 110. The antenna 118 may cover as much surface area as possible, which increases its electrical length and reduces the form factor. In some examples, the design of the antenna 118 includes helical structures, planar structures, or both. The antenna 118 is designed, in some examples, to operate in the ISM band of microwave frequencies, e.g., from about 2.4 GHz to about 2.5 GHz, e.g., about 2.45 GHz, e.g., from about 400 MHz to about 500 MHz, or from about 13 MHz to about 40 MHz. Such examples of the antenna 118 of the IMD 110 can be applied to any of the systems or methods described herein.

[0076] In one non-limiting example, the antenna 118 conforms to the shape of the IMD 110, e.g., conforms to a cylindrical shape. Slots of appropriate size and shape are added on the antenna's metallic structure and ground plane to produce multi-band operation. Metamaterial techniques, such as, but not limited to, meandering, split-ring resonators (SRRs) or arrays of other subwavelength elements are utilized to miniaturize the antenna and enhance coupling with the content of the capsule at the second operating band. Such examples of the antenna 118 can be applied to any of the systems or methods described herein.

[0077] In a non-limiting example, introducing SRR's on a compact Vivaldi antenna introduces resonant frequencies or broadens the operation bandwidth, and achieves useful properties for the antenna 118. An example of a Vivaldi antenna 220 is shown in FIG. 2B. The Vivaldi antenna 220 is a planar broadband-antenna including a conductor 222 and a potential source 224. The potential source 224 excites an electric field in the open space 226 which is terminated with a sector-shaped area 228. The excited electric field induces directional radiation along the plane of the conductor 222, as shown by the arrow. Printed circuit technology makes the Vivaldi antenna 220 cost effective at microwave frequencies in the ISM band.

[0078] In some implementations, the antenna 118 conforms to an inner surface of the first chamber 112, the second chamber 114, or both. Additionally or alternatively, the can antenna 118 conform to the outer surface of the IMD 110, exposed to the surrounding user tissue. There may be up to about three internal single-band antennas antennae 118. In such cases, the up to about three antennae 118 operate in the communications band disclosed, for example, but not limited to, about 13 MHz to about 40 MHz, about 400 MHz to about 500 MHz, or about 2.4 GHz to about 2.5 GHz. In some examples, there may be more than three internal antennae. In some examples there may be two internal antennae, one to communicate signals in a first frequency band and one to monitor changes in the second chamber in a second frequency band

[0079] In cases including the about three antennae 118 of the IMD 110, one example of utilizing the three antennae includes one used for external communications, one for monitoring agent delivery, and one which causes thermosensitive nanoparticles to warm up and release the agent when triggered from an external source or antenna, such as an antenna in the base 130. In some examples, a single antenna, for example a multi -band antenna, can be used for all three functions.

[0080] FIG. 2C shows an exemplary SRR assembly 240 is shown in FIG. 2C that includes nested split-ring resonators which can provide one or more features of the antenna 118 for the IMD 110. The split ring resonators 242 and 244 have square profiles with split ring resonator 242 having larger dimensions than split ring resonator 244 such that split ring resonator 244 nests inside split ring resonator 242. Such a configuration reduces the overall size of the SRR assembly 240 (e.g., miniaturize the antenna) and enhances coupling with the suspension fluid. Such examples of split ring resonators can be applied to any of the systems or methods described herein.

[0081] A numerically simulated signal loss (in dB) across a range of frequencies (in GHz) is shown in the line chart depicted in FIG. 2D. The dashed line is the simulated frequency response of the Vivaldi antenna (such as the antenna of FIG. 2B) from 1 GHz to 6 GHz showing several minimums across the spectrum of greater than -20 dB loss. The solid line is the simulated frequency response of a metastructure-enhanced Vivaldi antenna, such as the antenna of FIG. 2B enhanced with the SRRs of FIG. 2C. The solid line shows a loss (e.g., less than -40 dB loss) minimum at 5 GHz, the resonant frequency of the simulated Vivaldi antenna.

[0082] In some implementations, one or more passive resonators conform to the outer surface of the IMD 110, exposed to the surrounding environment, for example tissue to be treated. To reinforce the treatment by the therapeutic agent on the implantation site e.g., the affected organ or tumor 150, the base 130 transmits microwave radiation at a frequency at which the one or more passive resonators respond. The wirelessly transferred RF power allows the one or more passive resonators to resonate and thus increase their surface currents and emit thermal radiation, e.g., heat, to the surrounding tissue, e.g., tumor 150. This provides for local thermal therapy of the tissue e.g., tumor, to absorb the agents and improve therapy. As the passive resonators are powered by the radiation emitted by the external base 130, the duration of the thermal therapy session is controlled by the external base 130 and continues as long as the external RF radiation is emitted. Passive resonators therefore reduce the electric power needed to reinforce thermal therapy.

[0083] In some implementations, the one or more resonators are active, and their operation is controlled by the controller. After the therapeutic agent has been released into the tissue e.g., tumor, in some implementations, the external base 130 sends a command to initiate the local hyperthermia treatment by causing the IMD 110 to activate the resonators. In other implementation, the hyperthermia treatment is triggered by the IMD 110 independent of the external base 110, for example at the same time as actuating the gate. In either case, the controller o the IMD 110 then activates the resonators for a time duration determined by the command or pre-determined, for example. The active resonators are powered by the power source of the IMD 110.

[0084] In a non-limiting example, the passive or active resonators are LC resonators with an integrated micro-capacitor and planar inductors arranged on the outer surface of the IMD 110. [0085] In a non-limiting example, the passive resonators are metallic structures of subwavelength size to the resonant frequency, such as printed monopoles, meanders, spirals or split-ring resonators, arranged on the outer surface of the IMD 110.

[0086] In a non-limiting example, the resonators can achieve heating of the tissue and reinforce thermal treatment without requiring the presence of the CNPs. In the presence of the CNPs, the resonators can be designed to operate at the frequency where the CNPs respond and induce further heating of the tissue, e.g., tumor.

[0087] The IMD 110 can be manufactured from a material that is biosafe for implantation into a subject 10 and non-biodegradable to prevent degradation when exposed to biofluids present in the implant area. A non-limiting useful material is polyolefin, is a thermoplastic material which adheres onto the inner or outer surface of the IMD 110, the fibers of which are non-biodegradable. Other non-limiting options for the antenna material can depend on commercial availability and ease of use.

[0088] In some implementations, the suspension fluid contains conductive nanoparticles (CNPs), additionally or alternatively to the selected agents. The CNPs act as contrast agents for micro wave radiation, increasing the interaction of incident radiation at micro wave frequencies. The high conductivity of the CNPs facilitates the IMD 110 monitoring changes in the concentration of CNPs within the second chamber 114 by monitoring changes in the effective dielectric constant, effective conductivity, or both, as an indirect means of monitoring the amount of agent carried by the suspension fluid delivered.

[0089] The CNPs include a conductive material, such as a metal, metallic alloy, or metallic nanoparticle. Examples of the conductive material include, but are not limited to, zinc-oxide, zinc-ferrite, barium titanate (BaTiOa), and CCT (CaCua^Oi), carbon nanotubes, modified carbon nanotubes and graphene. In some examples, the CNPs feature a polymer, such as a conductive polymer material. Non-limiting examples of such a useful CNP is a (3, 4-ethylene dioxythiophene):poly(styrene sulfonate) (PEDOT:PSS) material or a Zinc ferrite (Zn-Fe) material. Such examples of CNP materials can be applied to any of the systems or methods described herein.

Conductive materials having an effective conductivity, e.g., above about 0.5 S/m and high dielectric contrast (e.g., in MW dielectric contrast imaging in a magnetic resonant environment) can be used when exposed to radiation of frequencies in a range from aboutl GHz to about 4 GHz (e.g., about 1.5 GHz to about 3 GHz, about 2 GHz to about 2.5 GHz, or about 2.4 GHz to about 2.5 GHz. The CNPs can include more than one population of CNPs (e.g., a zinc-oxide CNP and a zinc-ferrite material).

[0090] In some implementations in which the IMD 110 carries and releases CNPs responsive to microwave radiation, one of the antennae of the base 130 is configured to transmit a signal in a frequency band at which the CNPs are responsive to increase the thermal energy of, e.g., warm up, the CNPs, thereby raising the temperature of the surrounding tissue. The high conductivity of the CNPs induces resonances with the emitted MW radiation and causes the temperature of the CNPs to increase above the internal temperature of the surrounding tissue. The heated CNPs heat the area in which they are diffused, e.g., the local tumor area. Such an arrangement focuses the heating to the tumor 150 without heating the tissues surrounding the tumor.

[0091] In some implementations, the selected agents, are contained in thermosensitive TNPs which, in some examples, is a spherical vesicle. The TNP is composed, at least in part, of a thermosensitive substance and the selected agent is contained in the interior volume of the TNP. Containing the agents in TNPs facilitates controlled release, and reducing circulation of the selected agents after local release of the TNPs. In such implementations, the selected agents are released from the TNPs when the TNPs are heated above a threshold temperature. The TNPs release the agents over short time periods (e.g., within seconds) creating a rapid release of the agent into the surrounding tissue. The rapid release causes high concentration of agents confined within the tumor 150 area. Such examples of the TNPs can be applied to any of the systems or methods described herein.

[0092] Directed microwave exposure decreases damage to tissue surrounding the targeted tissue and is effective in increasing treatment outcomes if the affected region is diseased and is heated sufficiently to disrupt the TNP and release the contained selected agents. In some implementations, the system 100 achieves release of the selected agents from the TNPs by using CNPs and heating the surrounding tissue through resonant interaction with the CNPs.

[0093] The agent of interest (e.g., a therapeutic agent, a diagnostic agent, an imaging agent) is not limited to any particular type and can be e.g., a peptide, a protein, an antibody, a nucleic acid (e.g., an antisense oligonucleotide, an siRNA), a hormone, chemical compound, a vitamin, an enzyme, a ligand of a tumor antigen, an anti-tumor agent, a hormone receptor, a cytokine receptor, a growth factor receptor, an anti-neoplastic agent, a small molecule drug, radionuclide, element, or any combination thereof. Agents that are treatment drugs can be, for example, anything currently used to treat a diseased or cancerous tissue. Such examples of the treatment agents can be applied to any of the systems or methods described herein.

[0094] In some instances, the agent is an anti-cancer agent. See e.g., www.cancer.gov/about- cancer/treatment/drugs/cancer-type. In some cases, the agent is an agent for treating pancreatic cancer (e.g. PDAC). See, e.g., www.cancer.gov/about-cancer/treatment/drugs/pancreatic; Roth et al., Version 1. FlOOORes. 2020; 9: F1000 Faculty Rev- 131; Principe et al., (2021) Front. Oncol., doi.org/10.3389/fonc.2021.688377; and Hu et al., (2022) Front. Oncol., doi.org/10.3389/fonc.2022.828450, which are incorporated by reference herein.

[0095] In some instances, the selected agent is an anticancer agent such as, but not limited to, an alkylating agent, an antimetabolite, a spindle poison plant alkaloid, a cytotoxic antitumor antibiotic, a topoisomerase inhibitor, a monoclonal antibody or antigen-binding fragment thereof, a photosensitizer, a kinase inhibitor, an antitumor enzyme, an inhibitor of enzymes, an apoptosis - inducer, a biological response modifier, an anti-hormone, a retinoid, a nucleoside analog, or a platinum containing compound. Non-limiting examples of anticancer agents include: alkylating agents, for example, nitrogen mustards (e.g., Chlorambucil, Chlormethine, Cyclophosphamide, Ifosfamide, Melphalan, nitrosoureas (e.g., Carmustine, Fotemustine, Lomustine, Streptozocin), platinum containing compounds (e.g., Carboplatin, Cisplatin, Oxaliplatin, BBR3464), Busulfan, Dacarbazine, Mechlorethamine, Procarbazine, Temozolomide, ThioTEPA, and Uramustine; antimetabolites that target, for example, folic acid (e.g., aminopterin, methotrexate, pemetrexed, raltitrexed), purine metabolism (e.g., cladribine, clofarabine, fludarabine, mercaptopurine, pentostatin, thioguanine), pyrimidine metabolism (e.g., capecitabine, cytarabine, fluorouracil, floxuridine, gemcitabine); spindle poison plant alkaloids, for example, taxanes (e.g., docetaxel, paclitaxel) and vinca (e.g., vinblastine, vincristine, vindesine, vinorelbine); cytotoxic/antitumor antibiotics, for example, anthracycline antibiotics (e.g., daunorubicin, doxorubicin, epirubicin, idarubicin, mitoxantrone, valrubicin, carinomycin, nacetylachiamycin, rubidazone, 5- imidodaunomycin, N30 acetyldaunomycin, and epirubicin), bleomycin, mitomycin, and actinomycin;

[0096] In some instances, the anticancer agent is a topoisomerase inhibitor, for example, camptothecines (e.g., camptothecin, topotecan, and irinotecan), podophyllum (e.g., etoposide, teniposide). In some instances, the therapeutic agent is a monoclonal antibody or antigen-binding fragment thereof, for example, but not limited to, the anticancer monoclonal antibodies Alemtuzumab, Bevacizumab, Cetuximab, Gemtuzumab, Panitumumab, Rituximab, Tositumomab, and Trastuzumab. In some instances, the anticancer agent an enzyme, for example, asparaginase, pegaspargase and inhibitors of enzymes, for example hydroxyurea. In some instances, the anticancer agent is a apoptosis-inducer, for example, arsenic trioxide, Velcade and Genasense. In some instances, the anticancer agent is a biological response modifier, for example, Denileukin Diftitox. In some instances, the anticancer agent is an antihormone, for example, Goserelin acetate, leuprolide acetate, triptorelin pamoate, Megestrol acetate, Tamoxiifen, toremifene, Fulvestrant, testolactone, anastrozole, exemestane and letrozole. In some instances, the anticancer agent is a retinoid, for example, 9-cis-retinoic acid and all- trans-retinoic acid.

[0097] In some cases, the anticancer agent is a taxane such as, but not limited to, paclitaxel, nab-paclitaxel, docetaxel, cabazitaxel, tesetaxel, ortataxel, or a salt thereof. Examples of the salt include salts of basic groups such as amino groups, and acidic groups such as hydroxyl groups and carboxyl groups, which are commonly known. Examples of the salts of basic groups include salts of mineral acids such as hydrochloric acid, hydrobromic acid, nitric acid, and sulfuric acid; salts of organic carboxylic acids such as formic acid, acetic acid, citric acid, oxalic acid, fumaric acid, maleic acid, succinic acid, malic acid, tartaric acid, aspartic acid, and trichloroacetic acid and trifluoro acetic acid; and salts of sulfonic acids such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, mesitylenesulfonic acid, and naphthalenesulfonic acid. Examples of salts of acidic groups include salts of alkali metals such as sodium and potassium; salts of alkaline earth metals such as calcium and magnesium; ammonium salts; and salts of nitrogen- containing organic bases such as trimethylamine, trimethylamine, tributylamine, pyridine, N,N-dimethylaniline, N-methylpiperidine, N-methylmorpholine, diethylamine, dicyclohexylamine, procaine, dibenzylamine, N-benzyl- .beta. -phenethylamine, 1-ephenamine, and N,N'-dibenzylethylenediamine. [0098] In some cases, the anticancer agent is a platinum containing compound. In certain instances, the platinum containing compound is carboplatin or cisplatin. In some cases, the anticancer agent is the nucleoside analog gemcitabine. In some cases, the agent for treating pancreatic cancer is selected from the group consisting of paclitaxel, everolimus, erlotinib hydrochloride, 5 -fluorouracil, gemcitabine hydrochloride, irinotecan hydrochloride, olaparib, mitomycin, sunitinib malate, lanreotide acetate, lutetium Lu 177-dotatate, belzutifan, a combination of gemcitabine and cisplatin, a combination of gemcitabine and oxaliplatin, or a combination thereof. In some cases, the agent for treating pancreatic cancer is selected from the group consisting of leucovorin, 5 -fluorouracil, irinotecan and oxaliplatin, gemcitabine, paclitaxel, and combinations thereof. In some instances, where more than one agent is used, combinations of the drugs that operate with different mechanisms of action are employed.

[0099] In some cases, the treatment agents of the disclosure can include more than one antineoplastic agent, or more than one treatment agents can be used in the compositions or methods of the disclosure, each of which includes different active agents, for example, different anticancer agents. Other agents that can be used in the compositions or methods disclosed herein include, but are not limited to antibiotics, antifungals, anti-inflammatory agents, immunosuppressive agents, anti-infective agents, antivirals, antihelminthic, and antiparasitic compounds.

[0100] In some cases, the agent is contained in a thermosensitive substance, e.g., a TNP, such as, but not limited to, a thermosensitive polymer or a thermosensitive nanoparticle. See, e.g., US Patent Nos. 8,642,074; 9,956,175; 8,476,242; 11,166,913; and 11,166,914; Ta et a (2013) J. Control Release, 169(1-2): 112-125; Kneidl et al., (2014) Int, J. Nanomed. 9:4387-4398; de Matos et al., (2018) Europ. J. Pharmaceut. Biopharmaceut., 132: 211-221; Mo et al., (2019) ACS Biomater. Sci. Eng., 5, 5, 2316-2329; Li et al., (2021) Int. J. Nanomed. 15:6721-6734; Abuwatfa et al., (2022) Polymers 14, 925. doi.org/10.3390/polyml4050925; Wang et al., (2022) Curr. Drug Deliv. Mar 21. Doi: 10.2174/1567201819666220321110812; Gomes et al., (2021) J. Nanopart. Res. 24:30 (2021). doi.org/10.1007/sl l051-21-05352-9; Hongshu et al., (2019) Asian J. Pharmaceut. Sci. 14 (4):365-379; and Emamzadeh et al., (2019) ACS Appl, Bio Mater. 2, 3:1298-1309, which are incorporated by reference herein in their entirety.

In some instances, the patient has, or is at risk of developing, a cancer. In some cases, the cancer is a carcinoma, a sarcoma, a leukemia, a lymphoma, a myeloma, or a central nervous system cancer. In some cases, the cancer is a pancreatic, a prostate, a lung, a bronchus, a colon, a rectum, an urinary bladder, a breast, an ovarian, an uterine, an endometrial, a cervical, a kidney, a gastric, a liver, a skin, a blood, a bone, a gastrointestinal, a penile, a testicular, a vaginal, a vulvar, a non-small-cell lung cancer, a head and neck squamous cell, an esophageal, a renal cell, a colorectal a brain, a lymph node, an urothelial, or a thyroid cancer. In some examples, the subject has a pancreatic cancer (e.g., PDAC). In some examples, the subject has a melanoma. For example, for pancreatic cancer as standard of care can include leucovorin, 5 -fluorouracil, and irinotecan. This disclosure also provides and oxaliplatin, gemcitabine and paclitaxel. In some examples, the TNPs carry a combination of agents that operate with a different mechanism.

[0101] In some instances, the subject is a mammalian subject such as, but limited to, a human, cat, dog, horse, cow, pig, rat, rabbit, or sheep.

[0102] In some instances, the subject has, or is at risk of developing, a cancer. In some cases, the cancer is a carcinoma, a sarcoma, a leukemia, a lymphoma, a myeloma, or a central nervous system cancer. In some cases, the cancer is a pancreatic, a prostate, a lung, a bronchus, a colon, a rectum, an urinary bladder, a breast, an ovarian, an uterine, an endometrial, a cervical, a kidney, a gastric, a liver, a skin, a blood, a bone, a gastrointestinal, a penile, a testicular, a vaginal, a vulvar, a non-small-cell lung cancer, a head and neck squamous cell, an esophageal, a renal cell, a colorectal a brain, a lymph node, an urothelial, or a thyroid cancer. In one instance, the subject has a melanoma. In some cases, the subject has a pancreatic cancer (e.g., PDAC).

[0103] While the systems, methods, and compositions are useful to treat cancer, it is to be understood that the arrangements and compositions of this disclosure can be used to deliver selected agents to treat other diseases or disorders. Thus, any of the agents described above can be delivered to the subject in need thereof via the systems and methods of this disclosure. For example, the systems of this disclosure can be used to deliver to a subject in need thereof antibiotics, antifungals, anti-inflammatory agents, immunosuppressive agents, anti-infective agents, antivirals, anthelminthic, and/or antiparasitic compounds.

[0104] This disclosure also provides systems and methods used to deliver an imaging or diagnostic agent to image an internal organ or tissue, or to diagnose any disease or disorder affecting the tissue. For example, the compositions can be used to deliver diagnostic agents into the central nervous system or hard to reach tissues or organs.

[0105] In some instances, the system can be used to deliver an imaging and/or a contrast agent and or a diagnostic agent in combination with a therapeutic agent. The therapeutic agent either alone or in combination with an imaging, diagnostic, and/or contrast agent can be enclosed inside the TNPs. An imaging agent can have rapid and specific binding to the intended target, rapid clearance from blood circulation, excretion by the urinary pathway, high accumulation at the target site, and high in vivo stability. Such examples of the use of imaging or contrast agents can be applied to any of the systems or methods described herein.

[0106] The Molecular Imaging and Contrast Agent Database (MICAD), created as part of the Molecular Libraries and Imaging program in the NIH roadmap, contains information on imaging agents and contrast agents that can be used herein in molecular imaging. In some cases, the imaging agent is a small molecule, peptide, engineered protein, nucleosides, amino acids, aptamer, nanoparticle, a fluorescent agent, or a radionuclide. Ligand- targeted cancer-imaging agents are useful in identifying and localizing tumor masses, and for selecting patients for corresponding ligand-targeted treatment.

[0107] Radionuclides can be y, P, or a emitters. Nuclear medicine imaging involves the use of y radiation from radionuclides; radioimmunotherapy uses P, or a emitters. Typical radionuclides used in nuclear medicine imaging are, e.g., ¹³¹I (half-life 8 days), ¹²³I (half-life 13.3 h), ^{n i}In (half-life 67.3 h), "^mTc (half-life 6.02 h) ^2O1T1 (half-life 73 h), and ⁶⁷Ga (half-life 78 h). Non-limiting examples of imaging agents that can be used herein are provided in Fass, (2008) Mol. One,, 2(2):115-152; Lee et al., (2014) World J Gastroenterol. 20(24) :7864-7877; Quesada- Olarte et al., (2020) Aetas Urol Esp (Engl Ed), 44(6):386-399. Such examples of radioneucleotides can be applied to any of the systems or methods described herein.

[0108] In some cases, the imaging agent is 2-Deoxy-2-¹⁸F-fluoroglucose (FDG), Sodium ¹⁸F-fluoride (NaF), Anti-l-amino-3-¹⁸F-fluorocyclobutane-l-carboxcylic acid (¹⁸F-fluciclovine, FACBC), "^mTc-methoxyisobutylisonitrile (^99mTc-sestamibi), 3'-deoxy-3'-¹⁸F-fluorothymidine (FLT), 16a-¹⁸F-fluoro-17P-estradiol (FES), or 21-¹⁸F-fluoro-16a,17P-[(R)-(l'-a- furylmethylidene)dioxy]- 19-norpregn-4-ene-3, 20-dione (FFNP).

EXAMPLES

[0109] Referring now to FIG. 3, an exemplary IMD 310 is schematically illustrated. The IMD 310 depicts an exemplary implementation of the IMD 110 described herein. The IMD 310 includes a first chamber 312 which houses the internal battery, and control electronics. An antenna 318 is connected to the control electecronics in the first chamber 312 and extends into a second chamber 314. The antenna 318 is shown having an exemplary configuration and is not limiting.

[0110] The second chamber 314 is separated from a third chamber 320 by a rotary gate 316. The second chamber 314 is configured to contain a suspension fluid in which one or more agents are suspended. The rotary gate 316 controls the gating state between the second chamber 314 and the third chamber 320. When the rotary gate 316 is at least partially open, the second chamber 314 is in fluidic connection with the third chamber 320 and the suspension fluid flows between the chambers. The third chamber 320 is connected to the external environment by ports 324 arranged circumferentially around the longitudinal axis, A. The ports 324 are openings which fluidically connect the third chamber 320 to the external environment. When the suspension fluid enters the third chamber 320 from the second chamber 314, the suspension fluid exits the third chamber 320 through the ports 324 or a drug release system 330, discussed further below.

[0111] The IMD 310 includes conductive contacts 322 which are electrically connected to the battery and controller of the IMD 310. FIG. 3 depicts three contacts 322 though alternative examples may have fewer, or more, than three contacts 322. The most distal surface of the contacts 322 extend past the most distal surface of the IMD 310 such that when the IMD 310 is implanted, the contacts 322 are in contact with surrounding tissues. The battery, controller, and contacts 322 are configured to deliver an electrical signal to the surrounding tissues. The delivery of the electrical signal is controlled by an external base (not pictured).

[0112] The IMD 310 includes an anchoring attachment location 328 arranged at the distal end of the IMD 310 opposing the first chamber 312. The anchoring attachment location 328 provides a location at which a mechanical or/and suction attachment can be placed.

[0113] The IMD 310 includes an alternative drug release system 330 connected to the third chamber 320 containing the suspension fluid which is configured to release the agents (e.g., inject, infuse, or insert) at the distal point of the vessel towards the external environment. In some examples, the drug release system 330 is configured to penetrate the organs succeeding layers using a pointer/microneedle. In some examples both the drug release system 330 and ports 324 are present. In some examples only the drug release system 330 is present or only the ports 324 are present.

[0114] The following clauses set out disclosed examples:

1. A system for targeted agent delivery, comprising: an implantable device, comprising: a vessel defining a volume within the vessel, the volume subdivided into a first and a second chamber, the first chamber enclosed by the vessel and the second chamber having a port to an external environment; an antenna arranged within the first chamber and configured to communicate signals in a first frequency band and monitor changes in the second chamber in a second frequency band, the second frequency band being higher than the first frequency band; a gate arranged to reversibly seal the port against liquid flow, the gate being variable between an open state and a closed state; a battery arranged within the first chamber configured to provide power to a controller and the gate; and the system further comprising: an external device, comprising: one or more antenna for receiving and transmitting a signal in the first frequency band; a microwave generator; and a controller configured to: transmit a signal within the first frequency band including a command for the implantable device to actuate the gate to a flow-permissive state; receive a signal from the implantable device indicative of a volume change in the second chamber; compare the volume change to a volume change threshold; and transmit, responsive to the volume change exceeding the volume change threshold, a signal including a command for the implantable device to actuate the gate to a closed state.

2. The system of clause 1, wherein the gate comprises an ionic polymer metal-composite.

3. The system of clause 1 or clause 2, wherein the second chamber comprises a plurality of conductive nanoparticles and a plurality of agent nanoparticles.

4. The system of clause 3, wherein the nanoparticles comprise a therapeutic agent, an imaging agent and/or a diagnostic agent.

5. The system of any one of clauses 1-5, wherein the first frequency band is in a range from 2.4 GHz to 2.5 GHz.

6. The system of any one of clauses 1-4, wherein the first frequency band is in a range from 400 MHz to 500 MHz.

7. The system of any one of clauses 1-4, wherein the first frequency band is in a range from 13 MHz to 40 MHz.

8. The system of any one of clauses 1-7, wherein the gate is continuously variable between the open state and the closed state. 1 9. The system of any one of clauses 1-8, wherein the volume is further subdivided into a third chamber, and the gate is arranged between the second and third chamber.

10. The system of any one of clauses 1-9, wherein: the volume is further subdivided into a plurality of chambers; the gate is configured to reversibly seal the plurality of chambers against liquid flow individually; and the controller is further configured to control the gate for each of the plurality of chambers responsive to the received signal.

11. The system of clause 9, wherein the third chamber comprises one or more ports to the external environment, the ports arranged circumferentially around a longitudinal axis of the vessel.

12. The system of any one of clauses 1-11, wherein the gate comprises a rotary gate.

13. The system of any one of clauses 1-12, wherein: the vessel further comprises an anchoring device; the anchoring device is a mechanical grip anchoring device or a suction anchoring device; the battery is further configured to provide power to the anchoring device; and the controller is further configured to apply a potential to the anchoring device responsive to the received signal.

14. The system of any one of clause 1-13, wherein: the vessel further comprises at least one conductive contact configured to contact a tissue of an external environment in which the implantable device is implanted; wherein the battery is further configured to provide power to the at least one conductive contact; and the controller is further configured to apply a potential to the at least one conductive contact responsive to the received signal. tem of any one of clause 1-14, wherein: the implantable device further comprises a rotary dispensing device arranged within second chamber and configured to urge a fluid from the second chamber; the battery is further configured to provide power to the rotary dispensing device; and the controller is further configured to control the rotary dispensing device responsive to the received signal. lantable device for targeted agent release agents, comprising: a vessel defining a volume within the vessel, the volume subdivided into a first and a second chamber, the first chamber and second chamber arranged at opposing ends of the implantable device and the second chamber having a port to an external environment; an antenna arranged within the first chamber and configured to transmit and receive signals in a first frequency band and a second frequency band, the second frequency band being higher than the first frequency band; a gate arranged to reversibly seal the port against liquid flow and being variable between an open state and a closed state; a controller arranged in the first chamber; and a battery arranged within the first chamber and configured to provide power to the gate and the controller, the controller being configured to: receive power from the battery; receive signals from the antenna within the first frequency band; apply a potential to the gate, responsive to the received signal within the first frequency band, to control the gating state of the gate to at least a partially open state; receive signals from the antenna within the second frequency band indicative of a volume change in the second chamber; compare the volume change to a volume change threshold; and operate the gate, responsive to the volume change exceeding the volume change threshold, to the closed state.

17. The device of clause 16, wherein the vessel has a first dimension measuring less than 30 mm, and a second dimension less than the first dimension, the second dimension measuring less than 10 mm.

18. The device of clause 16 or 17, wherein the first frequency band is in a range from 2.4 GHz to 2.5 GHz.

19. The device of clause 16 or 17, wherein the first frequency band is in a range from 400 MHz to 500 MHz.

20. The device of clause 16 or 17, wherein the first frequency band is in a range from 13 MHz to 40 MHz.

21. The device of any one of clauses 16-20, wherein the second chamber comprises a plurality of conductive nanoparticles or a plurality of agent nanoparticles.

22. The device of clause 21, wherein conductive nanoparticles comprise one or more conductive materials.

23. The device of clause 22, wherein the conductive material comprises a metal-containing conductive material.

24. The device of clause 22 or 23, wherein the conductive material has an effective conductivity of greater than 1 S/m at a radiation frequency of greater than 1 GHz.

25. The device of clause 21, wherein the agent nanoparticles are disrupted by heat.

26. The device of clause 21, wherein the agent nanoparticles are disrupted by microwave radiation. 27. The device of clause 21, 25, or 26, wherein the agent nanoparticles comprise an agent for treatment of a disease or disorder, an imaging agent, a diagnostic agent, or any combination thereof.

28. The device of any one of clauses 16-27, wherein the gate comprises an ionic polymer metal-composite.

29. The device of any one of clauses 16-28, wherein the volume is further subdivided into a third chamber, and the gate is arranged between the second and third chamber.

30. The device of any one of clauses 16-29, wherein: the volume is further subdivided into a plurality of chambers; the gate is configured to reversibly seal the plurality of chambers against liquid flow individually; and the controller is further configured to control the gate for each of the plurality of chambers responsive to the received signal.

31. The device of clause 29, wherein the third chamber comprises one or more ports to the external environment, the ports arranged circumferentially around a longitudinal axis of the vessel.

32. The device of any one of clauses 16-27, wherein the gate comprises a rotary gate.

33. The device of any one of clauses 16-32, wherein the vessel further comprises an anchoring mechanism, which comprises a mechanical grip anchoring device or a suction anchoring device.

34. The device of clause 33, wherein the anchoring mechanism is a self-locking feature configured to arrest the device on the internal treatment site.

35. The device of clause 33 or 34, wherein the device is placed by a medical operator with the aid of imaging device.

36. The device of clause 33-35, wherein the imaging device comprises an endoscope or an echoendoscope. 37. The device of any one of clauses 33-36, wherein the battery is further configured to provide power to the anchoring device, and the controller is further configured to apply a potential to the anchoring device responsive to the received signal.

38. The device of any one of clause 16-37, wherein: the vessel further comprises at least one conductive contact configured to contact a tissue of an external environment in which the implantable device is implanted; the battery is further configured to provide power to the at least one conductive contact; and the controller is further configured to apply a potential to the at least one conductive contact responsive to the received signal.

39. The device of any one of clause 16-38, wherein: the implantable device further comprises a rotary dispensing device arranged within second chamber and configured to urge a fluid from the second chamber; the battery is further configured to provide power to the rotary dispensing device; and the controller is further configured to control the rotary dispensing device responsive to the received signal.

40. A method of delivering an agent to a subject, the method comprising: implanting a device into the subject in a vicinity of a targeted organ or tissue, the device comprising a chamber containing the agent to be delivered; directing electromagnetic radiation from a source outside of the subject to the device implanted in the subject, the electromagnetic radiation comprising a signal which, when received by the device, causes the device to release the particles from the chamber, releasing the particles from the chamber providing the particles to the targeted organ or tissue.

41. The method of clause 40, wherein the signal has a frequency in a range from 2.4 GHz to

2.5 GHz. 42. The method of clause 40 or 41, wherein the agent is an imaging agent, a diagnostic agent, and/or a therapeutic agent.

43. The method of any one of clauses 40-42, wherein causing the device to release the particles comprises causing the device to actuate a gate separating the chamber from an external environment.

44. The method of any one of clauses 40-43, wherein the agents are contained within particles.

45. The method of any one of clauses 40-44, wherein: the signal is a first signal and the frequency is a first frequency; and the method further comprises directing electromagnetic radiation from the source comprising a second signal having a second frequency in a range above the first frequency, the particles releasing the agents contained within the particles responsive to the second signal.

46. The method of any one of clauses 40-45, the signal further configured to cause the device to anchor the device in the vicinity of the target organ or tissue.

47. The method of any one of the clauses 40-46, the signal further configured to release the particles from one or more of a plurality of chambers.

48. The method of any one of the clauses 40-47, the signal further configured to cause the device to release the particles according to a pre-determined dosing rate.

EQUIVALENTS

[0115] Those skilled in the art will recognize, or be able to ascertain, using no more than routine experimentation, numerous equivalents to the specific examples described specifically herein. Such equivalents are intended to be encompassed in the scope of the following claims.

Claims

1. An implantable device for targeted agent release, the device comprising: a vessel defining a volume for containing an agent within the vessel and having a port to an external environment; one or more antennae; a gate arranged to seal the port against liquid flow, wherein the gate is variable between an open state and a closed state; a controller configured to communicate with an external device via the one or more antennae in a first frequency band and to actuate the gate to be in the open state in response to a signal received from the external device; and a power source to provide power to the controller and the gate.

2. The device of claim 1, the controller being configured to sense a sensing signal indicative of a fill level of the agent inside the volume via the one or more antenna.

3. The device of claims 1 or 2, the sensing signal being in a second frequency band different from the first frequency band

4. The device of claim 3, the first and second frequency bands being non-overlapping.

5. The device of claim 2, 3 or 4, the controller being configured to determine a change in the fill level of the volume from the sensed signal and to actuate the gate to be in the closed state in response to the change meeting a dosing threshold.

6. The device of claim 2, 3 or 4, the controller being configured to transmit a signal indicative of the sensing signal or the fill level to the external device and to actuate the gate to be in the closed state in response to a signal received from the external device.

7. The device of any preceding claim, wherein the gate comprises an ionic polymer metalcomposite.

8. The device of any preceding claim, wherein the volume comprises a plurality of conductive nanoparticles and a plurality of agent nanoparticles.

9. The device of any preceding claim, wherein the agent comprises a therapeutic agent, an imaging agent and/or a diagnostic agent.

10 The device of any preceding claim, wherein the device comprises one or more resonators disposed on the device so as to be able to heat an environment around the device.

11. The device of claim 10, wherein the one or more resonators are passive and excitable by an external RF field at their resonant frequency to produce heat.

12. The device of claim 10, wherein the one or more resonators are active and configured to be controlled and powered by the controller to produce heat.

13. The device of any preceding claim, wherein the gate is continuously variable between the open state and the closed state.

14. The device of any preceding claim, comprising a chamber, the gate being arranged between the volume and the chamber

15. The device of any preceding claim, wherein: the volume is subdivided into a plurality of chambers; the gate is configured to reversibly seal the plurality of chambers against liquid flow individually; and the controller is further configured to control the gate for each of the plurality of chambers responsive to the received signal.

16. The device of claim 14, wherein the chamber comprises two or more ports to the external environment, the ports being arranged circumferentially around a longitudinal axis of the vessel.

17. The device of any preceding claim, wherein the gate comprises a rotary gate.

18. The device of any preceding claim, wherein: the vessel further comprises an anchoring device, which is a mechanical grip anchoring device or a suction anchoring device; the power source is further configured to provide power to the anchoring device; and the controller is further configured to apply a potential to the anchoring device responsive to a received signal.

19. The device of any preceding claim, wherein: the vessel further comprises at least one conductive contact configured to contact a tissue of an external environment in which the implantable device is implanted; the power source is further configured to provide power to the at least one conductive contact; and the controller is further configured to apply a potential to the at least one conductive contact responsive to a received signal.

20. The device of any preceding claim, wherein: the implantable device further comprises a rotary dispensing device arranged within the volume and configured to urge a fluid from the volume; the power source is further configured to provide power to the rotary dispensing device; and the controller is further configured to control the rotary dispensing device responsive to a received signal.

21. The device of any preceding claim, wherein the vessel has a first dimension measuring less than about 30 mm, and a second dimension less than the first dimension, the second dimension measuring less than about 10 mm.

22. The device of claim 8, wherein the conductive nanoparticles comprise a conductive material

23. The device of claim 22, wherein the conductive material comprises a metal-containing conductive material.

24. The device of claim 22 or 23, wherein the conductive material has an effective conductivity of greater than about 1 S/m at a radiation frequency of greater than about 1 GHz.

25. The device of claim 8, or 22-24 wherein the agent nanoparticles are disrupted by heat.

26. The device of claim 8, or 22 to 25, wherein the agent nanoparticles comprise an agent for treatment of a disease or disorder, an imaging agent, a diagnostic agent, or any combination thereof.

27. The device of any preceding claim, wherein the vessel further comprises an anchoring mechanism, the anchoring mechanism comprising a mechanical grip anchoring device.

28. The device of any preceding claim, wherein the vessel further comprises an anchoring mechanism, the anchoring mechanism comprising a suction anchoring device.

29. The device of claim 29, wherein the anchoring mechanism is a self-locking feature configured to arrest the device on the internal treatment site.

30. The device of any preceding claim, wherein the implantable device is configured to be placed by a medical operator with the aid of an imaging device.

31. The device of any preceding claim, the volume being subdivided into a first and a second chamber, the first chamber and second chamber being arranged at opposing ends of the implantable device and the second chamber having the port to the external environment.

32. The device of any preceding claim, comprising an antenna arranged within the first chamber and configured to transmit and receive signals in a first frequency band and a second frequency band, the second frequency band being higher than the first frequency band.

33. The device of any preceding claim, comprising an antenna arranged within the first chamber and configured to communicate signals in a first frequency band and monitor changes in the second chamber in a second frequency band, the second frequency band being higher than the first frequency band.

34. An external device for controlling an implantable device as claimed in any preceding claim, the external device comprising: one or more antennae; and a controller configured to emit a first control signal in the first frequency band via the one or more antenna to cause the controller in the implantable device to actuate the gate to be in the open state.

35. The external device of claim 34, the controller being configured to: receive a signal indicative of a sensing signal indicative of a fill level or a signal indicative of a fill level from the implantable device; determine a change in the fill level from the signal; and emit a second control signal in the first frequency band via the one or more antennae in response to determining that the change has met a dosing threshold.

36. The external device of claim 34 or 35, comprising a microwave generator, the controller being configured to, subsequent to emitting at least one of the first and second control signals, cause emission of a microwave signal to heat tissue adjacent the implantable device.

37. The external device of claim 36, wherein the controller is configured to cause emission of the microwave signal at a frequency that is a resonance frequency of conductive nanoparticles dispensed from the implantable device.

38. The external device of claim 34, comprising: one or more antenna for receiving and transmitting a signal in the first frequency band; a microwave generator; and a controller configured to: transmit a signal within the first frequency band including a command for the implantable device to actuate the gate to a flow-permissive state; receive a signal from the implantable device indicative of a volume change in the second chamber; compare the volume change to a volume change threshold; and transmit, responsive to the volume change exceeding the volume change threshold, a signal including a command for the implantable device to actuate the gate to a closed state.

39. A system comprising the implantable device of any one of claims 1 to 33 and the external device of any one of claims 34 to 38.

40. A method of delivering an agent to a subject, the method comprising: implanting a device into the subject in a vicinity of a targeted organ or tissue, the device comprising a chamber containing the agent to be delivered; and directing electromagnetic radiation from a source outside of the subject to the device implanted in the subject, the electromagnetic radiation comprising a signal which, when received by the device, causes the device to release the particles from the chamber, the releasing the particles from the chamber providing the particles to the targeted organ or tissue.

41. The method of claim 40, wherein the signal has a frequency in a range from about 2.4 GHz to about 2.5 GHz.

42. The method of claim 40 or 41, wherein the agent comprises an imaging agent, a diagnostic agent, and/or a therapeutic agent.

43. The method of any one of claims 40-42, wherein causing the device to release the particles comprises causing the device to actuate a gate separating the chamber from an external environment.

44. The method of any one of claims 40-43, wherein the agents are contained within particles.

45. The method of any one of claims 40-44, wherein the signal is a first signal and the frequency is a first frequency, the method further comprising directing electromagnetic radiation from the source comprising a second signal having a second frequency in a range above the first frequency, the particles releasing the agents contained within the particles responsive to the second signal.

46. The method of any one of claims 40-45, the signal further configured to cause the device to anchor the device in the vicinity of the target organ or tissue.

47. The method of any one of claims 40-46, the signal further configured to release the particles from one or more of a plurality of chambers.

48. The method of any one of claims 40-47, the signal further configured to cause the device to release the particles according to a pre-determined dosing rate.

49. The method of any one of claims 40 to 48, comprising reinforcing the delivery of the agent to a target organ or tissue of a subject by directing electromagnetic radiation from a source outside of the subject to the device and thereby causing one or more resonators of the device to resonate and heat a target organ or tissue.