WO2009001243A1

WO2009001243A1 - Apparatus for controlled delivery of molecules using a controlled injection system

Info

Publication number: WO2009001243A1
Application number: PCT/IB2008/052373
Authority: WO
Inventors: Christopher S. Hall; Balasundar I. Raju; Chien T. Chin; William T. Shi
Original assignee: Koninklijke Philips Electronics N.V.
Priority date: 2007-06-22
Filing date: 2008-06-17
Publication date: 2008-12-31

Abstract

Apparatus for controlled delivery of molecules at a predetermined region of interest within a fluid- filled cavity or vessel by means of ultrasound activatable particles. Said apparatus comprises a system for locating the region of interest (1), a first injection system (4) for injecting said ultrasound activatable particles into said cavity or vessel, wherein said first injection system is adapted to adjust the flow rate of said ultrasound activatable particles and a second injection system (4) for injecting said molecules into said cavity or vessel, wherein said second injection system is adapted to adjust the flow rate of said molecules. The apparatus further comprises a delivery system (1) for delivering said molecules by activating the ultrasound activatable particles at the region of interest, a detection system for determining the delivery of the molecules at the region of interest and a controller (7) for controlling the first and second injection system and the delivery system in response to the detection system.

Description

Apparatus for controlled delivery of molecules using a controlled injection system

FIELD OF THE INVENTION

The present invention relates to an apparatus for controlled delivery of molecules at a predetermined region of interest within a fluid- filled cavity or vessel. In particular, the present invention relates to an apparatus for controlled delivery of therapeutic molecules at a predetermined region of interest within a subject by means of ultrasound activatable particles.

BACKGROUND OF THE INVENTION

Controlled drug delivery to a specific region of interest within the body of a subject is an important technique in the field of medical practice. It allows a directed impact onto a certain tissue, organ or the like while minimizing deterioration of other parts of the body which are not subjected to undesirable side-effects. Furthermore, the effective impact of controlled drug delivery facilitates reduction of dosage.

Several techniques and methods have been developed in order to selectively deliver drugs to specific regions. Ultrasound has the advantage over several other delivery mechanisms in that it can cause the localized release of a drug from transport particles with minimal effect on surrounding tissues. This allows for non- invasive and site-targeted delivery.

Various such ultrasound-assisted delivery methods have been disclosed. For example, US 5 580 575 describes a therapeutic drug delivery system comprising gas-filled microspheres containing a therapeutic, in particular gas-filled liposomes having encapsulated therein a drug. Once the microspheres containing the therapeutic have been introduced into the patient's body, a therapeutic compound may be targeted to specific tissues through the use of sonic energy, which is directed to the target area and causes the microspheres to rupture and release the therapeutic compound.

US 5 190 766 discloses a method of controlling the release of a drug by a sound wave by using a gas-containing elastic microcapsule as a drug carrier for selectively administering to a local region. In order to accelerate the release of the drug, the microcapsule is irradiated with a sound wave which has a frequency corresponding to the resonance frequency of the microcapsule in the living body.

EP 1 052 976 discloses a similar method using microcapsules as drug carrier, wherein the microcapsules have specific and predetermined acoustic properties such that the specific ultrasonic energy format required to rupture the microcapsules can be predetermined as a release threshold prior to injection into the subject. In addition, microcapsules can be tailored for specific rupture characteristics, e.g. for being non-rupturable at normal physiological pressures.

US 6 896 659 describes a method for ultrasound triggered drug delivery using hollow, agent-loaded microbubbles with controlled fragility. Said method further comprises the step of monitoring the location of the microbubbles by ultrasound or other suitable detection techniques to detect their presence at the region of interest.

However, a drawback of all methods using ultrasound for directed drug delivery disclosed so far is, that monitoring of the transport particles - if applied at all - happens with the drug or therapeutic agent already present in the body. Therefore conventional methods often provide inadequate control over the delivery of the drug leading to a large variability and poor reproducibility. Furthermore, current approaches often require large amounts of transport particles including the drug to be injected into the body before therapy even begins due to the need to co-locate the therapeutic zone with the focused ultrasound transducer's or imaging transducer's field of view.

SUMMARY OF THE INVENTION

It is an object of the present invention to provide an improved apparatus for controlled delivery of molecules at a predetermined region of interest within a fluid- filled cavity or vessel by means of ultrasound activatable particles, wherein the relevant parameters for molecule delivery are well-controlled. It would be advantageous if the apparatus reduced the amount of therapeutic molecules required and improved the dosage and spatial control of the molecule delivery. Furthermore, it would be desirable to provide a large degree of certainty, accuracy and repeatability with said apparatus. Therefore, the present invention provides an apparatus for controlled delivery of molecules to a region of interest within a fluid- filled cavity or vessel, in particular within a subject. The apparatus comprises a first injection system for introducing ultrasound activatable particles into the subject, wherein said injection system is adapted to adjust the flow rate of the ultrasound activatable particles. The apparatus further comprises a second injection system for introducing molecules, in particular therapeutic molecules, into the subject, wherein said injection system is adapted to adjust the flow rate of the molecules. The first and second injection system may be realized by a common or different injection system(s). In particular, first and second injection system may be one and the same system, or first and second injection system may be different injection systems. It is preferred that the flow rate of the ultrasound activatable particles and the flow rate of the molecules are individually adjustable. Moreover, the apparatus may comprise further flow rate adjustable injection systems for introducing further particles and/or molecules. Preferably, each injection system is controlled by a controller such that the flow rate of each injection system is individually adjustable and controllable.

The apparatus of the present invention comprises a system for locating the region of interest. In particular, the system for locating the region of interest may comprise a monitoring system for monitoring the location of the ultrasound activatable within the region of interest, i.e. within the region of interest in a subject. It is an advantage of the present invention that the region of interest may be already located by using the ultrasound activatable particles without activation of said particles by ultrasound. According to a further aspect of the invention, the monitoring system may detect the ultrasound activated particles, i.e. the ultrasound activatable particles which have been activated by means of ultrasound. The detection by the monitoring system is preferably based on ultrasound activable/activated particles without conjugated molecules. Moreover, the monitoring system is preferably adapted to image, observe or detect the perfusion of the region of interest such that the flow of the ultrasound activatable/activated particles can be optimally adjusted and controlled in the region of interest.

The apparatus further comprises a delivery system for delivering said molecules by activating the ultrasound activatable particles, preferably with conjugated molecules, at the region of interest. The delivery system is adapted for the controlled delivery of the molecules which are conjugated to the ultrasound activatable particles. The delivery system preferably comprises an ultrasound system for delivering a spatially controlled ultrasound pressure field to a region of interest, e.g. within the body of the subject, in order to activate the ultrasound activatable particles within this region.

The apparatus according to the present invention comprises a detection system for determining the delivery or the expected delivery of the molecules at the region of interest. The determining of the delivery or the expected delivery can be based on an imaging system which is adapted for imaging and/or detecting the ultrasound activated particles in vivo. According to a further aspect of the present invention, the detection system may be realized without using an imaging system. The determining of the delivery may then be based on measurable values, e.g. said detection system may be based on blood sampling or on monitoring a change in tissues response, e.g. breathing, heart rhythm, heart rate, and/or the like.

The above mentioned imaging system, which is preferably part of the detection system, may be equal with the above mentioned monitoring system, which is preferably part of the system for locating the region of interest. According to a further aspect of the invention, the monitoring system and the imaging system may be identical, i.e. one imaging system is used for the monitoring and imaging system. According to yet another aspect of the invention, the monitoring system and imaging system may be different imaging systems. The monitoring /imaging system(s) could be one or more of the following: ultrasound, Single Photon Emission Computed Tomography (SPECT), Positron Emission Tomography (PET), optical or photo-acoustic imaging, infra-red, x-ray Computed Tomography (CT) or Magnetic Resonance Imaging (MRI).

The apparatus of the present invention comprises a controller adapted to control the at least two injection systems, optionally further existing injections systems, and the delivery system, e.g. the ultrasound system, in order to optimize the delivery of the molecules. In this application the term "ultrasound activatable particles" means particles, that are suitable for activation through ultrasound. E.g., it could refer to microbubbles, which are stable under normal conditions and which can be forced to rupture by application of an ultrasound pressure field. Other examples of activatable particles include heat-activated liposomes. Nanoparticles such as heat sensitive polymers or phase-changing liquids or solids may also be included in this class of particles. Once the activatable particles are activated, they are referred to as "activated particles". It may further be advantageous, if the ultrasound activatable particles can be used as carriers for molecules.

The term "molecules" as used in the present invention refers to plasmid DNA, RNAi, antibodies, aptamers, sugars, oil-soluble and water soluble therapeutics, imaging tracers (e.g. radioactive isotopes) and the like. In certain embodiments, the molecules can be conjugated to ultrasound activatable particles by placing them within or on the surface of the particles.

The ultrasound activatable particles and the molecules are introduced into a subject, e.g. a body, by injection and/or infusion, wherein the flow and/or flow rate of the ultrasound activatable particles and/or the molecules can be adjusted independently with the first and second injection system. It is also conceivable that the apparatus according to the present invention is adapted to inject two or more different kinds of molecules into a body. These could be therapeutic molecules and/or other molecules, e.g. ligands, such as antibodies, aptamers, or certain sugars, in order to enhance the target specificity of the treatment using biochemical binding. Such an embodiment may use avidin coated particles which are mixed with biotinylated therapeutics, antibodies and/or imaging tracers (such as radioactive isotopes).

In some embodiments, the apparatus further comprises an interaction chamber for conjugating at least the molecules to the ultrasound activatable particles. The interaction chamber is adapted to mix the therapeutic molecules with the particles in such a way to conjugate the two. Specific flow conditions, interaction time and other factors are controlled by the controller. The conjugation of more than two species within the interaction chamber is also conceivable. In another embodiment of the present invention, the apparatus further comprises a user interface for providing input of a user to the controller.

In a further preferred embodiment, subject of the present invention is a kit comprising a first component of ultrasound activateable particles and a second component of molecules, in particular therapeutic molecules such as specific plasmid DNA, RNAi, or high- energy radio emitters to be used in conjunction with an apparatus according to the present invention.

The invention further relates to a method for controlling the delivery of molecules at a predetermined region of interest within a fluid-filled cavity or vessel by means of ultrasound activatable particles. The method comprises the steps: injecting said ultrasound activatable particles into said cavity or vessel, wherein the flow rate of said ultrasound activatable particles is adjusted, monitoring the injection of the activatable particles, injecting said molecules into said cavity or vessel, wherein the flow rate of said molecules is adjusted, delivering said molecules by activating the ultrasound activatable particles at the region of interest, determining the delivery or the expected delivery of the molecules at the region of interest, and controlling the injection of the ultrasound activatable particles and the molecules as well as the delivery in response to the detection . Preferably said method is implemented by the apparatus described above.

These and other aspects of the invention will be apparent from and elucidated with reference to the embodiments described hereinafter. BRIEF DESCRIPTION OF THE DRAWINGS

Fig. 1 schematically shows an apparatus for controlled molecule delivery using ultrasound according to a preferred embodiment of the present invention. Fig. 2 shows a flow chart describing a method of controlled delivery of therapeutic molecules using the apparatus according to a preferred embodiment of the present invention.

DETAILED DESCRIPTION OF EMBODIMENTS Fig. 1 schematically shows an apparatus for controlled molecule delivery using ultrasound according to a preferred embodiment of the present invention. The apparatus comprises an ultrasound device comprising a focused ultrasound surgery (FUS) transducer 1, a transducer standoff 2 and a FUS control system 3. The apparatus further comprises an injection system 4, which is connected to a reservoir 5 of therapeutic molecules and a reservoir 6 of ultrasound activatable particles, e.g., microbubbles, a controller 7 and a user interface 8.

The injection system 4 is adapted to inject material of reservoirs 5 and 6 into subject 9 via a single needle or catheter. The flow rate as well as the ratio of material from reservoir 5 and reservoir 6 is controlled by controller 7. In one embodiment of the present invention, the injection system 4 comprises two pumps (e.g. Harvard Bioscience syringe pumps), one containing the therapeutic molecules and the other containing the ultrasound activatable particles (e.g. microbubbles). Both pumps are adapted to be driven independently from each other by controller 7. In another embodiment a series of three or more pumps is arranged for. The output of the two, three or more pumps is combined to a single needle or catheter that enters the subject 9, the latter being a patient or an animal for preclinical studies. It is preferred to inject the output of the pumps intravenously. But subcutaneous, intramuscular or other types of injection are conceived as well.

In certain preferred embodiments the injection system 4 may further comprise an interaction chamber which is adapted to mix the therapeutic molecules with the ultrasound activatable particles and to conjugate the two. Appropriate flow conditions, interaction time and other parameters for conjugation of the species are controlled by the controller 7.

In some embodiments of the present invention, two or more different kinds of molecules and/or ultrasound activatable particles are injected. This may require several pumps and interaction chambers, connected with each other via several valves and flow control systems. All these components are operated independently by controller 7, before the output of said arrangement reaches the needle or catheter.

Subject 9 is positioned in a way allowing for locating the region of interest within the subject. The region of interest is preferably located by a monitoring system, e.g. by imaging the region of interest by means of an ultrasound device. This may be done by an additional ultrasound device (not shown in Fig. 1) or by the FUS transducer 1 in case said transducer is capable for imaging. An output of the imaging process is being sent to user interface 8. Controller 7 controls the ultrasound device and is in communication with user interface 8. The FUS transducer is adapted to apply ultrasound pulses of suitable pressure, frequency and/or duty cycle to a region of interest within the subject in order to activate the ultrasound activatable particles, thereby releasing the therapeutic molecules. Therein the application of the ultrasound pulse is spatially well controlled in order to release said therapeutic molecules only within the region of interest, whereas the ultrasound activatable particles stay intact elsewhere in the body of the subject. Moreover, the same FUS transducer or preferably another diagnostic ultrasound transducer or other imaging modality may further be used for imaging a region of interest using conventional imaging techniques.

The application of ultrasound pulses is controlled by FUS control system 3 which is in communication with user interface 8 as well. This allows for a user to choose a region of interest for application of the pulses and to input parameters like energy and/or duration of the pulse, depending on the specific medical task.

In certain embodiments of the delivery or the expected delivery may be detected by means of a detection system. Preferably, the detection system comprises an imaging system like ultrasound, Single Photon Emission Computed Tomography (SPECT), Positron Emission Tomography (PET), optical or photo-acoustic imaging, infra-red, x-ray Computed Tomography (CT), or Magnetic Resonance Imaging (MRI). According to the present invention the apparatus may further or alternatively comprise other detection techniques (not shown in Fig. 1) in order to determine or monitor the delivery of the therapeutic molecules. These may be blood sampling, measuring changes in tissue response, e.g., breathing, heart rhythm, heart rate or the like. Combinations of one or several of these systems with an embodiment of the apparatus of the present invention might be realized by means of an integrated system or a modular architecture.

Fig. 2 shows a flow chart describing a method of controlled delivery of therapeutic molecules using the apparatus of the present invention. First, the ultrasound activatable particles and the therapeutic molecules are placed in the injection system (Sl and S2) and the injection system is connected to the subject (e.g. a patient or an animal for preclinical studies) via a needle or catheter (S3). The subject is positioned in order to allow for a monitoring system, e.g. an ultrasound device, to properly locate or image a region of interest within the subject.

Then the controller starts injection or infusion of the ultrasound activatable particles into the subject (S4). In the mean time the controller monitors the injection/infusion of the ultrasound activatable particles (S5) using the monitoring system (e.g. an ultrasound imaging system) and adjusts the flow rate of the latter via the injection system (e.g. by changing a flow rate of a pump of the injection system) in order to optimize perfusion of the region of interest (e.g. an organ or specific tissue).

Afterwards, the therapeutic ultrasound system is placed in a correct location (S6) allowing for the ultrasound pulses to be delivered to the region of interest. This location can be optimized and verified by monitoring the impact of test pulses onto the ultrasound activatable particles. E.g., it may be visualized where microbubbles rupture due to the delivery of said ultrasound pulse. This allows for a good alignment of the region of interest, e.g. an organ, with a region, where the impact of the ultrasound suffices to rupture the microbubbles, without the therapeutic molecules being even present in the body of the subject. Once the therapeutic ultrasound is placed correctly with respect to the region of interest, the controller starts the injection/infusion of therapeutic molecules, e.g. plasmid DNA, with a controlled flow rate (S7). After a specific delay time the controller activates the therapeutic ultrasound transducer (S8) in order to deliver ultrasound pulses of predetermined energy, frequency and/or wave form to the region of interest and observes the activation of the ultrasound activatable particles (S9). The delay time may be a predetermined time derived, e.g., from the monitored time used by the microbubbles to perfuse the region of interest. The delay time may also be determined during injection/infusion of the therapeutic molecules by imaging the perfusion of the region of interest with the molecules.

The therapeutic ultrasound is delivered according to a protocol provided by the controller. For example, a certain number of pulses may be applied or the delivery might last for a certain number of heart beats. The protocol may also be determined by an additional imaging process during the application ascertaining delivery of the therapeutic molecules, e.g. by blood sampling or measuring a tissue response like breathing, heart rhythm, heart rate or the like. After successful completion of the protocol the controller halts the therapeutic ultrasound (SlO) and stops the injection/infusion of therapeutic molecules (Sl 1) and ultrasound activatable particles. Then a new therapeutic zone or region of interest is chosen (S 12) according to the specific medical task and the process is repeated until the entire therapy is complete. The new zone may be chosen from a pre-defined therapy map or by a user-interaction.

Furthermore, the ultrasound activatable particles, e.g. contrast bubbles, may be infused and used as a contrast agent in order to image and map the temporal (flow) distribution of the targeted region of interest (e.g. an organ). Then the flow of the therapeutic molecule, e.g. plasmid DNA, will be controlled in the same way as the contrast bubble injection so that the plasmid DNA concentration at a specific time at each location within the organ is known. The therapeutic ultrasound may be delivered according to the temporal concentration and flow velocity distributions. E.g., for a bonus plasmid DNA injection, therapeutic pulses will be delivered first to the high velocity flow region and then to regions of slower flow, and a larger ultrasound dosage (pulse length, pulse repetition frequency and/or amplitude) may be delivered to the region with a higher DNA concentration.

The apparatus of the present invention has several advantages. The present invention provides an apparatus for controlled delivery of therapeutic molecules using a guided ultrasound therapy device, wherein the relevant parameters for molecule delivery are well-controlled by a controller. The apparatus reduces the amount of therapeutic molecules required, since the controlled placement of the therapeutic ultrasound device uses ultrasound activatable particles only and thereby happens prior to injection/infusion of the therapeutic molecules. By monitoring the size of the interaction zone, the apparatus can alter the flow of therapeutic molecules to improve the dosage and spatial control of the molecule delivery. Furthermore, it provides a large degree of certainty, accuracy and repeatability of the targeted delivery, since delivery parameters are optimized and controlled prior to the delivery. The apparatus is easy to use, since it can be automated to a large degree by the use of a central controller. Finally, the method and apparatus have a large range of application in several medical fields using a large variety of diverse medical therapies.

Claims

CLAIMS:

1. Apparatus for controlled delivery of molecules at a predetermined region of interest within a fluid- filled cavity or vessel by means of ultrasound activatable particles, said apparatus comprising:

(a) a system for locating the region of interest; (b) a first injection system (4) for injecting said ultrasound activatable particles into said cavity or vessel, wherein said first injection system is adapted to adjust the flow rate of said ultrasound activatable particles;

(c) a second injection system (4) for injecting said molecules into said cavity or vessel, wherein said second injection system is adapted to adjust the flow rate of said molecules;

(d) a delivery system (1,2,3) for delivering said molecules by activating the ultrasound activatable particles at the region of interest;

(e) a detection system for determining the delivery or the expected delivery of the molecules at the region of interest; and (f) a controller (7) for controlling the first and second injection system and the delivery system in response to the detection system.

2. Apparatus according to claim 1, wherein first and second injection system are one and the same system.

3. Apparatus according to claim 1, wherein first and second injection system are two different injection systems, which may be similar.

4. Apparatus according to any one of claims 1 to 3, wherein the controller (7) is adapted to control the flow rate of the first injection system for injecting the ultrasound activatable particles and/or to control the flow rate of the first and second injection system for injecting the ultrasound activatable particles and the molecules.

5. Apparatus according to any one of claims 1 to 4, wherein said system for locating the region of interest comprises a monitoring system for imaging and/or detecting the ultrasound activatable particles at the region of interest.

6. Apparatus according to any one of claims 1 to 5 wherein the detection system for determining the delivery or the expected delivery of the molecules at the region of interest comprises one or more of the means selected from the group of blood sampling means, means for determining changes in tissue response, such as breathing, heart rhythm or heart rate, and means for a timed delivery.

7. Apparatus according to claim 5 or 6, wherein the monitoring system or imaging system, respectively, is selected from the following group: ultrasound imaging system, Single Photon Emission Computed Tomography (SPECT), Positron Emission Tomography (PET), optical or photo-acoustic imaging, infra-red, x-ray Computed Tomography (CT), Magnetic Resonance Imaging (MRI).

8. Apparatus according to any one of claims 1 to 7 wherein the detection system for determining the delivery of the expected delivery comprises an imaging system for imaging and/or detecting the ultrasound activatable particles in vivo.

9. Apparatus according to any one of claims 1 to 8, wherein the delivery system comprises an ultrasound system for delivering a spatially controlled ultrasound pressure field to the region of interest in order to activate the ultrasound activatable particles within said region of interest and thereby releasing the therapeutic molecules.

10. Apparatus according to claim 9, wherein the controller is adapted to start the ultrasound system, once a predetermined input from one or several of the monitoring/imaging system(s) of claims 3 or 4 is detected.

11. Apparatus according to any one of claims 1 to 10, further comprising an interaction chamber for conjugating the molecules to the ultrasound activatable particles.

12. Apparatus according to any one of the claims 1 tol 1, wherein the injection system is adapted to inject and/or infuse two or more different kinds of molecules and/or ultrasound activatable particles.

13. Apparatus according to any one of the claims 1 to 12, wherein the injection system is adapted to inject and/or infuse at least one type of molecules selected from the following group: plasmid DNA, antibodies, aptamers, sugars, biotinylated therapeutics, imaging tracers, radioactive isotopes, pharmaceuticals, protein molecules and complexes.

14. Apparatus according to any one of the claims 1 to 13, wherein the ultrasound activatable particles comprise microbubbles.

15. Apparatus according to any one of the claims 1 to 14, wherein the ultrasound activatable particles comprise perfluorocarbon droplets or nanoparticles.

16. Apparatus according to any one of the claims 1 to 15, wherein the ultrasound activatable particles comprise heat-activated liposomes.

17. Apparatus according to any one of the claims 1 to 16, further comprising a user interface for providing input of a user to the controller.

18. Kit comprising a first component with ultrasound activatable particles and a second component with user- supplied molecules to be used in conjunction with an apparatus according to any one of claims 1 to 17.

19. Method for controlling the delivery of molecules at a predetermined region of interest within a fluid- filled cavity or vessel by means of ultrasound activatable particles, said method comprising the steps:

(a) injecting said ultrasound activatable particles into said cavity or vessel, wherein the flow rate of said ultrasound activatable particles is adjusted;

(b) monitoring the injection of the activatable particles;

(c) injecting said molecules into said cavity or vessel, wherein the flow rate of said molecules is adjusted;

(d) delivering said molecules by activating the ultrasound activatable particles at the region of interest;

(e) determining the delivery or the expected delivery of the molecules at the region of interest; and

(f) controlling the injection in steps a) and c) and the delivery in response to the detection.