SYSTEM FOR FUNCTIONAL OR DIAGNOSTIC IMAGING AND METHOD THEREOF USING MAGNETO-ELECTRIC NANO-PARTICLES (MENPs)

Abstract

This invention provides methods and systems for achieving high-specificity killing of targeted cells using Magneto-Electric Nano-Particles (MENPs) and functional or diagnostic imaging that detects changes at the cellular level. Embodiments comprise injecting into a patient's body manufactured MENPs that have a higher tendency to accumulate near or attach to targeted cells through one or more physical forces and/or biological mechanisms; and applying a magnetic field to the MENPs to generate an action that is sufficient to cause death of the targeted cells, and using an imaging apparatus to image or detect a specific property of the MENPs or changes in a property of the MENPs due to the coupling of the MENPs with their surrounding environment.

Claims

1. A method for functional or diagnostic imaging that detects changes at the cellular level comprising injecting Magneto-Electric Nano-Particles (MENPs), which have a magneto-electric coupling property that changes their magnetic properties due to the electric fields of their surrounding environment in vitro into a biological sample or in vivo into a biological system; after a period of time or after the MENPs have reached a site to be imaged, using an imaging apparatus to image or detect a specific property of the MENPs or changes in a property of the MENPs due to the coupling of the MENPs with their surrounding environment; and mapping the detected or imaged specific property of the MENPs or changes in the property of the MENPs to the corresponding types or properties, or changes in the types or properties, of cells or bodily fluid in the immediate environment of the MENPs that caused the detected or imaged specific property or changes in the property of the MENPs.

1. method according to claim 1 further comprising a probing step by first applying an external magnetic field to generate electrical field around the MENPs to interact with the cells in the immediate environment of the MENPs to detect or amplify the effect of ionic or electrical properties of different cells or changes in the properties of cells; and using an imaging apparatus to image or detect the effect of the probing due to the further distinguished interactions of the MENPs with different cells.

3. The method according to claim 1 wherein the imaging apparatus images the magnetic resonance frequency(ies) of the MENPs and the specific property of the MENPs or changes in the property of the MENPs to be imaged or detected is the magnetic resonance frequency(ies) of the MENPs.

4. A system for functional or diagnostic imaging that detects changes at the cellular level comprising Magneto-Electric Nano-Particles (MENPs) which have a magneto-electric coupling property that changes their magnetic properties due to the electric fields of their surrounding environment and are to be injected in vitro into a biological sample or in vivo into a biological system; an imaging apparatus that images or detects a specific property of the MENPs or changes in a property of the MENPs due to the coupling of the MENPs with their surrounding environment; and a mapping module (or mapper) that maps the detected or imaged specific property of the MENPs or changes in the property of the MENPs to the corresponding types or properties, or changes in the types or properties, of cells or bodily fluid in the immediate environment of the MENPs that caused the detected or imaged specific property or changes in the property of the MENPs.

4. system according to claim 4, further comprising a probing apparatus that first applies an external magnetic field to generate electrical field around the MENPs to interact with the cells in the immediate environment of the MENPs to detect or amplify the effect of ionic or electrical properties of different cells or changes in the properties of cells; and an imaging or detection or functional module in the imaging apparatus to image or detect the effect of the probing due to the further distinguished interactions of the MENPs with different cells.

6. The system according to claim 4, wherein the imaging apparatus images the magnetic resonance frequency of the MENPs and the specific property of the MENPs or changes in the property of the MENPs to be imaged or detected is the magnetic resonance frequency(ies) of the MENPs.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0050] The present invention is illustrated by way of example, and not by way of limitation, in the figures of the accompanying drawings and in which like reference numerals refer to similar elements All the figures are schematic and generally only show parts which are necessary in order to elucidate the invention. For simplicity and clarity of illustration, elements shown in the figures and, discussed below have not necessarily been drawn to scale Well-known structures and devices are shown in simplified form, omitted, or merely suggested, in order to avoid unnecessarily obscuring the present invention,

[0051] FIG. 1 shows a magnet disk and an electromagnet apparatus used to generate external magnetic field to control MENPs.

[0052] FIG. 2 is a flow chart of an embodiment of functional or diagnostic imaging method or apparatus that detects changes at the cellular level using the ME coupling of MENPs with the nano-environment.

[0053] FIG. 3 is a flow chart of an embodiment for targeted killing of cancer or diseased cells using nano-electroporated MENPs that provide a new cancer treatment that is non-toxic or low-toxic.

[0054] FIG. 4 illustrates the constructive superimposition of magnetic field vectors from multiple magnets at targeted locations inside a patient's body that is sufficient to move MENPs along the superimposed magnetic field gradient or to cause nano-electroporation or killing at the focus point but not elsewhere.

[0055] FIG. 5 shows embodiment of (a) magnetic needles, (b) magnetic field conducting needles and (c) magnetic wires for applying magnetic field deep inside tissues with high accuracy.

[0056] FIG. 6 is a flow chart of a method for functional or diagnostic imaging that detects changes at the cellular level in an embodiment of the invention.

[0057] FIG. 7 illustrates a system for functional or diagnostic imaging that detects changes at the cellular level in an embodiment of the invention.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT

[0058] Reference may now be made to the drawings wherein like numerals refer to like parts throughout. Exemplary embodiments of the inventions may now be described. The exemplary embodiments are provided to illustrate aspects of the inventions and should not be construed as limiting the scope of the inventions. When the exemplary embodiments are described with reference to block diagrams or flowcharts, each block may represent a method step or an apparatus element for performing the method step.

[0059] The present inventions provide methods, processes or construction of an apparatus for using the unique physics of MENPs to achieve high-specificity killing of cancer cells via application of an external magnetic field to generate an electric field and/or mechanical motion after one or more MENPs have penetrated the cancer cells' membrane, without loading or coating any drug on the MENPs, and causing no harm or only minimum harm to normal cells.

[0060] In both cases (drug-loaded MENPs or MENPs alone), the MENPs have a non-zero magnetic moment and therefore, if administrated in a patient's body, can be remotely navigated through the blood circulation and/or lymph systems via application of adequately high remote magnetic field gradients (e.g., >1000 Oe/cm). The MENPs can be administrated via subcutaneous (SC) intratumoral (IT), peritumoral (PT), intraperitoneal (IP), or intravenous (IV) injection, or oral intake (OI), or by other means.

[0061] In case of IT, IP or PT injection, the passive targeting is initiated externally (by injecting directly into or near the tumor) One embodiment applies an external magnet field that serves to attract the MENPs at the tumor site and/or to cause the MENPs to penetrate the membrane of cancer cells, The magnetic field can be applied either via permanent magnets or electromagnets depending on the size and shape of the tumor. The external magnetic field is applied prior to or at the time of the IT, IP or PT injection and is maintained afterwards for a period of time. The strength of the external magnetic field is chosen to be (1) sufficiently strong to overcome the viscosity of the cellular microenvironment, preventing nano-particles from moving to other parts via circulation of body fluids and further amplifying the well-known Enhanced Permeability and Retention (EAR) effect that nano-particles tend to accumulate in tumor tissue much more than they do in normal tissue, (2) sufficiently strong to cause the MENPs to penetrate the membrane of cancer cells, but (3) not too strong to cause the MENPs to penetrate the membrane of normal cells. At a second stage, after the MENPs are inside the cancer cells, one embodiment applies an external magnetic field to generate local electric fields on the MENPs via the magnetic-electric (ME) coupling characteristics of the MENPs. When the electric field is sufficiently strong, it disrupts the mechanisms of the cancer cells or kills the cancer cell by electric shock. In another embodiment, the MENPs are coated with drugs and the combination of the electric field and drug kills the cancer cells.

[0062] One embodiment for targeting with IT, IP or PT injection uses a permanent magnetic disk 10 with a hole 11 in the'middle for the needle to go through, illustrated in FIG. 1a. The disk is first applied to the targeted site prior to or at the time of injection. The shape and magnetic field strength of the disk can be customized to the targeted site, where the required magnetic field strength is achieved by selecting the material and thickness of the disk. Another embodiment for targeting with IT, IP or PT injection uses an electromagnet 15 with a hole 16 in the middle whose size and shape is matched with the targeted site, and the required the magnetic field strength is achieved by selecting the number of windings of the coils and/or the amount and or frequency of electric current applied by a Current Driver and Controller, see FIG. 1b.

[0063] In case of IV administration (including IV injection and IV dripping using a catheter), drug-loaded MENPs and MENPs alone can also be further navigated to the tumor cells via application of magnetic field gradients. In one embodiment, MENPs that are sufficiently small (e.g., <100 nm) and have an elongated shape (e.g., elliptical, or nano-rods) are used in IV administration. We note that nano-rods propagate in the circulatory system easier than equivalent sized spheres. Such IV-administered MENPs can potentially reach every cell in the body through the body's circulatory system even without application of an external magnetic field. However, in one embodiment, an external magnetic gradient field is applied to guide the MENPs towards the cancer site to further improve the targeting capability. The external magnetic gradient field can be a static field or a dynamic field. One embodiment applies a magnetic field at a level of strength high enough to trigger the nano-electroporation effect to drive MENPs, with or without loaded drugs, inside the cancer cells but not high enough to affect the normal cells. This magnetic field can be applied either locally in the vicinity of the tumor or globally to the entire body. The duration of the field application ranges from hours to many days, maintained during the length of IV dripping or for a period of time after the IV injection or IV dripping, depending on the stage and type of cancer. In addition, to further improve the active targeting capability, the MENPs with or without loaded drugs, can be further conjugated with ligands or antibodies that are specific to certain surface receptors or other biomarkers which are over-expressed around the cancer cells. This causes the MENPs in the circulation to attach to cancer cells and facilitates the nano-electroporation by the externally applied magnetic field. In other words, the roles of ligands/antibodies and MENPs are complementary to each other: the ligands/antibodies enable delivery of MENPs towards the surface of cancer cells while MENPs induce the nano-electroporation to move inside cancer cells targeted by the ligands or antibodies. Both effects are specific to cancer cells and therefore the specificity of the combined effect can be significantly improved,

[0064] In another embodiment, a rotating or pulsating magnetic field is applied which generates a rotating or pulsating electric polarization on the MENPs to facilitate targeted nano-electroporation The strength and/or frequency of the rotating or pulsating electric polarization is selected to induce selective nano-electroporation of targeted diseased cells, i.e., the strength and/or frequency rotating or pulsating of the external magnetic field is chosen such that the MENPs only or mainly penetrate the membranes of one or more types of targeted cells and do not or mostly do not penetrate the membranes of other cells. Targeted penetration of the membrane of certain types of diseased cells are better achieved using rotating or pulsating polarization of the MENPs.

[0065] In one embodiment, after MENPs have penetrated through the cancer or other diseased cell membranes through nano-electroporation, one or more of the following mechanisms is applied to kill the cancer or diseased cells,

[0066] (A). Apply an external magnetic field to generate strong enough electric field on the MENPs inside the cancer or diseased cells to kill them, e.g., local electric fields on the order of 1000 V/cm, which can be attained a few nanometers away from MENPs via the application of an external magnetic field on the order of 100 Oe;

[0067] (B). Apply an alternating external magnetic field to induce an alternating electric field on the MENPs inside the cancer or diseased cells wherein the strength and frequency of the field is selected such that it disrupts the functions of these cells, thus causes them to die off;

[0068] (C). Apply an alternating external magnetic field to generate heat on the MENPs inside the cancer or diseased cells to kill them wherein the strength and frequency of the field is selected to generate sufficient heat to kill the cancer or diseased cells without harming surrounding cells or tissues;

[0069] (D). Apply an alternating external magnetic field to induce mechanical motions of the MENPs inside the cancer or diseased cells to disrupt the cell functions or to physically damage the cells from inside, causing them to die off; where the mechanical motions may include linear motion, slicing, collisions or vibrations, or combinations thereof.

[0070] In another embodiment, a ferromagnetic resonance strongly dependent on the interaction of MENPs with its nano-environment (in the proximity of a few nanometers away from the nano-particles) is used to selectively disrupt or shut down the operation of certain cellular organneles, e.g. nucleus, microtubules, and others, when MENPs are already inside the cancer cells. The ferromagnetic resonance of MENPs depends on the saturation magnetization, which in turn, because of the ME effect, strongly depends on the electric fields that are associated with the interaction of MENPs with the nano-environment. As the nano-environment changes, so does the saturation magnetization and consequently the ferromagnetic resonance frequency(ies). This resonant frequency or set of resonant frequencies can be varied in a wide range by varying intrinsic properties, e.g. the magneto-crystalline anisotropy energy and the exchange coupling constant, or extrinsic properties, e.g. the shape-induced anisotropy energy In addition, the resonant frequency(ies) can be controlled by application of an external DC magnetic field. By specifically selecting the resonant frequencies, certain functions of cancer cells can be shut down with a relatively high specificity on demand. For example, the microtubules responsible for cancer cell proliferation could be remotely controlled via ferromagnetic resonance of the MENPs. Namely, the resonant frequency of MENPs in the proximity (of 2 nm) of the microtubules changes because of the changes in the saturation magnetization. The saturation magnetization change is due to the ME effect caused by the interaction of the MENPs and the microtubules. An external AC magnetic field at the new modified resonant frequency can then be applied to disrupt or cause damages to, the microtubules.

[0071] Another embodiment is a functional or diagnostic imaging method or apparatus that detects changes at the cellular level, shown in FIG. 2. The first step 21 in FIG. 2 is the injection of MENPs in vitro into a biological sample or in vivo into a biological system, e.g., an animal or human body. In 22 in FIG. 2, after MENPs have reached a site to be imaged, because of the tight ME coupling of the MENPs, the ionic or electrical properties of different cells or bodily fluid in the immediate nano-environment of the MENPs, or in the cells to which MENPs are bound, cause different changes in the magnetic properties of the MENPs, thus their ferromagnetic resonance frequency(ies). In 24 in FIG. 2, a magnetic resonance imaging apparatus is used to image or detect the specific magnetic resonance frequency(ies) of the MENPs or changes in the magnetic resonance frequency(ies) of the MENPs. In 25 in FIG. 2, the detected or imaged specific magnetic resonance frequency(ies) of the MENPs or changes in the magnetic resonance frequency(ies) of the MENPs are then mapped to the corresponding types or properties, or changes in the types or properties, of cells or bodily fluid in the immediate nano-environment of the MENPs that caused the specific magnetic resonance frequency(ies) or changes in the magnetic resonance frequency(ies) of the MENPs. In 23 in FIG. 2, the embodiment may further include a probing step that first applies an external magnetic field to generate electrical field around the MENPs to interact with the cells in the immediate nano-environment of the MENPs to detect or amplify the effect of ionic or electrical properties of different cells or changes in the properties of cells, e g , causing nano-electroporation into cancer cells. The interactions of the MENPs with some cells will be further distinguished from other cells. Thereafter, a magnetic resonance imaging apparatus is used to image or detect the effect of the probing due to the further distinguished interactions of the MENPs with different cells, e.g., cancer cells and normal cells.

[0072] The above mechanisms of targeted killing of cancer or diseased cells using nano-electroporated MENPs provide a new cancer treatment that is non-toxic or low-toxic. The steps of a preferred embodiment, as shown in FIG. 3, comprise:

[0073] Step 1 (31 in FIG. 3): Injecting MENPs, via IT, PT, IP, IV (IV injection or dripping using a catheter) or by other means.

[0074] Step 2 (32 in FIG. 3, optional): Applying a first magnetic field externally to produce higher concentration of MENPs at and around a diseased site or in an organ or body part. This step is optional and applicable to a disease site this is localized, e.g., the site of a tumor, and is skipped and not or less applicable when the cancer or diseased cells are widely distributed, e.g., in the circulatory system or metastasized to many sites).

[0075] Step 3 (33 in FIG. 3): Applying a second magnetic field at a level A<H<B where A and B are thresholds so that the MENPs achieve nano-electroporation to penetrate targeted cancer or diseased cells but no or little nano-electroporation of healthy or non-targeted cells.

[0076] Step 4 (34 in FIG. 3): Applying a third magnetic field to induce the MENPs to generate one or more of the effects in (A) to (D) listed above to disrupt the function of the diseased cells

[0077] Steps 3 and 4 may be combined into a single step. For a disease that is localized, a localized second and/or third magnetic field this is confined to the disease site is applied. For a disease in which the targeted cells are widely distributed, a wide-area second and/or third magnetic field that covers a large body area or the whole or most part of the body is applied so that cancer or other diseased cells that are circulating in or have metastasized to other parts of the body can be penetrated and killed.

[0078] In one embodiment, the strength and/or frequency of the third magnetic field in Step 4 is chosen to cause the MENPs that have penetrated into cancer or diseased cells to kill these targeted cells but does not cause other MENPs that still remain in the body to penetrate or harm healthy or untargeted cells. In another embodiment, a sufficiently long waiting period is inserted between Steps 3 and 4 to give the body sufficient time to excrete most or all of the free MENPs that did not penetrate or bind to cancer or diseased cells out of the body. This reduces the risk of MENPs killing, healthy or untargeted cells and gives more freedom in selecting the strength and/or frequency of the third magnetic field in Step 4 to kill the diseased or cancer cells

[0079] Because of the physical (not chemical) nature and the targeting specificity of remote-field-controlled nano-electroporation, the above embodiments can be applied to the multi-drug-resistant (MDR) cancer cell lines that are known to develop immunity to the conventional chemistry-based drugs. For the same reason, the above embodiments can be applied to eradicate isolated (i.e., not aggregated into tumors) cancer stem cells, which are difficult to eradicate using the existing chemistry-based approaches.

[0080] Shape, size, ME coupling and other properties are important for the embodiments of this invention. One embodiment for making MENPs with a wide range of properties comprises first depositing a thin film with the required properties via sputter deposition, evaporation, or another deposition technique, and then using ion beam proximity lithography (IBL) or imprint or another advanced lithography to cut the thin films into MENPs of desired shapes and sizes.

[0081] One embodiment is an apparatus that is capable of generating one or more of the first, second and third magnetic fields described above. This embodiment may further include a sensor or imaging device that measures one or more of the following: the strength and/or gradient of the magnetic field at one or more location, the position and/or motion of the MENPs inside the body, or effective local electric field calculated from magnetic imaging of MENPs, and provide the measurements to a feedback control loop which controls the generation and application of the magnetic field to achieve desired strength, frequency and/or distribution of the magnetic field Yet another embodiment is an apparatus comprising multiple magnets 41 arranged in an enclosure to generate a 3-dimensional magnetic field with sufficient strength in tissues or organ deep inside a human body. The apparatus works by constructively superimposing magnetic field vectors 42 from multiple magnets 41 at targeted locations inside a patient's body, as illustrated in FIG. 4. This allows magnetic field strength sufficiently strong to attract MENPs or MNPs 43, cause them to move along the magnetic field gradient produced from the summation 44 of magnetic field vectors from all the magnets, to cause selective nano-electroporation of cancer cell, and/or to generate one or more of the cancer cell killing mechanisms in (A) to (D), at the targeted location but not strong enough at other locations to cause undesired effects on MENPs that may be still be present at other parts of the body. The magnets can be permanent magnets and/or electromagnets. In the case of permanent magnets, they can be physically moved to produce changing magnetic field gradients to guide MENPs to a location inside a human body. In the case of electromagnets, they can be electrically controlled, by selectively turning on or off, up or down, or changing the frequencies of the electric currents driving the electromagnets. The apparatus may further include a Magnetic Resonance Imaging (MRI) or a Magnetic Nano-particle Imaging (MNI) device that produces measurements or images of the 3D distribution of the magnetic field in real time or near real time, and use the measurements to control the generation of the 3D magnetic field to guide MENPs to the desired location inside a human body and/or to generate magnetic field at a desired location to produce nano-electroporation of diseased or cancer cells and/or elicit one or more of the mechanisms in (A) to (D) to kill the diseased or cancer cells. In one embodiment, the MENPs are made with adequately high magnetization value (above 10 emu/cc) to facilitate MNI.

[0082] A calibration procedure is performed first when it is applied to a patient at a fixed position to achieve sufficiently accurate mapping of the measurements or images of the 3D distribution of magnetic field to actual locations inside the patient's body. In one embodiment, the calibration procedure establishes a common coordinate system and all measurement points and points inside a human body are mapped into points in this common coordinate system. With accurate MRI or MNI and calibration, this apparatus can achieve pinpoint accuracy in killing diseased or cancer cells in the desired location inside a patient's body.

[0083] Another embodiment for pinpoint accuracy uses one or more magnetic needles 52 that is used to both inject solutions with MENPs 51 and produce the magnetic field to keep the MENPs in the injected cancer tissue area 53 and for nano-electroporation and cancer cell killing mechanisms, as shown in FIG. 5a. Another embodiment uses one or more highly magnetic field conducting needles 56 to conduct external magnetic field to a location deep inside a patient's body 53, as shown in FIG. 5b. In both cases, multiple needles can be used to generate a magnetic field to cover the volume of the targeted tumor 53. Yet, another embodiment injects or pushes one or more very thin magnetic wires 58 through the hollow of the injection needle of an injecting device 57 into the targeted site 53 to produce sufficient magnetic field at the targeted site for nano-electroporation and cancer cell killing mechanisms. One end of the magnetic wire is kept at the end of the injecting device 57 that is outside the body or connected to handle and the wire can be removed by pulling the wire through the injecting needle when the treatment is completed, as shown in FIG. 5c. The magnetic wire may further be self-coiling such that when it is pushed out of the needle and into the body, it will coil so that the mass of the wire will stay near the site of the injection, as shown in FIG. 5c. Furthermore, the wire may have a dull and smooth or spherical tip so that when it is injected, it causes minimal or no puncture of blood vessels. In all three embodiments illustrated in FIG. 5, multiple needles or magnetic wires can be inserted into different depth and locations in a targeted volume.

[0084] Another embodiment uses one or more of the various pinpoint embodiments described above, including projection of magnetic field into a site inside the body, using needles or wires, as an initiation to amalgamate MENPs to a site targeted by the pinpoint. The pinpoint method attracts MENPs nearby to the site and/or causes nano-electroporation of MENPs into cancer cells at the site. These MENPs are no longer mobile and further attract other passing by MENPs to the site, forming a positive-feedback self amalgamation process. A pinpoint method is used to plant a seed for the self amalgamation process that attracts more and more MENPs to the targeted site. The self amalgamation process can also start without applying a pinpoint method at sites where nano-electroporation of cancer cells occurs under a broad magnetic field. Once nano-electroporation of cancer cell occurs, the MENPs that entered into the cancer cells can no longer move away and their presence at the site automatically attract other MENPs nearby or passing by, starting a self amalgamation process.

[0085] Various exemplary embodiments of the invention provide a method for functional or diagnostic imaging that detects changes at the cellular level. As shown in FIG. 6, the method includes:

[0086] Step 610: injecting Magneto-Electric Nano-Particles (MENPs), which have a magneto-electric coupling property that changes their magnetic properties due to the electric fields of their surrounding, environment in vitro into a biological sample or in vivo into a biological system;

[0087] Step 620: after a period of time or after the MENPs have reached a site to be imaged, using an imaging apparatus to image or detect a specific property of the MENPs or changes in a property of the MENPs due to the coupling of the MENPs with their surrounding environment; and

[0088] Step 630: mapping the detected or imaged specific property of the MENPs or changes in the property of the MENPs to the corresponding types or properties, or changes in the types or properties, of cells or bodily fluid in the immediate nano-environment of the MENPs that caused the detected or imaged specific property or changes in the property of the MENPs.

[0089] In an embodiment, the method may further include a probing step by first applying an external magnetic field to generate electrical field around the MENPs to interact with the cells in the immediate nano-environment of the MENPs to detect or amplify the effect of ionic or electrical properties of different cells or changes in the properties of cells; and using an imaging apparatus to image or detect the effect of the probing due to the further distinguished interactions of the MENPs with different cells.

[0090] In an embodiment, the imaging apparatus images the magnetic resonance frequency(ies) of the MENPs and the specific property of the MENPs or changes in the property of the MENPs to be imaged or detected is the magnetic resonance frequency(ies) of the MENPs.

[0091] As shown in FIG. 7, the present invention also provides a system 700 for functional or diagnostic imaging that detects changes at the cellular level comprising: Magneto-Electric Nano-Particles (MENPs) 710 which have a magneto-electric coupling property that changes their magnetic properties due to the electric fields of their surrounding environment and are to be injected in vitro into a biological sample or in vivo into a biological system, an imaging apparatus 720 to image or detect a specific property of the MENPs or changes in a property of the MENPs due to the coupling of the MENPs with their surrounding environment; and a mapping module (or mapper) 730 that maps the detected or imaged specific property of the MENPs or changes in the property of the MENPs to the corresponding types or properties, or changes in the types or properties, of cells or bodily fluid in the immediate nano-environment of the MENPs that caused the detected or imaged specific property or changes in the property of the MENPs.

[0092] The system in FIG. 7 may further include a probing apparatus 740 that first applies an external magnetic field to generate electrical field around the MENPs to interact with the cells in the immediate nano-environment of the MENPs to detect or amplify the effect of ionic or electrical properties of different cells or changes in the properties of cells; and an imaging or detection or functional module 721 in the imaging apparatus to image or detect the effect of the probing due to the further distinguished interactions of the MENPs with different cells The imaging apparatus may image the magnetic resonance frequency(ies) of the MENPs and the specific property of the MENPs or changes in the property of the MENPs to be imaged, or detected is the magnetic resonance frequency(ies) of the MENPs.

[0093] Although the foregoing descriptions of the preferred embodiments of the present inventions have shown, described, or illustrated the fundamental novel features or principles of the inventions, it is understood that various omissions, substitutions, and changes in the form of the detail of the methods, elements or apparatuses as illustrated, as well as the uses thereof, may be made by those skilled in the art without departing from the spirit of the present inventions. Hence, the scope of the present inventions should not be limited to the foregoing descriptions. Rather, the principles of the inventions may be applied to a wide range of methods, systems, and apparatuses, to achieve the advantages described herein and to achieve other advantages or to satisfy other objectives as well.