Patent Publication Number: US-2017354601-A1

Title: Ion implantation of magnetic elements into nanodiamond particles to form composition for medical usage

Description:
FIELD AND BACKGROUND OF THE INVENTION 
     The present invention relates to composition for medical usage and method of preparing the same, and more particularly to magnetic nanoparticles which are formed by ion implantation of magnetic elements into nanodiamond particles, wherein such magnetic nanoparticles can serve as a composition for further use of various medical purposes. 
     Recently, a field of research dedicated to the treatment of cancer patients based on the localized heating effects of magnetic nanoparticles in vivo has been developed. For many years, scientists have been doing research and reported the potential use of heat treatment which can cure or shrink tumor. Hyperthermia is being widely used in cancer treatment, which utilizes heat to destroy cancerous tumors. In hyperthermia therapy, i.e., hyperthermia in cancer treatment, the effects of heat on cancer cells are well-known, and electromagnetic fields have been used to localize and concentrate heat by directly heating the magnetic nanoparticles so as to cause a temperature increase within nearby cancer cells. Also, the outcome measured by patient survival and tumor regression is better when heat and radiation are combined. Normal cells typically recover faster than cancer cells when exposed to either heat or the combination of heat and radiation. Additionally, normal tissues have more blood flow than cancerous tissue so that they dissipate heat better, and this is thus fortunate for cancer treatment by heat or heat and radiation combination. 
     In the conventional hyperthermia therapy, magnetic iron oxide/iron nanoparticles (such as Fe 2 O 3 , Fe 3 O 4 , Fe, etc.) are employed to be synthesized with targeting drugs for hyperthermia therapy. The magnetic iron oxide/iron nanoparticles are guided to cancer cells, and then they are induced to generate heat by exposure to an alternating radiofrequency magnetic field such that the cancer cells heating came from hysteresis losses from the magnetic iron oxide/iron nanoparticles. 
     However, the above mentioned magnetic iron oxide/iron nanoparticles exhibit several disadvantages including cytotoxicity and poor biocompatible properties. Moreover, since the magnetic iron oxide/iron nanoparticle has few carbon-hydrogen bonds or ionic bonds on the surface thereof, it is difficult to synthesize a large amount of chemotherapy drugs or targeted agents with the magnetic iron oxide/iron nanoparticle. Accordingly, it is necessary to provide a new type of magnetic nanoparticles which have much less toxic side effects for medical usage and can easily synthesize with a large amount of chemotherapy drugs or target agents so as to solve the technical problems in the prior art. 
     SUMMARY OF THE INVENTION 
     In order to solve the above-mentioned technical problems, an objective of the present invention is to provide a composition and a method of preparing the same. The composition comprises magnetic nanoparticles which are formed by embedding magnetic elements into nanodiamond particles by using ion implantation technique and such composition can be further synthesized with targeting agents and to deliver such the composition to tumor cells for hyperthermia therapy. Moreover, the magnetic nanoparticles in the composition can provide the use of magnetic resonance imaging to precisely diagnose tumor location and distribution. Thus, the delivery ability of compositions through the synthesized targeting agents can be monitored by using magnetic resonance imaging so as to determine whether enough concentration of compositions are reached at a target site in a patient for proper treatment. In addition, the composition can be further synthesized with other medicine agents, for example antimicrobial agent, such that the composition can be guided to concentrate at a targeted site in the patient by applying an external magnetic field so as to treat a bacterial infection or other diseases. 
     In order to achieve the above objective, the present invention provides a composition for medical usage, comprising: at least one magnetic nanoparticle including a nanodiamond particle and at least one magnetic element, wherein the at least one magnetic element is embedded into the at least one nanodiamond particle through ion implantation technique by using an ion implantation system. 
     In one preferred embodiment of the present invention, the at least one magnetic element is selected from the group consisting of at least one Iron (Fe), Manganese (Mn), Cobalt (Co), and Nickel (Ni) element. 
     In one preferred embodiment of the present invention, the composition further comprises at least one targeted agent synthesized with the nanodiamond particle of the at least one magnetic nanoparticle for targeted delivery of the composition to a target site in a subject to perform a hyperthermia therapy. 
     In one preferred embodiment of the present invention, the composition contains magnetic nanoparticle can provide the use of magnetic resonance imaging technique to precisely diagnose tumor location and distribution in an environment of the target site, such that a delivery ability of the composition through the targeting agent is monitored by using MRI so as to determine whether the composition and its required concentration has been delivered effectively to the target site in the subject for proper treatment. 
     In one preferred embodiment of the present invention, the composition further comprises at least one other medicine agent, for example antimicrobial agent, synthesized with the nanodiamond particle of the at least one magnetic nanoparticle, whereby the composition is suitable to be guided to concentrate at a target site of a patient by applying an external magnetic field. 
     In one preferred embodiment of the present invention, the ion implantation system comprising: an ion source assembly, for generating ions; an extraction assembly, for extracting the ions from the ion source assembly to form an ion beam; an analyzing magnet, for selecting the at least one magnetic element from the ion beam; and an end station, for supporting a workpiece which holds the nanodiamond particle and located in a path of the ion beam such that the at least one magnetic element is implanted into the workpiece thereby to embed the at least one magnetic element into the nanodiamond particle. 
     In one preferred embodiment of the present invention, the ion implantation system comprises a plasma immersion ion implantation. 
     The present invention further provides a method of preparing a composition for medical usage, comprising: providing a workpiece which holds at least one nanodiamond particle; disposing the workpiece on an ion implantation system; and embedding at least one magnetic element into the at least one nanodiamond particle to form a magnetic nanoparticle to obtain the composition by using the ion implantation system. 
     In one preferred embodiment of the present invention, the method further comprises: synthesizing at least one targeted agent with the at least one nanodiamond particle of the at least one magnetic nanoparticle to obtain the composition whereby the composition is suitable for targeted delivery to a target site in a subject to perform a hyperthermia therapy. 
     In one preferred embodiment of the present invention, the method further comprises: synthesizing at least one medicine agent with the at least one nanodiamond particle of the at least one magnetic nanoparticle to obtain the composition, whereby the composition is suitable to be guided to concentrate at a target site of a patient by applying an external magnetic field. 
     In one preferred embodiment of the present invention, the at least one medicine agent comprises at least one antimicrobial agent. 
     In one preferred embodiment of the present invention, the step of embedding at least one magnetic element into the at least one nanodiamond particle to form a magnetic nanoparticle by using the ion implantation system comprises: generating ions by an ion source assembly of the ion implantation system; extracting the ions from the ion source assembly to form an ion beam by an extraction assembly of the ion implantation system; selecting the at least one magnetic element from the ion beam by an analyzing magnet of the ion implantation system; and implanting the at least one magnetic element into the workpiece so as to embed the at least one magnetic element into the at least one nanodiamond particle. 
     In one preferred embodiment of the present invention, after the step of implanting the at least one magnetic element into the workpiece, the method further comprises: annealing the workpiece. 
     The present invention further provides a method of performing hyperthermia therapy in a subject, comprising: administering a composition to a target site in the subject, wherein the composition comprises at least one magnetic nanoparticle including a nanodiamond particle and at least one magnetic element, wherein the at least one magnetic element is embedded into the at least one nanodiamond particle by using an ion implantation system; and exposing the target site to an electromagnetic field to generate heat from the at least one magnetic nanoparticle so as to cause a temperature increase within the target site. 
     In one preferred embodiment of the present invention, the composition comprises at least one targeted agent synthesized with the nanodiamond particle of the at least one magnetic nanoparticle for targeted delivery of the composition to a target site in a subject. 
     In one preferred embodiment of the present invention, after the step of administering a composition to a target site in the subject, the method further comprises: monitoring an using magnetic resonance imaging (MRI) to precisely diagnose an environment of the target site in the subject and to monitor and determine whether the composition has reached the target site with a desired concentration for hyperthermia therapy. 
     The present invention further provides a method of treating a bacterial infection, comprising: administering a composition to a target site in the subject; and guiding the composition to concentrate at the target site of the subject by applying an external magnetic field; wherein the composition comprises: at least one magnetic nanoparticle including a nanodiamond particle and at least one magnetic element, wherein the at least one magnetic element is embedded into the at least one nanodiamond particle by using an ion implantation system; and at least one antimicrobial agent synthesized with the nanodiamond particle of the at least one magnetic nanoparticle. 
     The present invention further provides a method of using magnetic resonance imaging (MRI) to diagnose a disease, comprising: administering a composition to a target site in a subject; and using magnetic resonance imaging to diagnose an environment of the target site in the subject and to monitor and determine whether the composition has reached the target site with a desired concentration, wherein the composition comprises: at least one magnetic nanoparticle including a nanodiamond particle and at least one magnetic element, wherein the at least one magnetic element is embedded into the at least one nanodiamond particle by using an ion implantation system. 
    
    
     
       BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS 
       In order to illustrate the technical solutions in the embodiments of the present invention or in the prior art more clearly, the following briefly introduces the accompanying drawings required for describing the embodiments or the prior art. The accompanying drawings in the following description are merely some embodiments of the present invention, and persons of ordinary skill in the art may still derive other drawings from these accompanying drawings without creative effort. 
         FIG. 1A  shows a schematic diagram of a composition according to a first preferred embodiment of the present invention. 
         FIG. 1B  shows an enlarged view of a portion of  FIG. 1A . 
         FIG. 1C  is a schematic diagram showing magnetic elements implanted into a nanodiamond particle for obtaining the composition of  FIG. 1A . 
         FIG. 2  shows a schematic diagram of a composition according to a second preferred embodiment of the present invention. 
         FIG. 3  shows a schematic diagram of the magnetic nanoparticle of the composition further synthesized with medicine agents. 
         FIG. 4  depicts a schematic diagram showing an ion implantation system for performing a method of preparing magnetic nanoparticles according to a preferable embodiment of the present invention. 
         FIGS. 5A and 5B  illustrate schematic diagrams respectively showing nanoparticles obtained from a workpiece of the ion implantation system of  FIG. 4 , and how to separate magnetic nanoparticles and non-magnetic nanoparticles of the nanoparticles of  FIG. 5A . 
         FIG. 6  depicts a schematic diagram showing a method of preparing a composition by using a plasma immersion ion implantation. 
     
    
    
     DESCRIPTION OF SPECIFIC EMBODIMENTS OF THE INVENTION 
     Please refer to the accompanying drawings, similar parts are denoted with the same reference numerals. The following description is based on the particular embodiments of the present invention, and they should not be construed as limiting the invention to the other embodiments which are not discussed in detail herein. 
     Please refer to  FIG. 1A , which shows a schematic diagram of a composition  10  according to a first preferred embodiment of the present invention.  FIG. 1B  shows an enlarged view of a portion of the composition  10  and  FIG. 1C  is a schematic diagram showing magnetic elements  120  implanted into a nanodiamond particle  110  for obtaining the composition  10  of  FIG. 1A . As shown on  FIG. 1B , the composition  10  comprises a plurality of nanodiamond particles  110  and a plurality of magnetic elements  120 , where the magnetic elements  120  are selected from atoms having ferromagnetism, such as Iron (Fe), Manganese (Mn), Cobalt (Co), or Nickel (Ni) elements. Moreover, as shown on  FIG. 1B  and  FIG. 1C , the magnetic elements  120  are directly implanted into each nanodiamond particle  110  by using an ion implantation system, so that the plurality of magnetic elements  120  are embedded into the nanodiamond particle  110  so as to form a magnetic nanoparticle  100 . 
     It should be noted that, in the present invention, since the nanodiamond particles  110  employed exhibit no obvious cytotoxicity to human cells, and do not induce significant abnormality in cellular functions, the composition  10  is of particular benefit in biomedical and medical applications, e.g. drug delivery, therapy, and diagnostic techniques. However, the scope of the present invention is not limited to the nanodiamond particle only; any other nanoparticles which exhibit no obvious toxicity and have excellent biocompatibility for cancer diagnosis and therapies as well can be selected and within the scope of the present invention. Furthermore, since the nanodiamond particle  110  has a large loading capacity for synthetizing with various types of agents/drugs due to its large surface area to volume ratio, it is advantageous to modify and utilize surface functional properties of the nanodiamond particle  110  to conjugate with therapeutic agents for a specific purpose or multiple purposes usage, such as to deliver a drug with localized distribution to cancer cells, limited diffusion to increase uptakes in cancer cells, image capability to locate cancer cells precisely, and increased drug retention period for cancer treatment. In addition, the surface of the magnetic nanoparticles  100  can be modified to form bonds with folate moieties to effectively target cancer cell which usually is over-expressed with folate receptors than normal cell. So that the cancer cells targeted by the magnetic nanoparticles  100  bonded with folate moieties can have high death rate after hyperthermia therapy. 
     Please refer to  FIG. 2 , which shows a schematic diagram of a composition  20  according to a second preferred embodiment of the present invention. The composition  20  comprises at least one magnetic nanoparticle  100 , in which the nanodiamond particle  110  of the magnetic nanoparticle  100  is further synthesized with targeted agents  200 . Due to the magnetic elements  120  have ferromagnetism, the composition  20  is suitable for use in hyperthermia therapy, where the nanodiamond particle  110  serves as a carrier for in vivo delivery of the magnetic elements  120  to a target site in a subject including a human being or an animal. To be more specific, to perform the hyperthermia therapy in the subject includes the following steps. Firstly, the composition  20  is administered to the subject, and the magnetic nanoparticles  100  will be introduced close to or within the target site by the targeted agents  200 . Next, after the magnetic nanoparticles  100  are located at the target site, the target site is exposed to an electromagnetic field effective to generate heat from the magnetic nanoparticles  100  so as to cause a temperature increase within the target site to destroy cancer cells thereof. In addition, in the present invention, since the magnetic nanoparticles  100  of the composition  20  include the magnetic elements  120 , the magnetic nanoparticles  100  can provide the use of magnetic resonance imaging technique to precisely diagnose tumor location and distribution in a patient. Thus, an environment of the target site and the delivery ability of composition  20  through the synthesized targeted agents  200  can be monitored by using magnetic resonance imaging (MRI) so as to determine whether the composition  20  and its desired concentration has been delivered effectively and reached the target site in the subject for proper treatment. Methods of magnetic resonance imaging in the subject are well-known in the art. It should be noted that since the composition  20  includes the magnetic elements  120  which have superior MRI signal enhancement capabilities in vivo, the composition  20  also can be used to diagnose other diseases as well. 
     On the other hand, in order to ensure that the administered drugs including medicine agents (such as antimicrobial agents) can be successfully concentrated at a correct location in a subject (i.e., human being), the drugs can be synthesized with the magnetic nanoparticle  100  of the present invention. Please refer to  FIG. 3 , which shows a schematic diagram of a composition  30  according to a third preferred embodiment of the present invention. The composition  30  comprises at least one magnetic nanoparticle  100 , in which the nanodiamond particle  110  of the magnetic nanoparticle  100  is further synthesized with medicine agents  300 . Since the magnetic elements  120  have ferromagnetism, the composition  30  can be easily guided into a desired location through applying an external magnetic field to the desired location. Therefore, the delivery efficiency of the medicine agents  300  can be increased, and a total intake amount of drug (i.e., the composition  30 ) can be reduced so as to prevent side effects associated with administration of the medicine agents  300 . In addition, if the magnetic nanoparticle  100  is further synthesized with antimicrobial agents, the composition  30  is suitable for treating a bacterial infection. 
     Please refer to  FIG. 4 , which depicts a schematic diagram showing an ion implantation system  400  for performing a method of preparing magnetic nanoparticles according to a preferable embodiment of the present invention. The ion implantation system  400  includes a high voltage power supply  410 , an ion source assembly  420 , an arc chamber  422 , an extraction assembly  424 , an analyzing magnet  430 , and an end station  440 . The method of preparing the magnetic nanoparticles according to the present invention includes the following steps. Firstly, a workpiece  450  which holds nanodiamond particles is provided and disposed at the end station  440  of the ion implantation system  400 . Specifically, the workpiece  450  holding nanodiamond particles is manufactured by performing the steps of: dissolving nanodiamond powder in deionized water to form a solution; dropping the solution on a substrate (e.g. an oxidized silicon wafer); and removing the deionized water from the substrate by heating the substrate under a lamp, so as to form the workpiece  450  holding the nanodiamond particles. 
     After the workpiece  450  holding the nanodiamond particles is disposed at the end station  440 , the ion implantation system  400  is switched on, and ions are generated by the ion source assembly  420  from feeding materials into the arc chamber  422 . Next, the ions are extracted from the ion source assembly  420  to form a first ion beam  462  by the extraction assembly  424  which provides electrical potential difference between the ion source assembly  420  and the extraction assembly  424 , so that the first ion beam  462  gains energy to leave the ion source assembly  420  toward downstream. 
     When the first ion beam  462  is directed into the analyzing magnet  430 , the desired magnetic elements are selected from the first ion beam  462  by the analyzing magnet  430 , and a second ion beam  464  including the magnetic elements is thus formed and directed from the analyzing magnet  430  into the end station  440 . In the end station  440 , the workpiece  450  holding the nanodiamond particle is located in a path of the second ion beam  464 . Therefore, after the second ion beam  464  is guided into the end station  440 , the workpiece  450  is implanted by the second ion beam  464  with a controlled final energy to embed the magnetic elements into the nanodiamond particles such that the magnetic nanoparticles are thus formed. 
     It should be noted that, the crystal lattice structure of the nanodiamond particle may be damaged after performing the ion implantation process, so an annealing process is employed to repair the damage of the nanodiamond particle. To be specific, after the magnetic elements are implanted into the nanodiamond particles, the workpiece  450  is annealed. Moreover, the crystal lattice structure of the nanodiamond particle being successfully repaired by performing the annealing process can be proven by employing Raman spectroscopy to examine the structural changes of the nanodiamond particle before performing the ion implantation process, after performing the ion implantation process, and after further performing the annealing process. For example, according to the experimental result, the original nanodiamond particles have a diamond peak at 1332.5 cm −1  and a broad peak at 1579 cm −1 , which is probably due to surface graphitic structure. The full width at half maximum (FWHM) of the diamond peak is 10.1 cm −1 . After implanting Fe ions into the nanodiamond particles, the diamond peak is shifted to 1317 cm −1  with a much wider FWHM of 98.5 cm −1 . The blue shift of the Raman peak and the widening of the FWHM are obviously indicative of that the crystal lattice structure of the nanodiamond particle is damaged. 
     Furthermore, after annealing, the diamond peak become very strong and is restored to the original position at 1332.4 cm −1  and the FWHM is reduced to 11.1 cm − . Also, the other peak related to the surface sp 2  bonds is disappeared. The result clearly indicates that the diamond structure is restored and the unwanted surface graphitic structure or its compounds are eliminated concurrently. 
     Please refer to  FIGS. 5A and 5B , which illustrate schematic diagrams respectively showing nanoparticles obtained from the workpiece  450  of the ion implantation system  400  of  FIG. 4 , and how to separate magnetic nanoparticles  100  and non-magnetic nanoparticles, i.e., non-doped nanodiamond particles  130  of the nanoparticles of  FIG. 5A . As shown on  FIG. 5A , after the magnetic elements  120  are embedded into the nanodiamond particles  110  to form the magnetic nanoparticles  100 , the magnetic nanoparticles  100  and some non-doped nanodiamond particles  130  are removed from the substrate of the workpiece  450  by using an ultrasonic bath of deionized water. In this embodiment, since the nanodiamond particles  110  are stacked on the substrate (e.g. Si wafer) with multi-layers, only a part of the nanodiamond particles  110  will be implanted by the magnetic elements  120 . As shown on  FIG. 5B , in order to sort out the magnetic nanoparticles  100 , a magnetic filter  500  can be employed. The magnetic filter  500  may be a magnetic-activated cell sorting tool (MACS® Separator, Miltenyi Biotec Co.). The magnetic nanoparticles  100  embedded with the magnetic elements  120  are attracted by the magnet filter  500  and gathered to the adjacent walls when the nanodiamond solution, which is prepared by dissolving the removed nanoparticles from the workpiece  250  in deionized water, passes through the magnetic filter  500 . Also, the non-doped nanodiamond particles  130  will directly pass freely through the magnetic filter  500  in downward direction. Then the attached magnetic nanoparticles  100  can be flushed out by injected deionized water. Finally, the magnetic nanoparticles  100  are obtained and they can be collected in a beaker with deionized water. 
     Please refer to  FIG. 6 , which depicts a schematic diagram showing a method of preparing a composition by using a plasma immersion ion implantation  600 . In this embodiment, the plasma immersion ion implantation  600  is used for embedding magnetic elements into nanodiamond particles which are located on a bombardment target  610  of the plasma immersion ion implantation  600 . 
     In summary, in the present invention, the magnetic nanoparticles of the composition are prepared by implanting magnetic elements into nanodiamond particles using ion implantation technique for medical usage such that the disease can be effectively treated without exhibiting cytotoxicity to normal cells due to the magnetic elements are embedded with the non-toxic nanodiamond particles. For example, the magnetic nanoparticles of the composition can be further synthesized with targeted agents, whereby the composition can be precisely delivered to tumor cells for hyperthermia therapy. Moreover, the magnetic nanoparticles of the composition can increase provide the use of magnetic resonance imaging to precisely diagnose tumor location and distribution in a patient. Thus, the delivery ability of the composition through the synthesized targeted agents for tumor treatment can be monitored by using magnetic resonance imaging directly so as to determine whether enough magnetic nanoparticles have reached a target site in a patient for proper treatment. In addition, the composition can be further synthesized with medicine agents, e.g. antimicrobial agents, such that the composition can be guided to concentrate at a target site in the patient by applying an external magnetic field so as to treat a bacterial infection or other diseases. 
     The above descriptions are merely preferable embodiments of the present invention, but are not intended to limit the scope of the present invention. Any modification or replacement made by those skilled in the art without departing from the spirit and principle of the present invention should fall within the protection scope of the present invention. Therefore, the protection scope of the present invention is subject to the appended claims.