Application Progress of Nano-material in Molecule Functional Imaging with Radionuclide Tracing Technique and Targeted Treatment
Published Date: May 14, 2014
Application Progress of Nano-material in Molecule Functional Imaging with Radionuclide Tracing Technique and Targeted Treatment
*Yao Ning, Chen Xue-qi, Wang Rong-fu
Department of Nuclear Medicine, Peking University First Hospital, Beijing 100034, China
*Corresponding Author: Yao Ning, Department of Nuclear Medicine, Peking University First Hospital, Beijing 100034, China
Citation: Yao Ning, Chen Xue-Qi, Wang Rong-Fu (2014) Application Progress of Nano-material in Molecule Functional Imaging with Radionuclide Tracing Technique and Targeted Treatment. J Mole Biol Tech 1(1): 5.
The development of molecular imaging with radionuclide tracing and treatment relies on the advancement of precise probes at the cellular and molecular levels. The novel specific tumor-targeting probes have been exploited in the design of nanoscale carriers being able to deliver radioactive molecules in a selective manner. These nano-materials have shown better image contrast by tissue-targeting and cell-targeting. In addition, because of the variety of the materials and the uniqueness of the structures, nanoprobes can realize multimodal imaging at molecular level, and this imaging can complement each other's advantages of different imaging modals. The treatment groups are joined into the nanoparticle, then a new nanoprobe form-the theranosis nanoprobe, which has synchronously realized the diagnosis and therapy at the molecular level. At the same time, the application of intelligent nanoprobes can achieve the smart control of drug releasing and reduce the side effects of cancer treatment. In a word, the development of this new drug delivery system about nanoparticles has brought about a new breakthrough of the nuclear medicine.
Keywords: Nano-Material; Intelligent Nanoprobe; Multimodal Imaging; Theranosis
Nano-materials have the mesoscopic size range of 5 to 200 nm, and this property allows their unique interaction with biological systems at the molecular level . As nano-materials have special volume and structure, they have several special natures that are different from the conventional materials , such as a number of surface active centers, high catalytic efficiency, high surface activity, low toxicity and less susceptible to be degraded by various of enzymes in vivo. These special features make nano-materials be widely used in biomedical fields, such as drug delivery, molecular imaging, vaccine preparation and so on . Nano-delivery systems have been extensively and deeply studied in the field of molecular nuclear medicine as the rapid development of nano-materials and nano-technology [4-6].
There are many different kinds of nano-materials. Now the materials used in nuclear medicine are not only liposomes , but also dendritic polymers , polymer micelles  and so on. Nanoparticles could encapsulate drug in sac or combine with specific ligands, antibodies, imaging agents and other small molecular substances on the surfaces. Those changes are able to effectively regulate the speed of drug releasing, improve the drug targeting, target and image the lesion sites. In addition, the modifications of the nanoparticles surface also change the polarity, increase permeability of biological membrane and improve the bioavailability of drugs.
The Investigation from World Health Organization (WHO) showed that cancer had already become one of the main reasons for human death, and the patient number would be more than 131 million by 2030. As early as 2005, American National Cancer Research Center has already presented a cancer nanotechnology program that combined nanotechnology, cancer research and molecular biology together to change the methods of cancer prevention, diagnosis and treatment. In recent years, nanomaterials have been widely used in tumor imaging and treatment. For tumor imaging and therapy, the ideal radionuclide probes should accumulate at the tumor sites maximally, and form a good contrast with the normal tissue. The combination of radionuclide and nano-material makes a better distribution of radionuclide probe in the targeting tissue. At the same time, the nanoparticles loaded chemotherapeutics can also reduce the side effects during the process of chemotherapy. Compared with traditional imaging materials, nano-materials have greater image signal, better targeting effect, and superior pharmacokinetic. This paper elaborates on the progress in the field of applications of nanomaterial in functional imaging with radionuclide tracing technique and targeted treatment.
Unique Advantages of Nanoparticles
Combination of Active and Passive Targeting Transport
Compared with the traditional drugs, nano-materials can achieve passive and active targeting transport by virtue of the advantages from their unique sizes and materials. The mechanism of passive targeting transport lies in the enhanced permeability and retention effect (EPR) . There are 600-800nm gaps among the tumor blood vessels adjacent vascular endothelial cells, which are different from the normal human blood vessels, and the lymphatic drainage is poor in the tumor tissue. These factors cause the enhanced permeability and retention effect (EPR), and this effect results in the nanoparticles passing through the gaps and arriving at the tumor tissue, realizing passive targeting transport. Studies have shown that the nano-materials transport efficiency is much higher than the conventional materials . As the research moves along, it is found that the nano-materials are suitable for penetrating the gaps of tumor angiogenesis epithelial cells at early stage and successfully improving the bioavailability of drugs at last. However, the tumor interstitial fluid pressure at advanced stage is higher than the pressure at early stage, and the tumor types and anatomical sites are also different from tumor to tumor. The reasons above lead to the reduction of drug uptake and effluence of nanoparticles, so the active targeting delivery systems are designed to solve this problem. Targeting ligands and antibodies are coupled to nano-materials surfaces, and the nano-delivery systems could actively target tumor tissue where specific receptors or antigens are expressed or over expressed on. Active targeting drug delivery improves delivery efficiency. For example, the gold nanoparticles  could be coupled with peptide ligands, say RGD sequence, which participate the progress of tumor angiogenesis, and the gold nanoparticles also carry infrared fluorescent probes on the surfaces and anticancer drugs in the sacs. When the assembled nanoparticles enter the human body, the ligands RGDs specifically recognize the integrin αVβ3. For the integrin αVβ3 is highly expressed on tumors during the progress of tumors angiogenesis, gold nanoparticles aggregate in the sites of tumors. Nanoparticles could realize active targeting transport by the guide of ligands RGDs. The property of passive targeting transport is realized by the enhanced permeability and retention effect, and the active targeting transport is realized by conjugating specific ligands or antibodies to the surface of nanoparticle [13,14]. In a word, the targeting efficiency has been improved through the united effects from both passive targeting transport and active targeting transport.
Nano-materials are the materials sized between 1-100nm or the materials using nano-materials as the basic units . Due to different choice of original materials and fabrication methods, varieties of shapes and sizes of nanoparticles are formed, which meets the scientific and clinical needs, such as liposomes, polymer drug conjugates, polymer micro bubbles and so on [16-18]. In the mid 1990s, a new concept of nanoparticles surface engineering is put forward by the International Materials Conference, namely to change the nanoparticles surface structures and surface states by physical and chemical methods, which gives the nanoparticles new properties and improves the physical shapes. Through modifications, the nanoparticles could enhance surfactivity, increase solubility of insoluble drugs, implement long cycle in vivo, increase the drug action time and improve the bioavailability [19,20].
Reduce or Reverse the Multidrug Resistance
When it comes to the therapy of cancer, multidrug resistance is one of the prime factors that affect the cancer treatment. It is mainly manifested as no obvious change after anticancer therapy or tumor recurrence after a period of effective treatment. One of the main reasons of multidrug resistance is the existence of some natural barriers such as blood brain barrier (BBB). The low permeability of BBB is due to microvessel endothelial cells in human brains. These cells contain active efflux pump systems, which remove a large volume of probes from brain to the blood, and the acidic environment in tumors can result in resistance through neutralization. Further, high interstitial pressure may also lead to extravasation of molecules. In addition, the change of some enzymatic activity, the alteration of cell apoptosis regulating path and the increase of drug effluxion are all the factors that cause the multidrug resistance. It could be concluded that the existence of multidrug resistance have serious effects on the efficiency of anticancer drugs, so a new method to reduce or bypass the multidrug resistance is urgent to be found. The research on nano-materials makes a new way for the improvement of antitumor efficiency. Literatures [21-23] showed that the anticancer drugs with nano-delivery systems could effectively pass through the blood-brain barrier and get to the intracranial tumors. Furthermore, the efflux pump effect could be overcome by using nano-materials. For example, anticancer drug doxorubicin could be encapsulated by poly-cyanoacrylate nanoparticles that are used for preventing doxorubicin from the acidic environment before entering the cells. Once the nanoparticles get into the cells, cyanoacrylates hydrolysis and the hydrolysates form ion pairs with doxorubicin, then the ion pairs overcome the effect from efflux pumps located in the cell membranes. The whole process realizes the reversion of drugs outflow successfully [24,25]. The therapeutic effects have been proved better than the traditional medicine in the animal experiments. Beyond that, endocytosis is achieved by the combination of the ligands on the surfaces of nanoparticles and the receptors on the cell membranes, which could bypass the effluxion of the nanoparticles and reduce multidrug resistance.
Figure1. Schematic presentation of: A)Sphere, B)hydrogel: Swollen and collapsed state, C)micelles, D)Capsule.
Application of Nanomaterials in Nuclear Medicine
Molecular Imaging with Radionuclides using Nano-materials
Molecule functional imaging with radionuclide tracing techniques is usually divided into two general modalities, single photon emission computed tomography (SPECT) and positron emission tomography (PET). These imaging techniques are all of great clinical value for earlier recognition of the presence and the extent of malignancy based on the fact that biochemical changes generally are prior to anatomical changes. PET is one of the most sophisticated molecular imaging technologies now. The imaging modality has high sensitivity and the relevant animal experiments can be extended to clinical application directly. The most commonly used contrast agent for PET is 18F-fluorodeoxyglucose (18F-FDG) at present. Since most tumors have the characteristics of high glucose metabolism rate, 18F-FDG is widely used in cancer imaging. However, as FDG is a kind of glucose metabolism imaging agent rather than tumor-specific imaging agent, FDG-PET can not accurately show the outline and spread of all the tumors. After modified the nanoprobes with the isotopes, ligands, antibodies, corresponding functional groups, the image is clearer and the diagnosis is more precise than the unmodified modality . A polymer nanoprobe  coated with monoclonal antibody has the capability of specifically combining with endothelial cells. The real-time research about biodistribution and pharmacokinetics in vivo has been carried out with this probe successfully. A carbon nanotube  is coupled with peptides RGDs and 64Cu for PET imaging in mice, and the probe could accumulate in the tumor well. A cross-linked dextran iron oxide nanoparticle (CLIO)  is linked with 18F, and then this nanoprobe obtains an image with high signal to noise ratio.
Compared with PET imaging, nano-materials used in SPECT are easier to radiolabel, and with more radionuclides to choose. These characteristics determine that nano-materials are applied in SPECT more widely. Hereinafter the nano-materials applications in SPECT/CT are elaborated. Doxil is the liposome that is entrapped doxorubicin and has been used in clinical practices. 186Re-Doxils and PEG doxorubicin liposomes  are intravenously injected into nude mice with transplanted head and neck cancers separately. Doxils have aggregated in the tumor 20 times the PEG liposomes. The 99mTc-DTPA-labeled dendrimer polyamide is synthesized , and the copolymers have exhibited excellent stability both in vitro and vivo. SPECT scan has shown that the copolymers successfully target to the KB tumor cells in mice. The multiwall carbon nanotubes  have bonded with the 10-hydroxycamptothecin derivatives, and 99mTc has been attached to the amino group that is a portion of the carbon nanotubes. The scan showed that the carbon nanotubes distribute rapidly in liver, spleen and other organs and tissues; the signal intensity increases 2-4 hours after injection; and the signal has remained for 4-22 hours. The reagent Pam-Tc/Re-800 , as a novel multifunctional diagnostic reagent, can be used not only in near-infrared light (near-infra red, NIR) imaging but also in SPECT imaging.
Molecular imaging is the subject that studies the molecular visible detection with imaging technique, and studies the qualitative and quantitative changes of molecule, cell and gene in vivo. Radionuclide imaging, magnetic resonance imaging and optical imaging are the three main techniques in this field, and there are advantages and disadvantages in any kind of imaging method alone. Multimodality imaging refers to the combination of the single imaging modes, which can achieve complementary advantages of different imaging modes and make up for the disadvantages of the single one. Multimodality imaging is the developing direction of molecular imaging in the future. The key of achieving multimodality imaging is the exploration, design and preparation for the multimodality molecular probes. Compared with the poor detection accuracy and common false positive of the single imaging mode, multimodality imaging realizes the multi-targeting recognition and improves the diagnostic sensitivity and accuracy. Nano-materials are one of the best choices for multimodality molecular probes because of their unique properties. Nanoparticles could form various sharps of internal spaces such as spherical shape, cylindrical shape, ring shape in the assembly process. Different imaging agents are loaded into internal or external spaces. For example, The superparamagnetic iron oxide nanoparticles  were put into the nanoparticle internal space. A variety of ligands were also loaded to nanoparticles, and the nanoparticles actively combined with the tumor cells after they arrived at the target organs. It meaned that one operation completed SPECT/CT and MRI imaging simultaneously. The distribution and elimination, physiological and pathological status of the probes could be obtained from different respects. For another example, a new liposome  carrying both radionuclide and fluorescein has been developed, which means the liposome is radiolabelled with iodine and also carries fluorescent probe. This dual functional probe for the multimodality imaging-SPECT imaging and fluorescence imaging simultaneously is used to study how the nanoparticles break the barriers against the multidrug resistance and track the infringement and permeability of tumor blood vessels. It is found that the degree of retention depends on local blood flow and nanoparticle size itself. Bigger nanoparticles are more prone to multidrug resistance in the region of local blood flow fast, while smaller nanoparticles are less prone to multidrug resistance in the region of local blood flow slow. Beyond that, the nanoparticles with ligands on the surface could effectively overcome the pressure from interstitial fluid, and compel the effluent nanoparticles back to the blood system by active targeting transport. Some magnetic microbubbles are also labeled with radionuclide , such as 99mTc-microbubbles labeled by functional groups DTPA, TOPA or others. These multimodality probes obtain the anatomical and functional information from different angles through SPECT/CT/MR imaging, which obviously promote the efficiency of diagnosis.
Targeted Treatment with Radionuclide using Nano-materials
Nano-materials have unique advantages in targeted radionuclide therapy, especially in the development of intelligent nano-materials and the application of nano-materials in theranosis. The development of nano-materials has mainly experienced three stages. The first generation of nano delivery systems realizes passive targeting transport based on the enhanced permeability and retention effect. The appearance of EPR relies on the modified hydrophilic shell and its unique size and structure. As the research moves along, it has been found that the factors such as the diversification of tumor types, the diversity of anatomic sites and increasing interstitial fluid pressure in the advanced tumors all cause the difficulty of nano-drugs entering the tumor tissue as expected. For all the reasons above, the second generation of nano-delivery system, active targeting delivery system, receives the attention. The nanoparticles connect the target polypeptides, receptors, ligands and other small molecules in the nanoparticles surfaces, and this progress achieves active targeting delivery and improves the efficiency of tumor therapy and imaging successfully. Before long, it is found that although the second generation of nano-delivery system realizes the active targeting delivery, there are still some unnecessary side effects at the same time. Therefore, the intelligent nano-delivery system, as the third generation of nano-delivery system, begins to be researched. The tiny differences such as PH value and temperature between the normal tissues and tumor tissues are used to develop intelligent groups [37,38], such as PH sensitive groups and temperature sensitive groups. The nano-delivery system achieves intelligent control by conjugating these intelligent groups to nanoparticles. When the nanoparticles arrive at the normal tissues, the drugs would not be released into blood and tissues because the drugs are still coated by nano-material shells. However, the intelligent nanoparticles will open shells once they feel the change of PH value or temperature in the area of tumor tissues. Then the released drugs begin to work, so the intelligent nanoparticles minimize the side effects by the effect of intelligent groups. For example, because the environment around the tumor has lower pH value and less metal proteinase 2(MMP2), the cell penetrating peptides which can be activated in the environment of lower pH value and less metalloproteinase 2 are constructed, then the cell penetrating peptides are attached to the surface of nanoparticles. Once the nanoparticles feel the change of pH value or metalloproteinase 2, the cell penetrating peptides will be activated and nanoparticles start to internalize into the tumor cells. The anti-vascular endothelial growth factor iRNA and doxorubicin packaged by the nanoparticles are released into the tumor cells, and then the drugs restrain tumor angiogenesis and promote tumor cell apoptosis. The results showed that the nanoparticles have better targeting to tumor vessels, less side effects and more obvious anti-cancer effects .
So far, the main methods of tumor therapies are operation, radiotherapy and chemotherapy. Some patients can only accept chemotherapy for some reasons and other patients also need chemotherapy after surgery. It is very important to evaluate metabolic situation of chemotherapeutic drugs and the acting sites since the demands of chemotherapy are so large. As always, diagnostics and therapeutics belong to two different subjects. A new word " theranosis " has been paid more and more attention recently, which means one operation could realize the diagnosis and treatment of disease at the same time. Although this concept is proposed in recent years, the application of theranosis can be traced back to 50 years ago. At that time, 131 I was used for diagnosis and treatment of hyperthyroidism and thyroid cancer in the field of nuclear medicine, while radioimmunoassay is used for diagnosis and therapy of some tumors lately . A mature theranosis imaging agent can be effectively transported to the target sites, and provide explicit imaging signals and abundant drug solubility in the target sites . It is found that the nanoparticles have incomparable advantages in the application of theranosis, and the chemotherapeutic drugs are coupled with imaging agents by the medi of nanoparticles. For example, the fluorescent nanoparticles are firstly synthesized [41,42], then the doxorubicin are encased into the nanoparticles, and the fluorescence signals from the site of tumor cells could be collected by the optical imaging instrument once the nanoparticles arrived at the mice bodies. This operation achieves the tracing of drug transportation and metabolism in vivo, locates the action site for the target imaging, and what’s more important, it could implement imaging and treatment simultaneously. The animal experimental results showed that the effect was improved compared with the non-nano-delivery systems, and the delivery systems have a definite potential in the applications of theranosis.
In summary, the unique advantages of nano-materials are definite, and the characteristics are inimitable compared with conventional materials, especially in specificity, targeting and superior absorption. Molecule functional imaging with radionuclide tracing techniques can trace the changes of disease in the cells and molecules, which realize the estimation of the disease microenvironment in vivo, and have made a revolutionary impact on modern and future medical model. Molecular probes are the basis of molecular imaging, which herald the direction of the development on medical imaging technology. Nanoprobes have overcome the defects of traditional probes. To a certain extent, nanoprobes solve the problems that the common molecular probes could not. It has already made remarkable achievements in molecular imaging field. More and more nanoprobes have come to clinical applications from basic researches. There are advantages and disadvantages of various molecular imaging techniques in aspects of temporal and spatial resolution, penetration depth, energy range availability of probes and so on. The combination of various imaging techniques will provide more comprehensive information. The new multi-functional imaging probes are "smart" and "competent", and they can not only be applied in a variety of imaging techniques, but also own therapeutic effects. In recent years, the researches on multimodal molecular imaging and theranosis have already achieved significant progression. However, the long-term effects about nano-materials on human are still not very clear. In addition, another factor of the main restrictive reasons for the clinical application of nanoparticles is the toxic effects . Now the scholars all over the world are committed to the development of the new nano-materials, in order to make the new materials more intelligent and avirulent. Therefore, the application of nano-delivery systems in the field of nuclear medicine has brought new opportunities and challenges for tumor diagnosis and treatment.
We acknowledge the contributions of our research group of Department of Nuclear Medicine of Peking University First Hospital. We thank Dr. Wang and Dr. Chen for their suggestions in revising of this article. This work was supported by grants from Natural Science Foundation of China (NSFC 30870729, 81071183) (http://www.nsfc.gov.cn/Portal0/default152. htm); Ministry of Science and Technology of China (project 2011YQ030114 and 2011YQ03011409) (http://www.most.gov.cn/eng/); Research Fund for the Medicine and Engineering of Peking University (Fund BMU20120297)(http://en.coe.pku.edu.cn/); and Research Fund Key Laboratory of Radiopharmaceuticals (Beijing Normal University), Ministry of Education, Department of Chemistry, Beijing Normal University, Beijing, China (120201)(http://radiopharm.bnu.edu.cn/). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
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