RECENT ADVANCES AND INNOVATION
|Year : 2004 | Volume
| Issue : 3 | Page : 321-328
|Molecular imaging : A review- part I (Fundamentals and genetic perspective)
S Merchant, S Pruthi, S Mohan, N Merchant
Dept. of Radiology and Imaging, LTM General hospital, Sion, Mumbai-400022, India
Click here for correspondence address and email
| Abstract|| |
Molecular imaging is a promising field, which aims at developing and testing various tools, reagents and methods to image specific molecular pathways in humans, particularly those that are key targets in disease processes. Unlike 'classical' diagnostic imaging; instead of the symptoms-oriented search that operates empirically to modify the behavior of the patient, molecular medicine sets forth to probe molecular abnormalities that are the basis of the disease, rather than to image the end effects of these molecular alterations. Radiologists will play a leading role in directing developments of this embryonic but rapidly expanding field. This article presents some basics in molecular sciences and the fundamentals of molecular imaging including itsgenetic perspective and shows how imaging can be used, to assess specific molecular targets. In the future, specific imaging of such targets will allow earlier detection and characterization of disease, earlier and direct molecular assessment of treatment effects, and a more fundamental understanding of the disease processes.
Keywords: Molecular Imaging
|How to cite this article:|
Merchant S, Pruthi S, Mohan S, Merchant N. Molecular imaging : A review- part I (Fundamentals and genetic perspective). Indian J Radiol Imaging 2004;14:321-8
|How to cite this URL:|
Merchant S, Pruthi S, Mohan S, Merchant N. Molecular imaging : A review- part I (Fundamentals and genetic perspective). Indian J Radiol Imaging [serial online] 2004 [cited 2019 Sep 20];14:321-8. Available from: http://www.ijri.org/text.asp?2004/14/3/321/28612
| Introduction|| |
Traditional medicine diagnoses diseases based on their signs and symptoms. Remedial therapy is then applied to modify those symptoms, since the origin of the disease is unknown in most cases. It is a very empirical environment. Instead of this symptoms-oriented search that operates empirically to modify the behavior of the patient, molecular medicine assists us in going to the very basis of life and helps us to identify the molecular basis, including genetic origins of diseases. It may be possible eventually to manipulate the individual's genetic constitution appropriately, to get rid of disease processes.
Molecular medicine is binary. We go back to the beginning of life to understand the instructions that cause cells to become what they are - both good and bad. If cells can write code, we can write code too. We can even fix code and can then change the instructions to restore the cell to its normal function or terminate it, if we so desire eg. terminating cancerous cells. Sometimes a given mutation may be simultaneously good and bad, depending on circumstances. The sickle-cell mutation confers resistance to falciparum malaria and the cystic fibrosis mutation resistance to cholera. The downside, of course, is that the homozygous mutation state in such cases is lethal. However, gene therapy is still some way off from entering the realms of reality.
To enhance such a study the potential contributions of biomedical imaging, bioengineering and bioinformatics to emerging research areas, such as functional genomics, proteomics, molecular biomechanics and drug delivery systems, tissue and cell engineering, quantitative biology and computer modeling, molecular and computational imaging, computer-aided diagnosis, metabolic imaging, ultra fast and integrated imaging systems; are of prime importance.
In the 21st century, it is likely that radiology will continue to grow by interfacing with new and important domains such as information technology and molecular biology and by playing a more central role in general medical education, biomedical research and noninvasive therapeutic interventions. The profession will require many radiologists who can provide leadership to bridge the many gaps between the various frontiers and the traditional core of radiology.
Molecular information can be obtained with some but not all of the presently used "high-end" imaging technologies. Optical imaging technology (including diffuse optical tomography, phase-array detection, photon counting, near-infrared fluorescence imaging), high-spatial-resolution MR and nuclear imaging techniques (eg, positron emission tomography [PET]),fusion imaging and micro imaging systems (micro CT, micro MR, micro US) play an important role in the field. Each of these techniques has its particular advantages and disadvantages and the use of one or the other technique is mostly dependent on the specific research question and hypothesis to be tested.
Most traditional cross-sectional imaging techniques such as magnetic resonance (MR) imaging, computed tomography (CT) and ultrasonography (US) are based on physical properties (eg, absorption, scattering, proton density, relaxation rates) and physiologic states (eg, blood flow) as the main source of contrast for the purposes of disease detection and characterization. Apart from these, molecular imaging is built on other imaging techniques (nuclear and optical imaging) and is aimed at the exploitation of specific molecules as the source of image contrast. This paradigm shift from nonspecific physical to specific molecular sources is the underlying tenet for many of the current molecular imaging research efforts.
The key elements to sampling molecular information are (a) the use of special imaging probes with high specificity, (b) appropriate amplification strategies and (c) sensitive systems capable of producing high resolution images. For example, in vitro demonstration of messenger RNA requires the use of a complementary probe, an amplification method such as polymerase chain reaction (PCR) and detection systems.
In vivo molecular imaging is more challenging than in vitro detection, primarily because of the need for probes to be biocompatible, the presence of additional delivery barriers and the necessity for developing special in vivo amplification strategies. There are four broad areas in which considerable research efforts will thus be necessary: development of (a) suitable in vivo affinity ligands ("molecular probes"); (b) efficient organ and intracellular targeting strategies; (c) amplification strategies (because typical target concentrations are in the pico- to nanomolar range) and (d) imaging systems with high spatial resolution and sensitivity.
Positron emission tomography (PET) is frequently used when a substrate to a given target exists that can easily be labeled with a positron emitter, for example labeled 2'-fluoro-5-iodovinyl-1-β-D-arabinofuranosyl-uracil (FIAU) or ganciclovir for imaging of viral thymidine kinase gene expression. Nuclear imaging techniques are also especially suited to track small amounts of labeled therapeutic drugs and to investigate multiple drug resistance or delivery systems such as viral vectors.
MR imaging has two particular advantages over techniques that involve the use of isotopes: higher spatial resolution (micrometer rather than several millimeters) and the fact that physiologic and anatomic information can be extracted simultaneously. In comparison with isotope techniques, however, MR imaging is several magnitudes less sensitive (millimolar rather than picomolar), which is why reliable signal amplification strategies must be developed.
Finally, optical imaging techniques have already been developed for applications in molecular and cellular biology (eg, fluorescence microscopy) and in vivo surface imaging. Newer approaches have been advocated that may ultimately lead to the development of tomographic optical imaging systems in the near-infrared spectrum. One of the appealing advantages of near-infrared optical imaging is that quenched fluorescent labels that become brightly fluorescent after specific molecular interactions with their targets, can be used. Another notable advantage of optical techniques is the fact that multiple probes with different spectral characteristics can be used for multichannel imaging, similar to in vitro karyotyping.
Magnetic Resonance Imaging ability was enhanced significantly with the development of functional MRI. The revival of interest in Molecular Imaging has expanded the frontiers of MRI even further. Molecular Imaging has the potential to be the next frontier in Imaging; this article will try and explain the fundamental issues involved in molecular imaging, both its basics and intricacies, including the Genetic perspective
Defining Molecular imaging
The term molecular imaging can be broadly defined as the "visualization and characterization of biologic processes at the cellular and molecular level". In contrast to "classical" diagnostic imaging, it probes the molecular abnormalities that are the basis of the disease, rather than imaging the end effects or symptoms of these molecular alterations. Radiologists will play a leading role in directing developments of this embryonic but rapidly growing field. In the future, specific imaging of such targets will allow earlier detection and characterization of diseases, earlier and direct molecular assessment of treatment effects and a more fundamental understanding of disease processes.
Molecular imaging is a growing research discipline aimed at developing and testing novel tools, reagents and methods to image specific molecular pathways in vivo; particularly those that are key targets in disease processes. Our current assessment of disease is based on anatomic changes or, more recently in specialized cases, physiologic changes that are a late manifestation of the molecular changes that truly underlie diseases. Imaging of these molecular changes will directly affect patient care by allowing much earlier detection of diseases. We may potentially be able to image molecular changes that we currently define as "predisease states," which would allow intervention at a time when the outcome can be significantly altered. In addition, by directly imaging the underlying alterations of diseases, we will potentially be able to directly image the effects of therapy. Thus, we will play a direct role in determining the effectiveness of treatment, shortly after therapy has been initiated; in comparison in some instances many months are often required today to determine whether pharmacological or biological intervention has been beneficial.
DNA, GENES and the basic cell structure
The entire gamut of genetic information required to form and sustain life is contained in the DNA molecule. All living entities, including viruses and bacteria, fungi, plants, animals and humans use this universal instruction language. Nucleic acids (DNA and RNA) are assembled from nucleotides, which consists of three components; a nitrogenous base, which is covalently linked to a sugar-phosphate backbone (the sugar moiety is a 5-carbon molecule). The sugar ring may be a ribose or a deoxyribose i.e, the 2' carbon may have a hydroxyl functional group in the ribose sugar or may have only a hydrogen in the deoxyribose sugar. DNA has the deoxyribose form whereas RNA has the ribose form of the pentose. There are 2 types of nitrogen-containing bases found in nucleotides: purines and pyramidines. The purines commonly found in nucleic acids are adenine and guanine. The important pyramidines are cytosine, thymine and uracil. DNA is composed of four chemical bases: adenine, thymine, cytosine and guanine (ATCG). Nucleic acids are single stranded or double stranded polymers of nucleotides. Each strand is made up of nucleotides covalently linked through a 3', 5'-phosphodiester bond. In the double stranded DNA and RNA molecules, strands of these specifically pair with each other through the bases to form a structure that resembles a ladder. 'A'specifically pairs with 'T' or 'U', whereas 'G' specifically pairs with 'C', through hydrogen bonds. Although there are exceptions to this pairing rule, this specificity forms the basis for the information stored in the DNA.
To form a protein, a chain of covalently linked amino acids, is formed from the information in the DNA. The region of DNA that codes for a protein contains information for the amino acids present in the protein chain, in sets of three, i.e. three nucleotides code for an amino acid. This set of three is called a 'codon'. The part of the DNA that codes for a particular protein is called the gene for that protein. In other words a gene can be defined as a specific region of a chromosome that codes for a protein (or polypeptide).
The entire ladder as described above is compacted around other proteins called as histones (this helps in maintaining structure and regulating gene expression) and is referred to as a chromosome [Figure - 2]. Collectively, there are 23 chromosome pairs are found in each of the human somatic cells. The human genome is the collection of genes that code for proteins present across the entire human species.
A single gene typically consists of several thousand base pairs. There are estimated 60,000-100,000 genes in the human genome4. During protein synthesis, the information from the DNA is read by first separating the two strands of DNA and synthesizing an RNA strand using DNA as the template. This messenger RNA (mRNA) forms the template for the final products: proteins.
Transcription, the first stage in gene expression, involves transfer of information found in a double stranded molecule, to the base sequence of a single stranded RNA molecule called the messenger RNA. The RNA molecule that is made in the cell nucleus from DNA is called messenger RNA ('mRNA') because it is responsible for carrying the 'message' from the nucleus to the cytoplasm, the outer part of the cell, where the code in the mRNA will be translated into protein. The process of conversion of information from the mRNA sequence to the amino acid sequence of a protein is known as translation and constitutes the second step in gene expression. The mRNA message is 'read' in groups of three bases at a time. Each group of three bases is called a triplet or codon as mentioned earlier. The process of making a protein is called translation and is very similar to translating from one language to another - in this case from the four-letter (A,T,G,C) language of DNA into the 20-letter language (the 20 amino acids) of proteins. The estimated 80,000 proteins perform all functions of life, both inside and outside cells.
An organism must be able to store and preserve its genetic information, pass that information along to future generations and express that information as it carries out all the processes of life. The major step involved in handling genetic information is illustrated by central dogma of molecular biology. Genetic information is stored in the base sequence of DNA molecules. Ultimately during the process of gene expression this information is used to synthesize all the proteins made by an organism.
Variations in DNA that predispose to illness may exist from birth (genetic defects) or be acquired during the course of life (mutation). Although DNA will frequently copy itself and perform protein synthesis infinite times, occasional errors in DNA replication or damage to DNA do occur. On rare occasions, the cellular machinery is unable to rectify these errors or the body is unable to remove them and as a result, disease occurs-for example, cancer. Hereditary Nonpolyposis Colorectal Cancer (HNPCC) is one such example which results from a deficiency in the ability to repair mismatched base pairs in DNA, which are accidentally introduced during replication.
Knowledge of the sequence of the human genome allows the identification and understanding of the function of all human genes. From here, one can begin to unravel the complicated processes involved in biology.
Role of MRI and its molecular imaging tools
The gaze of researchers looking for clues regarding the future of molecular imaging increasingly falls on MR. Through a combination of sophisticated new contrast agents and changing technology, MR is making impressive advances in tracking gene expression, identifying the functional and metabolic changes that precede anatomic evidence of disease, gauging drug delivery and effectiveness and monitoring basic cellular processes.
The main advantage of using MR to image gene expression is its high spatial resolution and the ability to extract more than one measurement parameter, at a given imaging session. MR imaging is several magnitudes less sensitive (millimolar rather than picomolar), which is why reliable signal amplification strategies must be developed. This is usually achieved by using targeted and/or "smart" MR contrast agents coupled with biologic amplification strategies. One particularly robust amplification system is based on cellular internalization of (super) paramagnetic probes such as monocrystalline iron oxide nanoparticles (MION's) . Another strategy to amplify genetic information for MR imaging is through a second reporter system. Such a model system is based on the capability of a single enzyme to catalyze the production of many other molecules in cells and, the latter become detectable with MR imaging. Paramagnetic chelates that change magnetic properties at enzymatic hydrolysis ("smart contrast agents") have recently been used in the imaging of gene expression.
Monocrystalline iron oxide nanoparticles or MIONs, are essentially iron oxide superparamagnetic nanoparticles that are wrapped in dextran. Cross-linked iron oxide nanoparticles or CLIOs, are much more stable than MIONs. These particles are coated with a cross-linked polymer on the surfaces of iron oxide crystals, which renders them resistant to common organic solvents. Transferrin molecules can be attached to each iron oxide particle with chemical linkers, increasing the particle's affinity for the transferrin receptor and directing the contrast agent to attach it to the receptors of cells that over express the transferrin receptor, making MR about 16 times as effective in detecting changes in signal intensity.
Although this contrast-enhancing behavior can be used to improve the efficacy of MRI for cancer diagnosis, researchers plans to report gene expression with the aid of the agent. Vectors have been developed that position a therapeutic gene and a transferrin gene side by side in a vector. The expression of the transferrin receptor gene product therefore is a surrogate measure for the expression of the therapeutic gene product.
A dextran-coated iron oxide colloid is cross-linked with epichlorohydrin and treated with ammonia to yield amino-derivitized, cross-linked iron oxide nanoparticles. The addition of amine groups during dextran cross-linking makes it possible to attach a wide variety of homing molecules to the particle's exterior-not just transferrin, but antibodies, snippets of DNA and other compounds. This advance has opened up entirely new avenues of research.
In laboratory experiments, CLIOs have been attached to multiple sets of DNA building blocks or oligonucleotides, each of which matches up with a complementary set of building blocks on the cancer cell's messenger RNA. Additional building blocks on that piece of messenger RNA in turn match up with other CLIOs, in a process that is repeated over and over. The final result is a large aggregate of nanoparticles easily detected by MR.
Researchers at Washington University in St. Louis5 are using a different MR contrast agent to target cell surface receptors in blood vessels. Gregory Lanza and Samuel Wickline have co-invented a nanoparticle composed of a perfluorocarbon emulsion coated with a layer of lipid5. Into the lipid outer layer they can incorporate hundreds of homing molecules, such as antibodies, peptides or even better, peptidomimetics. These organic molecules mimic short protein fragments but are so small that 200 to 300 can squeeze onto the surface of each nanoparticle, ensuring that the contrast agent adheres to several cell surface receptors at the same time and stays in place long enough to be imaged.
Also linked to the lipid layer of each nanoparticle are up to 90,000 molecules of gadolinium-DTPA, a payload large enough to overcome MR's partial volume effects and enable detection of targeted cells. The perfluorocarbon nanoparticles have opened new doors in both cardiovascular and oncologic imaging. The particles may be able to identify dangerous atherosclerotic plaque, for example, by targeting the fibrin found in the blood clots that form on the plaque's ruptured surface. Researchers are also developing ways to detect angiogenesis, a process that plays a key role in both atherosclerosis and cancer. For generations, a canary in a cage warned miners of the presence of poisonous gases while they still had time to dash to safety. Now, angiogenesis-the ability of cancers to produce blood vessels is playing a similar role in oncology. Diagnostic tests measuring this cellular behavior show promise for faster diagnosis and earlier reports on the effectiveness of therapy. By targeting a protein dubbed alpha v beta 3-integrin (v 3); it is possible to detect the immature blood vessels that characterize angiogenesis. Interaction between integrin v 3 and extracellular matrix is crucial for endothelial cells sprouting from capillaries and for angiogenesis. Furthermore, integrin-mediated signals co-operate with growth factor receptors to promote cell proliferation and motility. Besides being the most important survival system for nascent vessels by regulating cell adhesion to matrix, v 3 integrin participates in the full activation of Vascular Endothelial Growth Factor Receptor (VEGFR-2) triggered by Vascular Endothelial Growth Factor (VEGF-A), which is an important angiogenic inducer in tumors, inflammation and tissue regeneration.
Although sophisticated new MR contrast agents often go after similar molecular imaging targets, "smart" agents do their work with special flair, remaining undetected until arriving at the job site. Smart agents cage gadolinium within the delivery molecule, shielding it from water protons and rendering it silent until the intended target-an enzyme or cellular ion, for example, opens the cage door. Then, the interaction between water and gadolinium results in changes in T1 relaxation that can be detected by MR5.
The best known example of smart contrast agents is EgadMe. EgadMe consists of chelated gadolinium caged by a galactopyranose molecule. The cage door is opened only when EgadMe comes in contact with a β-galactosidase enzyme. β-galactosidase is excellent for tracking gene expression and cell lineage. β-galactosidase is an enzyme manufactured by the gene lac-Z plasmid, a marker gene often used by developmental biologists. The presence of β -galactosidase means the lac-Z gene in those cells is turned on. While the "turned-off" EgadMe washes out of the cells, the "turned-on" agent lingers to light up the cells where gene therapy is expressed.
An agent, similar to EgadMe, has been developed to study autoimmune function triggered by the absence or presence of caspase enzymes that contribute to the onset of apoptosis. A peptide that is a substrate for one of the caspase enzymes is used instead of galactopyranose as the cap.
Another chemical configuration may reveal the presence or absence of matrix metalloprotease peptides (MMPs). Researchers believe cancer cells manufacture the peptides to eliminate the interstitial space around the cancer cell in order to start angiogenesis. By further altering the EgadMe model to selectively turn on the MR agent when it encounters MMPs, one can potentially gain an early measure of a cell cluster's transformation into cancer.
Functional MRI Approaches
Researchers are finding ways to apply functional MR techniques to molecular imaging. They have tested a protocol on animals and humans to examine the value of apparent diffusion coefficient (ADC) in tumors for measuring therapeutic responses. The data suggest a strong relationship between an early rise in ADC and the ultimate therapeutic response. Dr. Brian Ross at the University of Michigan, who pioneered this technique, has applied it with favorable results in children with brain tumors and in animal models.
Researchers believe that MR perfusion measures the growth of interstitial volume caused by cellular necrosis or apoptosis. "Apoptosis" is programmed cell death - triggered, for example, after irreparable mutations are sensed - and the absence of apoptosis is a precursor of malignancy, because cells that are potentially unregulatable and need to be killed off aren't killed? An early response of apoptosis is cell shrinkage; with resultant export of cations, particularly sodium and potassium and a concomitant loss of cell water occur. The early response in necrosis is cell swelling, which produces an effect opposite to early apoptosis. It is followed by a loss in the integrity of the plasma membrane.
The ability to distinguish apoptosis from necrosis would allow clinicians to differentiate the two mechanisms of gene expression treatments. Low doses generally can lead to apoptosis and higher doses induce necrosis. An oncologist could use this information to determine how well therapy is working, soon after its administration and dosing could be modified to optimize its effectiveness.
| Conclusion|| |
Molecular medicine is rapidly transforming medical Imaging. The promise of molecular imaging is that specialized imaging techniques might allow us to image molecular events such as enzyme activity, drug delivery, gene expression or in identifying the functional and metabolic changes that precede anatomic evidence of disease. Some of these are already available in humans and animals; for example, with positron emission tomography (PET), the uptake of glucose is readily assessed and can be quantified. With MRI, the microscopic movement of water molecules inside cells can be assessed with diffusion imaging. However, newer approaches hope to use novel reporter technologies to identify specific molecular events. For example, the ability to visualize a particular gene identified by gene therapy or the expression of a particular gene is a key goal of many researchers.
What does this all mean for radiology in 2010? New diagnostic procedures and agents will help identify either the genotype or molecular phenotype of abnormalities in vivo. Activatable MR agents may play a role if researchers can discover how to get these large molecules to penetrate cell membranes and to deal with the amplification techniques required to produce sufficient signal for imaging.
Glossary of Commonly Used Terms in molecular imaging.
Amplification Molecular biology : increase in the number of copies of specific DNA fragments (polymerase chain reaction); in Molecular imaging it implies increase in imageable signal
Angiogenesis : Growth of new blood vessels
Apoptosis : Programmed cell death involving a regulated intracellular proteolytic enzyme cascade
Base pair : Two bases (adenine and thymine or guanine and cytosine) held together by weak bonds (hydrogen bonds)
cDNA Complementary DNA that is synthesized from an mRNA template using the reverse transcriptase enzyme
Chelate A heterocyclic compound having a metal ion attached by coordinate bonds to at least two nonmetal ions
Cloning 1: Production of cells, all genetically identical, from a single ancestor; 2: production of multiple copies of a single gene or DNA segment
DNA : Deoxyribonucleic acid, the molecule that encodes genetic information and is assembled from nucleotide
Gene : Ordered sequence of nucleotides, located in a certain position on a chromosome that codes for a protein.
Gene expression : Process by which genetic information stored in the base sequence of DNA molecule is used to synthesize proteins required for operating a cell.
Gene product : RNA or protein resulting from expression of a gene.
Gene therapy : Treatment or prevention of disease by transferring genes.
Genome : Sum of all the genetic information in chromosomes of a given organism
Hybridization : Reversible binding of a two complimentary strand of DNA or RNA to form a double stranded molecule (double stranded DNA or a DNA/RNA hybrid double stranded molecule)
mRNA : Messenger RNA, which carries the information specifying the amino acid sequence of a protein to the ribosomes
Mutation : Any permanent, heritable change in DNA base sequence of an organism
Nucleotide : Subunit of DNA or RNA consisting of a base (adenine, guanine, thymine or cytosine in DNA; adenine, guanine, uracil or cytosine in RNA), a phosphate and a sugar molecule (deoxyribose in DNA and ribose in RNA)
Oncogene : A gene associated with cancer; arises form preexisting normal genes that have been altered by both viral and non viral factors; many oncogenes are involved in controlling the rate of cell growth
Plasmid : Autonomously replicating circular extrachromosomal DNA distinct from the bacterial genome; some plasmids are capable of integrating into the genome; multiple genetically engineered plasmids are also used as cloning vectors
Polymerase chain reaction : Amplification of a DNA sequence by using a polymerase and specific base primers; successive cycles result in rapid and specific amplification of the desired sequence
Progenitor cell : Immature cells that are capable of self-renewal and differentiation
Promoter : It is the binding site for RNA polymerase. Binding establishes where transcription begins, in which direction and which strand of DNA is used as template
Protein : Molecule composed of amino acids in a specific sequence derived from mRNA; proteins are essential for cellular functioning
Reporter gene : Encodes for an easily detectable protein
RNA : Ribonucleic acid; classes of RNA: messenger RNA, transfer RNA, ribosomal RNA, other small RNAs
Stem cell : Earliest progenitor cell from which differentiated cell types originate
Transcription : First stage in gene expression with production of mRNA from DNA template
Transduction : Successful gene transfer and expression (viral system)
Transfection : Successful gene transfer and expression (nonviral system)
Transgene : Foreign gene that is transferred into a target cell or tissue
Translation : Second stage in gene expression with production of amino acid sequence of a protein from RNA template
Vector : Vehicle or an agent (virus, liposome) in which a gene can be delivered
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Dept. of Radiology and Imaging, LTM General hospital, Sion, Mumbai-400022
Source of Support: None, Conflict of Interest: None
[Figure - 1], [Figure - 2], [Figure - 3], [Figure - 4], [Figure - 5], [Figure - 6]
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