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Biotecnología Aplicada

versión On-line ISSN 1027-2852

Biotecnol Apl vol.30 no.3 La Habana jul.-set. 2013

 

REVIEW

 

Theranostics and Molecular Imaging: New concepts and technologies for drug development

 

La teranóstica y las imágenes moleculares: Nuevos conceptos y tecnologías para el desarrollo de fármacos

 

 

Carlos Cabal, Daniel Darias, Evelio González, Alexis Musacchio

Grupo de Imágenes, División de Química Física. Centro de Ingeniería Genética y Biotecnología, CIGB. Ave. 31 e/ 158 y 190, Cubanacán, Playa, CP 11600, La Habana, Cuba.

 

 


ABSTRACT

Some of the bases, challenges and expected outputs of the Molecular Magnetic Resonance Imaging and the Theranostics in the near future are presented in this paper. The Molecular Imaging, which evolution in the last years is truly surprising, is becoming a real tool for decreasing the cost and accelerating the stages of drug discovery and development processes. The new Theranostic platforms and the integration of imaging technologies have opened novel and revolutionary opportunities in medicine and biotechnology-based pharmaceutical industries. The strategy of joining therapeutic and imaging agents into one nano platform has the potential to diagnose disease and to treat and monitor the therapeutic response in vivo at molecular level. It simultaneously enhances the control, evaluation and optimization of drug delivery, release and its efficacy. These theranostic formulations are also increasing the Molecular Magnetic Resonance sensibility to some picomoles. Remarkably, it is widely considered that the conjugation of paramagnetic complexes with versatile macromolecules and natural nanostructures is the most important and fastest way to obtain original theranostic formulations. The optimum use and wider applicability of Molecular Imaging relies on the best possible design of the pre-clinical and clinical trials taking into account the imaging technologies from the very same beginning. The complex problem of personalized medicine, combined therapy, and the synchronization of the therapy of choice with diagnosis may find an outstanding solution in the Theranostics approach.

Keywords: theranostics, drug development, molecular imaging.


RESUMEN

En este artículo se discuten algunas de las bases, los retos y el uso de las imágenes moleculares y la teranóstica en un futuro cercano. Las imágenes moleculares, cuya evolución en los últimos años ha sido sorprendente, se han convertido en verdaderas herramientas para disminuir los costos y acelerar todas las etapas de los procesos de descubrimiento y desarrollo de nuevos fármacos. La integración de las actuales plataformas de la teranóstica con las tecnologías de imágenes ha abierto oportunidades novedosas y revolucionarias en la medicina y las industrias biotecnológicas y farmacéuticas. La estrategia de unir agentes diagnósticos y terapéuticos en una nanoplataforma ofrece la posibilidad de diagnosticar, tratar y monitorear la respuesta terapéutica in vivo a nivel molecular. Esto permite mejorar simultáneamente la evaluación, la optimización, el control y la eficacia de la distribución y liberación de los medicamentos. Estas formulaciones teranósticas también han incrementado la sensibilidad de las imágenes moleculares de resonancia magnética hasta algunos picomoles. Como conclusión se afirma que la conjugación de complejos paramagnéticos con macromoléculas y nanoestructuras naturales flexibles es la vía más importante y rápida para obtener nuevas formulaciones teranósticas. Para optimizar los ensayos preclínicos y clínicos es necesario que desde el inicio se diseñen teniendo en cuenta las posibilidades de las tecnologías de imágenes. Los problemas complejos asociados con la medicina personalizada, la terapia combinada y la sincronización entre las acciones diagnósticas y terapéuticas encuentran una excelente solución en el campo de la teranóstica.

Palabras clave: teranóstica, desarrollo de drogas, imágenes moleculares.


 

 

INTRODUCTION

Molecular Imaging, which evolution in the last years is truly surprising, is strongly connected to biology, chemistry and the pharmaceutical industry [1-18]. There are, at least, three main reasons to focus on Molecular Imaging regarding drug development: 1) the large sequence of steps from drug discovery through development, at a very high cost and being time-consuming; 2) the current scientific problem of systems biology; and 3) the recent acknowledgement of imaging as a branch of the Theranostics, i.e., the relationship of therapy and diagnostic at nanoscale level.

Of them, the first reason relies on the values of Molecular Imaging methods as powerful technologies lowering costs and accelerating the steps from drug discovery through pharmaceutical development. They provide simultaneously all the information obtained by the previous complex sequence of steps from the laboratory research to production and the final clinical use [12-18]. The requirements of the pharmaceutical industry are the final purpose catalyzing the advances of Molecular Imaging science and technologies. The second comprises one of the main questions of systems biology: how to transform the molecular information from cells, tissues, organs and organism into understandable knowledge on complex phenomena? [19, 20]. In fact, the equivalencies between molecular and classical imaging methods allow us to obtain, at the same time, rich in vivo information about structure and functionality at all the possible life organization levels, from a single cell through an entire organism (Figure).

The basic idea of Theranostics consists on creating a nanocapsule containing a drug and an imaging contrast agent as a single formulation, supporting the follow-up in vivo of the action of the drug [21-23] (Figure). Theranostic ideas and methods are producing a revolution, creating original technology platforms and challenging the established concepts. Three fields of drug development are covered by imaging as Theranostics: delivery, release and efficacy evaluation. Indeed, imaging was remarked in the FDA’s Critical Path Initiative as a key technology to overcome the bottleneck in the development and registration of innovative medicines [24].

The Positron Electron Tomography (PET), Single Photon Emission Computed Tomography (SPECT), Computer Tomography (CT), ultrasound (US), and the Magnetic Resonance Imaging (MRI) together with a diversity of optical methods are the most important imaging platforms for drug development (Figure). The advantages and restrictions of the different imaging modalities have been addressed in the scientific literature [2-6, 11-13, 18]. These technologies have the potential to enhance our understanding of disease and drug activity during the pre-clinical and clinical drug development phases. They are, in general, complementary rather than competitive techniques [3, 5, 11, 13, 15]. That’s why it is indispensable to affirm that the best approach to consider a specific problem is the multi-modal imaging; this imaging hybrid has the potential to provide the desired results.

The needed amount of suitable animal models is one of the restrictions and the source of increased costs during drug development. Imaging methods can help on replacing, reducing and refining the use of animal models imaging in drug delivery and release studies [13].

Imaging technologies must begin at early stages of the research process in order to support all the critical phases of drug discovery and development such as the ‘proof of biology’ and the ‘proof of concept’ [24, 25]. In fact, there have been recently summarized [26] the imaging methods possibilities and tasks in drug discovery and development framework as: 1) identifying the disease phenotype, 2) pre-selection of target populations, 3) monitoring in real time dose and dose scheduling (pharmacodynamics and pharmacokinetics), 4) validation of drug efficacy and time course of efficacy, 5) individual patient management, and 6) imaging to guide biopsy sites for genomic and proteomic assays.

Additionally, choosing the imaging modality during drug development depends primarily on the specific question to be addressed. However, of them, only MRI is able to bring anatomical, physiological and molecular information of a living system in the same study. One of the most important and less appraised advantage of MRI is the possibility to study a large assortment of different animal models, and also, to be employed in the clinical studies. This advantage permits the scale of MRI procedures from preclinical to clinical research without any essential change in the experimental conditions with the subsequence benefit of lower costs and time reduction. In this review, considerations will focus mainly on molecular MRI (mMRI) and its connections with drug discovery and development. Some of the principal challenges, limitations and possible outputs of mMRI related to the Theranostics are also discussed.

 

THERANOSTICS AND MOLECULAR IMAGING

The MRI has an anatomical resolution record of about 10-50 micrometers, which is enough to study the structures typically addressed in biomedical research [2-6, 11-14, 24], while its sensibility is about 0.1 micromoles, yet far from the optimum [3, 5, 11, 12, 14, 18]. The contrast agent (CA) is one of the fields waiting for optimization to increase MRI sensitivity. In the annals of imaging, CA development has been steadily evolving to become a molecular magnetic marker or a magnetic label. At this moment, CA plays two evident and strong related roles in mMRI: to increase images’ contrast and to be a molecular magnetic label to follow those different processes at all living levels in the neighboring areas of the labeled molecule. Furthermore, the molecular marker had increased the mMRI sensitivity and is expected that it can be in the range from nanomoles to some picomoles.

The mMRI sensitivity is related to the change of the relaxivity of the CA [2-4]. The increase of the relaxivity results in a greater image contrast or the ability to detect the CA at a lower concentration. The relaxivity depends on the CA complex structure (ligand field strength and symmetry) and its kinetics and molecular interaction. The molecular interactions modulate the symmetry and the strength of the ligand field of the CA complex. This idea is essential to understand the action mechanism of the CA as a molecular MRI marker. When the CA interacts with its surroundings, the relaxivity changes and the MRI contrast becomes different. One of the most important problems, from the chemical point of view, is to modify the complex structure to obtain the biggest relaxivity in order to achieve the highest sensitivity.

Theranostics formulations could include, besides the CA, several other agents like therapeutic, target, and improving permeation agents [2-4, 21-23, 27-30]. This means that it is possible to improve simultaneously the biodistribution properties and to follow the therapeutic achievement imaging by mMRI with Theranostic formulations [1-5, 27-30]. This is one of the most essential concept developments of the last decade. More and more the new therapeutic formulation will contain other agents enhancing the delivery, releasing and the efficacy of the drugs besides the CA as a marker, in order to visualize its localization and action inside the living body in vivo. The CAs are commonly classified into two main categories, i.e. endogenous or intrinsic and exogenous or extrinsic [1-4].

For the purpose of the mMRI, there are three principal ways to label the necessary CA or to obtain a magnetic marker. The first one consists in the management of the intrinsic magnetic pools, which are present inside the biological system. The second one is the use of extrinsic paramagnetic complexes and the super paramagnetic particle or magnetic nanoparticle (MNP). Finally, the existing natural nanoparticle can be labeled if conjugated to paramagnetic complexes. These natural nanoparticles could be either intrinsic or extrinsic agents.

The different magnetic states of hemoglobin (Hb) were the first intrinsic CA used for clinical and research purposes [1, 2]. The changes of the Hb magnetism have been the basis of the functional MRI (fMRI) for more than 20 years. The essential idea is that the oxyHb is a diamagnetic molecule and the deoxyHb is a strong paramagnetic complex. Then, when a physiological process is taking place at tissue level, the metabolism grows and, as a consequence, an increase of the rate of change of the oxy to deoxyHb also occurs. More oxyHb becomes to be deoxyHb and, as a result, the magnetism variation produces intensities changes in the MR images.

A more newer intrinsic genetic control mechanisms of contrast in order to follow by MRI physiological process at cellular level have been described in literature [31]. The basic idea of those genetic mechanisms consists on using a gene that manages the production of intracellular proteins, for example metalloprotein, which inside the cell forms a CA with the endogenous metal ions. Instead, the base of the semi genetic mechanism is to guide the synthesis of a cell surface protein which facilitates the introduction of extrinsic CA into the cell or into a convenient vesicle. It can be expected, that these and other different genetically controlled contrasts will be introduced into practice in the near future.

Another approach to provide contrast is a Magnet-ization Transfer (MT) technique termed Chemical Exchange Saturation Transfer (CEST) and the Paramagnetic Chemical Exchange Saturation Transfer (PARACEST) using the same principle of saturation transfer in the presence of an extrinsic paramagnetic complex. These endogenous mechanisms for MT are used clinically and exploit a pool of hidden water in some tissues [2-4, 32, 33]. These methods promise to become a good alternative to increase the contrast and to obtain molecular information for several applications (for more information see references [2-4, 32, 33]).

The Gadolinium complexes were the first extrinsic CA with a very wide application in the clinical studies during the last 20 years [1-4, 9, 13, 27-29, 34-48]. There are two main categories of chelating ligand approved for clinical use, one a linear ligand, the diethylenetriaminepentaacetic acid (DTPA) and the other based on the macrocyclic ligand 1,4,7,10-tetra(carboxymethyl)-1,4,7,10-tetraazacyclododecane (DOTA). The relaxivity obtained for this complex is about 3.9 mM-1s-1 [4]. New modifications were done to the Gd(DTPA) and Gd (DOTA) complexes’ structure in order to change its biodistribution, its pharmacokinetics and to increase the relaxivity, i.e., to raise the sensitivity [2-5, 27-29, 35-48]. For this purpose, the principal complex Gd(DTPA) is conjugated with many other kinds of polymer formation such as polyamine, polyethylene glycols (PEG), polysaccharides, PLL, and albumin. These conjugations permit the control of the biodistribution, to prolong the blood retention time and to vary the membrane permeability [2-5, 27-29, 35-48]. This development opens a new qualitative application: the resulting complex can be a marker and also a transporter of the active principle to the target.

Other paramagnetic complexes composed by Transition or Lanthanides metals ions are being used in the research, pre-clinical and clinical studies [1-4, 49, 50]. The most successful and promising of these CAs are those with Mnn+ complexes.

In the last ten years the attention to MNP as a relative well known development associated to Theranostics has increased [1-4, 27, 30, 51-59]. The Iron core in this MNP is coupled with a biopolymer in order to make the particle biocompatible. This biopolymer around the core allows also the conjugation of contrast and therapeutic agents. Recently, the biodistribution and pharmacokinetics of uniform magnetite MNP chemically-modified with polyethylene glycol has been studied [60]. By successive MRI, the evolution of tissue contrast, absorption speed, time of residence and excretion of this MNP was followed in the liver for a month. On the basis of these results, different metabolic routes that determine the fate of MNP has been proposed [60].

The carbon nanotubes and other nanostructures like nanobubbles in colloid suspension are other flexible nanoframeworks for the mMRI [2-4, 61-64]. They have a very large free surface in which is possible to coordinate different types of drugs, monoclonal antibodies, CA, cell penetration peptides and molecules to the control of the drug delivery and release [1-5, 61-64].

The diversity of possible molecular arrangements is practically infinite; nevertheless, the most important are those which have a flexible framework, for example, the dendrimers and the PEG [2-4, 21, 27, 50, 52, 65-71]. These two macromolecular platforms permit forming a very large specific molecular formation designed to solve great concrete biopharmaceutical problems [2-4, 39-42, 65-69, 72]. These macromolecular formation are flexible because is possible to control the molecular mass, size and shape with a relative high precision. Also, it has a relative high number of functional group (reactive sites) to be conjugated with CA, solubility improver, receptor ligand and drugs. In the case of PEG it is also possible to change the core size [69].

It has been demonstrated that the size control is determinant to improve, besides other properties, the relativities, blood retention time and also influences targeting of the Theranostics formulation [3, 4, 6, 27, 39-48, 65-71, 73, 74]. A dendrimer conjugated with Gd(DTPA) called Gadomer 17 have a relaxivity 16 mM-1s-1, i.e., about four times greater than the Gd(DTPA) [65]. In another report [66] these nanoparticles can be preferentially targeted to blood or to the lymphatic track depending on the particle’s size. The lowest the size of the dendrimers, the highest the distribution into the blood vessels, with dendrimers being increasingly distributed into the lymphatic vessels at larger particle sizes. Some groups have evaluated the rheology, permeability and other properties of these NP formulations as a function of particles’ shape [73, 74].

The dendrimer and PEG flexibility provides a tight control over the absorption, the distribution and clearance profiles of the formulations based on these polymers. That’s why they have been explored as delivery vectors for the different drug administration routes: oral, intravenous, subcutaneous, pulmonary and even transdermal delivery [66].

Multifunctional, multimodal and multistage nanoprobes combining CA for different imaging modalities (for example PET and MRI) either the arrangement of different active molecules for the combined therapies have attracted great interest [75-79].

Much more extended studies have been carried out using macromolecular formations such as: liposomes, ensomes, miscelle ensome, mesomes and LipoCEST [2-4, 33, 80-82]. Some of these molecular formations are self-assembly NP. They are generally composed of copolymers with both hydrophobic and hydrophilic segments. The core of the NP and its surface provide an effective loading compartment for the drug and the CA. Nevertheless, some of these molecular structures have a relatively low relaxivity because of the small intensity water exchange among particle associated water and the free one.

Natural macromolecular formations akin to high density lipoproteins (HDL) [2-4, 83-86], Ferritin and virus-like particles (VLPs) [83] have been conjugated with different paramagnetic complexes, drugs and molecular improver. The obtained particles have very good Theranostics characteristics including a high relaxivity and the capacity to be loaded with elevated amounts of paramagnetic complexes. These natural macromolecular particles have several advantages because of their relatively low toxicity, good pharmacological behavior and also because the immunological system does not reject it [83]. In an early work [87] human and rat red blood cells were loaded with Gd(DTPA) to create a blood pool MRI CA. The relaxivity tended to increase, together with retention times and contrast enhancement in different organs.

A family of biodegradable macromolecular CAs has also been reported [2-4, 43-46]. Some of these CAs are based on proteins polymers allowing control over CA properties, as well as the polydisulfide Gd complexes [45, 46]. These novel formations can act as macromolecular CA for in vivo imaging and be excreted rapidly as a low molecular weight agent. The progress in the area of biodegradable CAs is very promising. In summary, these nanoparticulated macromolecular formations mentioned provide a promising platform for Theranostic formulation of increased delivery and release control, optimizing the residence time and the permeability in the different compartments, improving drug targeting and CA loading into the target, decreasing the toxicity and increasing the relaxivity, and, as consequence, the sensitivity of the mMRI.

The conjugation of paramagnetic complexes with versatile (flexible) macromolecules and natural nanostructures is the most important and fastest way to obtain new Theranostic formulations at present.

Despite the faster growth in number of Theranostic nanocarriers in latest years, the number of these formulations approved for clinical purposes is still very few and its relativities are in a relative low narrow range [4, 88]. Nevertheless, a growing rate of approved compounds for clinical use is expected to be increased in the near future.

New Theranostics nanocarriers with a very high relaxivity implying an essential raise of the mMRI sensibility were announced a few years ago. As example [4, 89, 90], a dendrimer was presented as component of a new porous carrier system. This porous carrier system has three key component features: a stabilized polymer shell, a porous membrane structure and dendrimer-attached Gd complexes encapsulated inside the porous vesicular carrier system. This macronano structure has a relaxivity greater than 300 000 mM-1s-1. Another interesting nanocarrier was developed [59], in which the obtained NP based on perfluorocarbon carrying 94 000 Gadolinium chelates produced relativities of 1.69 × 106 mM-1s-1 at 1.5 T and 910 000 mM-1s-1 at 4.7 T. Strikingly, this is approximately one million times greater than Gd (DTPA). This enables a minimum detection limit (sensitivity) in the range of a few to 102 pmoles concentration [59]. It is predictable that these Theranostics formulations will play a special role in the development of new nanomacromolecular formations and that the sensitivity of mMRI will be increased in several orders of magnitude.

Let's emphasize that the mMRI sensitivity increases as a result of the development of new kind of Theranostics formulations, in several order higher than those obtained by the high cost MRI hardware progress. The increase in sensitivity will allow to widen the range of application and to extend the use of clinical MRI equipments to the pre-clinical studies progressively.

 

SOME REMARKS, CHALLENGES, TASKS AND EXPECTED OUTPUT

To successfully exploit the opportunities of Molecular Imaging for drug development, several challenges and tasks need to be taken into account. Let’s mention some of them.

A very important restriction of the Theranostics impact is associated with the development and validation of custom-made Theranostics new formulations. Theranostics formulations for the clinical studies must move throughout the sequences of steps for drug discovery and development until its approval by a regulatory agency. However, it is possible to design strategies to accelerate this process with an optimum selection of the molecular framework. Whereas the process is occurring, it’s possible and necessary to increment the intensity and effectiveness use of the Theranostic formulations in the research and the pre-clinical studies.

As a result of new hardware and software development either of the existing methods and novel principles, it is possible to affirm that new imaging technologies will be introduced in the near future. Effective efforts should be done to decrease the cost of MRI machines, which limits its extended use.

Only some words to pay our attention to a very new imaging method: the Magnetic Particle Imaging, which emerged few years ago [91-93]. This new technology together with the MRI promises to have a very high sensitivity and resolution in the same machine [93].

Nevertheless, the most important expected improvement will occur in the field of original Theranostics biodegradable formulation, decrease of toxicity and enhancement of the delivery, release and clarifying profiles. Simultaneously, this formulation will enlarge the efficacy of the combined and personalized therapies and its imaging control.

More effective and standardized methods for the characterization of the molecular formation used in the Theranostics are emerging. The understanding of the molecular interaction inside the living bodies with the CA is essential for these new developments.

Delivering the drug to the target with high precision and control is the essential endeavor of the drug delivery systems. This growing technology represents one of the most rapidly advancing areas; and specially, controlled drug release as a field of pharmaceutical technology has rapidly diversified recently [94].

Responsive drug delivery and releasing systems have essentially two main parts: a sensor that detects the environmental parameter which stimulates drug release and the respective delivery device [94]. Signals that have been employed to trigger drug release can be classified into two groups: those who are intrinsic and those who are extrinsic to the body, and according to a definite physiological characteristic or external radiation triggered the release of the drugs contained within a specific nanocarrier.

In the Theranostics approach, several terms have been coined for carriers, such as ‘intelligent’ or ‘smart’ carriers, because of their ability to manage a stimulus by receiving, transmitting and processing it; and also, they are ‘intelligent’ in the sense that they can perceive the prevailing stimuli and respond by exhibiting changes in their physical or chemical behavior, resulting in a controlled release of entrapped or attached drug or molecular improvers such as permeability and retention time [95]. Among the intrinsic we can find: pH mechanism [23, 95-98], temperature sensitive [23, 99], enzymatic stimuli reactive [96-98], diffusion controlled [95, 96], antibodies targeted [23, 85] and redox potential [97]. The extrinsic include: nanoelectromechanical systems [100-102], magnetic field [61, 97, 100, 103], electric field, ultrasonic signals [100], light and laser exposure [97, 100, 104-107], and others. The development in this ground is really starting; however, a relative not easy way is necessary to be crossed to make all those advances compatible with the concrete biological, biomedical and biopharmaceutical requirements and regulations. Molecular Imaging technologies can make a contribution in this direction.

Lastly, in order to make an optimum use and to contribute toward the enlargement of the possibilities of Molecular Imaging is important to have the best design of the pre-clinical and clinical trials. Imaging methods must be taken into account from the very beginning. Before starting the trials, it is necessary to consider the standardization and the synchronization of the diagnostic and therapy protocols. In the Theranostics approach this complex problem may find an outstanding solution.

In summary, mMRI techniques are increasing the contrast, resolution (below 50 µm), sensitivity (in the range of nano to some picomoles) and creating new and powerful tools to make more and more important contributions to research and development in biology, biomedicine, and either the biopharmaceutical and biotechnological industries. In fact, Molecular Imaging is becoming the largely expected tool that could contribute to decrease time, costs and to raise the robustness of the stages for drug discovery and development.

 

ACKNOWLEDGEMENTS

The authors wish to thank to the CIGB for supporting this work. Thanks to Prof. Dr. Della Védova from the National University La Plata, Argentina, and to Dr. Gerardo Guillén Nieto and Dr. Eduardo Martínez from CIGB, for the stimulating discussion and collaboration.

 

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Received in January, 2013.
Accepted in April, 2013.

 

 

Carlos Cabal. Grupo de Imágenes, División de Química Física Centro de Ingeniería Genética y Biotecnología, CIGB. Ave. 31 e/ 158 y 190, Cubanacán, Playa, CP 11600, La Habana, Cuba. E-mail: carlos.cabal@cigb.edu.cu.

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