Molecular Imaging of Brain Tumors Using Liposomal Contrast Agents and Nanoparticles




The first generation of cross-sectional brain imaging using computed tomography (CT), ultrasonography, and eventually MR imaging focused on determining structural or anatomic changes associated with brain disorders. The current state-of-the-art imaging, functional imaging, uses techniques such as CT and MR perfusion that allow determination of physiologic parameters in vivo. In parallel, tissue-based genomic, transcriptomic, and proteomic profiling of brain tumors has created several novel and exciting possibilities for molecular targeting of brain tumors. The next generation of imaging translates these molecular in vitro techniques to in vivo, noninvasive, targeted reconstruction of tumors and their microenvironments.


Key points







  • •

    The advent of genomic, proteomic, and high-throughput screening technologies has made available many new targets for brain tumor imaging; however, target availability and accessibility need to be carefully considered when designing imaging probes.


  • •

    Nanoparticles, although largely still only used in preclinical studies, are a versatile tool for targeted imaging of physiologic and molecular aspects of brain tumors through many clinically used modalities.


  • •

    Liposomes can be used to transport diverse payloads in vivo, including contrast agents and drugs, and may be functionalized to increase circulation half-life and achieve targeting specificity.


  • •

    Polymeric, gold, and iron oxide nanoparticles have been used for diverse applications in preclinical studies; however, the utility of other methods, such as quantum dots and self-assembling DNA molecules, is yet to be established.






Introduction


The development of nanoparticles involves manipulating a variety of molecular constructs, including metals, lipids, polymers, proteins, and nucleic acids. These particles typically range from 1 to 100 nm (although some may be as large as 400 nm) and may enhance imaging contrast through their intrinsic molecular properties or by serving as a scaffold for carrying imaging agents. Importantly, nanoparticles have been used therapeutically as well for targeted drug delivery and during surgical resection of tumors. Several approaches have been developed to functionalize nanoparticles to enable transport of water-soluble drugs, increase the half-life of the particles and their cargo in vivo, and minimize the side effect profile of toxic free agents.


This article provides an overview of the molecular targets available for brain tumor imaging, then focuses on the use of liposomal contrast agents for imaging some of these targets. It next discusses other classes of nanoparticles, including those that show potential in preclinical studies, such as gold nanoparticles, quantum dots, and self-assembling DNA molecules, and others that have been used in clinical studies, such as iron oxide nanoparticles.




Introduction


The development of nanoparticles involves manipulating a variety of molecular constructs, including metals, lipids, polymers, proteins, and nucleic acids. These particles typically range from 1 to 100 nm (although some may be as large as 400 nm) and may enhance imaging contrast through their intrinsic molecular properties or by serving as a scaffold for carrying imaging agents. Importantly, nanoparticles have been used therapeutically as well for targeted drug delivery and during surgical resection of tumors. Several approaches have been developed to functionalize nanoparticles to enable transport of water-soluble drugs, increase the half-life of the particles and their cargo in vivo, and minimize the side effect profile of toxic free agents.


This article provides an overview of the molecular targets available for brain tumor imaging, then focuses on the use of liposomal contrast agents for imaging some of these targets. It next discusses other classes of nanoparticles, including those that show potential in preclinical studies, such as gold nanoparticles, quantum dots, and self-assembling DNA molecules, and others that have been used in clinical studies, such as iron oxide nanoparticles.




Molecular targeting of brain tumors


The molecular properties and availability of cellular and molecular targets dramatically influences the type of imaging modality and the nanoparticle platform used for detection. The flow of detectable biological information is amplified by transcription and translation, starting with 2 copies of a gene in DNA, which is transcribed to 10 2 to 10 3 copies of messenger RNA (mRNA), which is then in turn translated into 10 2 to 10 6 polypeptides. These polypeptides may assemble to form enzymatic proteins, whose function can be further used to amplify signals from target detection. Several methods have been developed for the discovery of new targets and for the design of efficient, high-affinity probes for them. These approaches include genomic and transcriptomic sequencing to identify differentially expressed genes in brain tumors, high-throughput robotic screening, phage display, rational design, and combinatorial approaches.


Barriers to Nanoparticle and Probe Entry


Despite the rapid discovery of new targets and probes, the accessibility of cellular targets can limit their detection by nanoparticles because these molecules do not cross lipid bilayers and diffuse through cytoplasm easily ( Fig. 1 ). On entering the vasculature, the nanoparticles have to cross the endothelial layer to encounter the appropriate target cell. In the case of brain tumor targeting, the presence of the blood-brain barrier (BBB) presents an additional, significant challenge for the entry of nanoparticles. Once the nanoparticles gain entry into the brain parenchyma, the most accessible cellular targets are cell surface proteins. An additional barrier, the cell membrane, needs to be traversed for detection of most RNAs and cytosolic proteins. In contrast, both the cell and nuclear membranes must be crossed to reach DNA targets, making them the most difficult to detect. The localization of a particular target is therefore critical when considering the material properties and design of a nanoparticle.




Fig. 1


The accessibility and distribution of molecular targets in a cell.


To circumvent the physiologic barriers that prevent nanoparticle and probe binding to their targets, several approaches have been used for brain tumor imaging. Surface chemical modifications are often used, such as polyethylene glycol (PEG) coating, and result in longer circulatory half-lives caused by decreased uptake by the reticuloendothelial system, which helps to achieve a uniform distribution of nanoparticles to increase distribution to all cellular targets. In certain circumstances, if the location of a tumor is known, localized delivery of nanoparticles may enhance detection of the desired target. Another approach allows cellular tracking through the detection of internalized nanoparticles into the cytoplasm from cell surface proteins. To gain entry into the brain, the use of ligand-bearing targeted nanoparticles for penetrating the BBB has also been extensively studied.


Signal Amplification


Given the difficulty of traversing cellular barriers and the low abundance of DNA and mRNA in cells, these are seldom targeted because significant signal amplification would be needed for appreciable detection. A few successful attempts have been made to tether nucleic acids to gold, carbon, and platinum nanoparticles. Several recent efforts have also enabled better detection of nucleic acid targets by exponential signal amplification. These approaches include nanosensors for specific DNA or RNA base pairing, rolling circle amplification, branched DNA amplification, hybridization chain reaction, and single-molecule RNA fluorescence in-situ hybridization. The applicability of these approaches to tumor imaging in clinical settings has yet to be established.


Unlike nucleic acids, proteins are abundant and accessible targets in living cells. As such, several approaches have been developed to amplify signal from protein detection. These approaches include manipulating the physiochemical behavior of a probe after target binding, harnessing unique cellular biochemistry to trap probes, and augmenting probe kinetics to increase effective target concentration.


Probe Classifications


Nanoparticles are in 3 classes of probes when used for brain tumor imaging: (1) compartment probes, (2) targeted probes, and (3) smart probes. Compartment probes are used to measure physiologic parameters, such as flow and perfusion. In this case, the properties of this probe force its compartmentalization to a specific region in the body, and allows an indirect measure of a particular process. Targeted probes contain a target-recognition moiety, which binds to the target molecule, and a contrast moiety, which is the signal being detected during imaging. An example of a targeted probe includes α v β 3 antibodies conjugated to gadolinium(III) [Gd(III)]–containing liposomes, which have been used for preclinical imaging of blood vessels. Smart probes require a trigger to activate, and in this way have an enhanced signal/background ratio compared with other probes. An example of a smart probe is EgadMe, a Gd chelating agent that occupies 7 of 8 Gd(III) coordination sites conjugated to a galactopyranose residue that blocks the remaining Gd(III) coordinate site. In the presence of a β-galactosidase, the blocked Gd(III) site is freed, allowing access to water for contrast enhancement. Calcium-activated and zinc-activated MR contrast agents have also been used in smart probes to detect activation of biochemical pathways in cells.




Liposomal contrast agents


Liposomes have been used as a particularly versatile class of nanoparticles for both diagnostic and therapeutic use in the central nervous system. They are composed either of a single bilayer, known as unilamellar vesicles, or multiple bilayers, known as multilamellar vesicles (MLVs). The approaches to fabricate liposomes and the ways in which they can be designed for targeting cellular and molecular processes for brain tumor imaging are discussed later.


Design and Functional Properties of Liposomes


Liposomes can vary in size depending on the method used to synthesize them. These methods include high-pressure extrusion and sonication. High-pressure extrusion is used for the synthesis of MLVs greater than 100 nm in diameter and large unilamellar vesicles (LUVs) 50 to 400 nm in diameter with remarkable consistency. Sonication is mostly used for the synthesis of small unilamellar vesicles (SUVs) of less than 30 to 50 nm.


The clearance of liposomes is predominantly mediated by the reticuloendothelial system, which consists of macrophages and other phagocytes in the hepatic and splenic compartments. This clearance depends on the size and surface properties of each liposome; traditional liposomes usually have half-lives of around minutes to hours, whereas liposomes larger than 200 nm have shorter half-lives because of more efficient immune clearance. These half-lives can be prolonged to more than 18 hours by coating the surface of liposomes with hydrophilic biopolymers such as PEG, creating so-called stealth liposomes that are better equipped to evade the immune system.


Liposomes have hydrophilic cores that may encapsulate imaging contrast agents or other compounds, such as drugs. As such, they have been used for diverse applications in both diagnostic imaging and therapeutics. Several trials have successfully shown the use of liposomes in delivering chemotherapeutic agents, including cytarabine, doxorubicin, and daunorubicin, as well as nucleic acids for gene therapy. They have further been used in image-guided therapeutic delivery by inclusion of both an imaging agent and a drug.


These nanoparticles have also been used for physiologic and molecular imaging using MR imaging and computed tomography (CT) by serving as carriers of gadolinium-based and iodine-based contrast agents. Liposomal contrast agents encapsulating a high payload of conventional iodine contrast agent molecules (∼1 million iodine atoms per liposome) have enabled ultrahigh-resolution CT imaging of rodent cerebrovasculature ( Fig. 2 ). Significant effort has been made to develop liposome-based MR imaging contrast agents. These nanoparticles have been successfully used as blood-pool contrast agents and for imaging neurovasculature and monitoring convection-enhanced drug delivery in vivo. As targeted probes, liposomes have been used to enhance targeting of brain tumors, for convection-enhanced delivery (CED), and to deliver boron for neutron-capture therapy.




Fig. 2


Ultrahigh resolution in vivo CT imaging of mouse cerebrovasculature using a long-circulating liposomal-iodine contrast agent. Thick-slab maximum intensity projection (MIP) images in ( A ) sagittal, ( B ) axial, and ( C ) coronal planes showing the arterial and venous circulatory system in the mouse brain. ( D ) Three-dimensional (3D) volume-rendered image of the mouse circle of Willis. The CT images were acquired on a micro-CT scanner at 19-μm isotropic spatial resolution.

( Adapted from Starosolski Z, Villamizar CA, Rendon D, et al. Ultra high-resolution in vivo computed tomography imaging of mouse cerebrovasculature using a long circulating blood pool contrast agent. Sci Rep 2015;5:10178; with permission.)


Targeting of Tumors Using Liposomes


Delivery of nanoparticles to tumors may involve passive diffusion or active targeting. The ability to create small liposome nanoparticles allows passive targeting of liposomes to brain tumors by means of diffusion through leaky vasculature surrounding tumor cells. Through this mechanism, referred to as the enhanced permeation and retention effect, liposomes carrying therapeutics or contrast agents can pool in the interstitial space of a tumor. The use of liposomes for molecular targeting of brain tumors involves conjugation of cell surface receptor recognizing antibodies to PEG chains on the liposome outer coat. Approaches to target multiple surface receptors using a single liposome have also been described. Liposomes can thus be targeted to the tumor microenvironment or to the endothelium of blood vessels within it. These approaches have been used to increase specificity of drug delivery by targeting the folate, transferrin, and epidermal growth factor receptors. In addition, triggered release liposomes have also been developed. These nanoparticles are designed to release contents, such as chemotherapeutics, in response to environmental changes such as temperature and pH.


Liposomes as MR Imaging–based Contrast Agents for Brain Tumors


The use of Gd core-encapsulated (CE-Gd) and surface-conjugated (SC-Gd) liposomes as T1-based MR imaging contrast agents has been validated extensively in animal models ( Fig. 3 ). Liposomes that use both core and surface Gd stores are referred to as dual-Gd liposomes. Of note, liposome cores encapsulated with ultrasmall superparamagnetic iron oxide particles (USPIOs) may be used for enhanced signal in T2-weighted MR imaging. These contrast agents have prolonged circulation, which provides uniform signal intensity and enhancement compared with traditional Gd chelates, thus making them ideal for steady-state imaging like MR angiography.




Fig. 3


Liposomes as MR imaging contrast agents. ( A ) Gadolinium (Gd) core-encapsulated (CE-Gd) or surface-conjugated (SC-Gd) liposomal MR imaging contrast agents coated with PEG. ( B , C ) High-resolution in vivo MR angiography of mouse cerebrovasculature using a long-circulating liposomal-Gd contrast agent (SC-Gd). Thick-slab MIP images in ( B ) sagittal and ( C ) coronal planes showing the arterial and venous circulatory system in the mouse brain. The mouse circle of Willis is shown in the coronal image. The images were acquired using a 3D gradient recalled echo sequence at 100-μm isotropic spatial resolution on a permanent 1.0-T MR scanner.

( Courtesy of Z. Starosolski, K. Ghaghada, A. Annapragada.)


Thus, in preclinical studies, CE-Gd liposomes have been shown to result in lower background signal and increased vessel clarity in the spine and heart compared with conventional contrast agents. SC-Gd liposomes show higher T1 relaxivities compared with CE-Gd liposomes because water molecules do not have to diffuse through the lipid bilayer to interact with Gd atoms. As such, these agents have been used for higher-resolution imaging of both arterial and venous central nervous system vasculature, including the circle of Willis. Dual-Gd contrast agents afford the advantage of signal amplification from both modes of Gd pooling.


Unlike extracranial tumors, the presence of the BBB presents significant challenges to the entry of liposomes and other nanoparticle contrast agents into the brain. Focused ultrasonography-mediated enhancement of BBB permeability for augmenting intratumoral transport of liposomes has been studied. Active targeting of liposomes has also been examined for imaging of brain tumors. Importantly, although most nanoparticles are able to localize to brain tumors by extravasation through blood vessels, they are still large enough that this diffusion is limited by slow kinetics. Other smaller contrast agents are able to traverse the tumor microenvironment more rapidly through diffusion via brownian motion. CED is an approach whereby a burr hole is drilled into the brain, and a therapeutic or contrast agent is infused via a catheter directly into the tumor site. The positive pressure gradient of the infusion process reliably distributes the agent over the entire tumor volume, and, when the gradient normalizes, the distribution of the agent becomes diffusion limited. However, this approach has several limitations, including its invasive nature, limited versatility in terms of the shape and distribution of agent delivery, and often overtreatment, although overtreatment may be beneficial when trying to ensure tumor removal outside the expected margins.


Several preclinical studies have shown the safe and effective administration of liposome-encapsulated therapeutics to brain tumors using CED. These studies were limited in that they were unable to track the extent of nanoparticle delivery. Other studies in primate brains have used CE-Gd liposomes to monitor in real time the distribution of therapeutic nanoparticles infused into brain tumors by CED. The coencapsulation of both Gd contrast agents and therapeutics has enabled more accurate tracking of CED-mediated treatment of brain tumors.




Nonliposomal nanoparticles for brain tumor imaging


In addition to liposomes, several other types of nanoparticles have been used for brain tumor imaging, including other lipid-based nanoparticles, such as micelles, as well as polymeric, gold, and iron oxide nanoparticles. Recently, semiconductor nanocrystals, or quantum dots, that have tunable optical properties have also been used during surgery and in tumor imaging. A brief discussion of nucleic acid nanoparticles and their potential future application in molecular imaging is provided here.


Lipid-based Nanoparticles


Like liposomes, micelles and lipid-coated perfluorocarbon (PFC) nanoparticles are lipid-based nanoparticles. Micelles are approximately 10 to 50 nm in diameter. They are composed of several self-assembling amphiphilic molecules, which aggregate to form spherical particles that have a hydrophilic outer surface and a hydrophobic core. These nanoparticles can be used for imaging by tethering contrast moieties to the amphiphilic components. Often these micelles are PEGylated, which allows better immune evasion and prolonged circulation in the body. In addition, their surfaces can be further modified with proteins that facilitate cell-surface receptor binding in order to achieve tumor-specific targeting. An advantage of the hydrophobic core is that it may be used to deliver water-insoluble payloads.


PFC nanoparticles tend to be much larger than micelles, usually around 250 nm in diameter. They are composed of a lipid monolayer encapsulating a hydrophobic PFC core. The lipid monolayer can be used to carry contrast or therapeutic agents, or molecules to facilitate tumor targeting. PFC nanoparticles have been investigated preclinically for molecular imaging of brain tumors and the cardiovascular system. These nanoparticles may be used in both proton-based and 19 F-based MR imaging, because of the presence of fluorine atoms (perfluorocarbon) in the core interior. In addition to their use in MR imaging, PFCs along with porphysomes, which are liposomelike nanoparticles, have been used in photoacoustic imaging in the brain.


Polymeric Nanoparticles


Many years of investigation have gone into the synthesis and customization of biodegradable polymers, and this has been harnessed for molecular imaging. Dendrimers build the backbone of perhaps the most well-described class of polymeric nanoparticles. Dendrimers are highly branched, synthetic polymers that are effectively functionalized by conjugation to contrast moieties and may also be used for theraputics. These nanoparticles have been used effectively for brain tumor imaging with both MR imaging and CT. Importantly, antibody-conjugated dendrimers can be used for increased target specificity to brain tumors.


Biodegradable polymers including polylysine, polylactic acid, polylactic coglycolyic acid, and PEG-based polymers can be used to generate a homogeneous preparation of nanoparticles from 10 nm to 10 3 nm. These biopolymers can be effectively functionalized by fine-tuned control of nanoparticle size and structure, and by the conjugation of functional molecules or contrast agents. In particular, such polymeric nanoparticles have been used to effectively deliver chemotherapeutics to brain tumors.


Iron Oxide Nanoparticles


Perhaps the most widely described MR imaging contrast agents to date are iron oxide nanoparticles. These particles are composed of an iron oxide core that is stabilized with a coating of dextran or another hydrophilic polymer. They are developed either as USPIOs or supermagnetic iron oxide particles (SPIOs). USPIOs are less than 50 nm in diameter and have lower T2 relaxivities during MR imaging, thus they have been used as blood pool contrast agents. In contrast, SPIOs range between 50 and 200 nm in diameter, and have high T2 relaxivites. Therefore, they are used predominantly for T2-weighted MR imaging.


To date, these nanoparticles are the only ones approved for use as a contrast agent in humans, although several have been withdrawn by the manufacturers. They have a plasma half-life of more than 18-hours, which is significantly longer than traditional Gd-based contrast agents. They have been used as a contrast agent for brain tumor imaging and for visualizing blood vessels in the tumor microenvironment. When coated with dextran, these nanoparticles are rapidly taken up by T lymphocytes; as such, they can be effectively used to image the immune response in inflammatory diseases, tumors, and lymph nodes, such as for cancer staging. Given their long half-life and rapid uptake by dividing cells, these nanoparticles have been further used for MR imaging tracking of stem cells and microglia.


Gold Nanoparticles


A variety of gold nanoparticles have been developed and tested in preclinical imaging. The high attenuation of gold, compared with iodine, makes gold nanoparticles attractive for radiograph and CT imaging. Spectral CT imaging using a combination of gold nanoparticles and liposomal-iodine contrast agents has been investigated to simultaneously visualize tumor vasculature and intratumoral uptake of nanoparticles. Gold nanoparticles have a silica core covered by an extremely thin gold shell and have been investigated for multimodality imaging. These particles are extremely versatile because the core dimensions and shell thickness can be varied to impart the ability either absorb or scatter light, or x-rays. As a result, gold nanoparticles can be used in optical imaging and for highly sensitive surface-enhanced Raman scattering, which has been used for real-time visualization of tumor margins during surgical resection. Gold particles synthesized to absorb in the near-infrared spectrum have been used as a cancer therapeutic in certain animal models by means of photothermal ablation of cells. In humans, a similar approach has been used in trials for treatment of head and neck cancers. In addition, these nanoparticles are the most commonly used inorganic nanoparticle, along with quantum dots, in photoacoustic imaging.


Quantum Dots


As with gold nanoparticles, quantum dots have unique, flexible optical properties that can be modulated by altering their size. They are composed of a core made of a semiconductor material, usually a cadmium derivative, covered by an inert metallic layer. These nanoparticles have been used for optical imaging of the molecular properties of various tumors and may be helpful for guiding neurosurgical resection of brain tumors. Transferrin-conjugated quantum dots have been used for brain tumor targeting by virtue of binding to the transferrin receptor. The utility of these nanoparticles may be limited because they contain cadmium, which can be cytotoxic.


Self-assembling Nucleic Acid Nanoparticles


Recent advances in DNA origami have led to the development of self-assembling nucleic acid nanoparticles, which have the potential to be highly customizable in size and shape, and also able to carry a wide variety of payloads. Although still far away from practical use for clinical imaging, these nanoparticles have been used for small interfering RNA delivery to cells and may be conjugated to other nanoparticles, such as quantum dots and gold nanoparticles.




Summary


The promise of in vivo characterization of the attributes of brain tumors is becoming closer to reality each day. Although primarily in the preclinical realm, many of the technologies described in this article are being used in vivo. It is hoped that these technologies will continue to mature over the coming decade to more widespread clinical use in the same way as advanced functional approaches have come to fruition over the past decade.


Disclosure: The authors have nothing to disclose.



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Sep 18, 2017 | Posted by in MAGNETIC RESONANCE IMAGING | Comments Off on Molecular Imaging of Brain Tumors Using Liposomal Contrast Agents and Nanoparticles

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