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DOI: 10.1148/radiol.2432060307
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(Radiology 2007;243:340-347.)
© RSNA, 2007

Reviews

Nano- and Microparticle-based Imaging of Cardiovascular Interventions: Overview1

Xiaoming Yang, MD, PhD

1 From the Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, Md; and Department of Radiology, Image-Guided Bio-Molecular Interventions Research, University of Washington, 1959 NE Pacific St, HSC AA-036, Box 357987, Seattle, WA 98195-7987. Supported by National Institutes of Health grant R01 HL078672. Received February 16, 2006; revision requested April 20; revision received May 2; accepted June 1; final version accepted August 14; final review by author November 14. Address correspondence to the author (e-mail: xmyang{at}u.washington.edu).


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 PARTICLES
 PARTICLE FUNCTIONS
 APPLICATION OF NANO- AND...
 CONCLUSION
 ESSENTIALS
 References
 
The rapid progress of nanoscience and the application of nanotechnology are changing the foundations of diagnosis, treatment, and prevention of cardiovascular diseases. As the core of nanotechnology, nano- and microparticles offer "three-in-one" functions as imaging agents, target probes, and therapeutic carriers. While nano- and microparticle-based imaging of cardiovascular interventions is still in its developing phase, it has already presented the exciting potential to monitor primary interventional procedures for precise therapeutic delivery, enhance the effectiveness of delivered therapeutics, and monitor therapeutic efficiency after interventions performed to treat cardiovascular diseases. This article provides an overview of the current status of the application of nano- and microparticles in the imaging of cardiovascular interventions.

© RSNA, 2007


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
PARTICLES
 PARTICLE FUNCTIONS
 APPLICATION OF NANO- AND...
 CONCLUSION
 ESSENTIALS
 References
 
Nanotechnology is a scientific field devoted to the manipulation of atoms and molecules to construct miniature structures for new molecular assemblies at the nanometer scale size (1–3). The rapid innovations and expansions of a wide spectrum of nano- or microscale techniques have opened new avenues for diagnosis and treatment, as well as prevention, of cardiovascular diseases. The construction of nano- and microparticles with imaging-detectable biomaterials enables the production of different types of diagnostic imaging agents. Modification of the physical and chemical properties of these imaging particles, such as the conjugation of ligands to the particle surface, enables generation of site-specific ligand-molecule interaction, which therefore permits visualization of the targets and assessment of the functionality of target sites at the molecular level, termed molecular imaging. Furthermore, loading of therapeutics such as genes and drugs into the target nano- and microparticles leads to the generation of new approaches for site-specific delivery of therapeutics, and thus, target-specific therapies for disease. The application of nanotechnology to the molecular imaging of the cardiovascular system has been reviewed in several excellent articles (3–5). Thus, this review will focus on the current status of the application of nanotechnology to the imaging of cardiovascular interventions, with specific emphasis on imaging of nano- and microparticle-based cardiovascular gene and drug therapy.


   PARTICLES
TOP
 ABSTRACT
 INTRODUCTION
 PARTICLES
PARTICLE FUNCTIONS
 APPLICATION OF NANO- AND...
 CONCLUSION
 ESSENTIALS
 References
 
Although a size definition to distinguish nanoparticles from microparticles has not been standardized, nanoparticles are typically defined as ranging from 5 to 700 nm in diameter and microparticles as being approximately 3 µm in diameter (3,6). Because of the difference in their physical size, nanoparticles can enter the cells and create functions inside the cells such as generation of intracellular imaging, targeting of molecules, and delivery of drugs or genes into the cells, while microparticles usually perform these functions on the endothelium and extracellular matrix. The most commonly used nano- and microparticles include liposomes, emulsions, polymeric microspheres, and microbubbles. Liposomes are essentially phospholipids, that is, uni- or multilamellar vesicles with an internal space that shields the encapsulated agent from degradation in the plasma (7). Emulsions, which are chemically distinct from liposomes, are oil-in-water–type mixtures and are stabilized with surfactants to maintain their size and shape (3). Polymeric spheres, made from different polymers, are readily produced, are inexpensive, and show no signs of toxicity in vivo (5,8). Microbubbles, made of albumin or charged lipid, function by resonating in an ultrasound beam and rapidly contracting and expanding in response to the pressure changes of the sound wave (6). Therapeutics carried by modified liposomes, emulsions, polymeric spheres, and microbubbles provide decreased systemic toxicity, targeted delivery to specific tissues, and higher doses delivered to the target (9).

In addition to these commonly used particles, new types of nano- and microscale particles have been recently introduced, such as (a) quantum dots (also called semiconductor nanocrystals or artificial atoms), which manifest stable (nonquenching) fluorescent properties at various wavelengths and offer new capabilities for multicolor optical coding in gene expression and in vivo imaging (3,10); (b) aquasomes (carbohydrate-ceramic nanoparticles), which have cores composed of nanocrystalline calcium phosphate for drug and antigen delivery (11); (c) dendrimers, which can be attached to therapeutic and diagnostic agents by means of chemical modification (12); (d) gold nanoparticles, which remain unoxidized at the nanoscale size to produce good contrast for computed tomography (CT) (13); and (e) metal nanoshells, which consist of spheric dielectric nanoparticles surrounded by an ultrathin, conductive, metallic layer and can be used as a near-infrared contrast agent for optical imaging (14).


   PARTICLE FUNCTIONS
TOP
 ABSTRACT
 INTRODUCTION
 PARTICLES
 PARTICLE FUNCTIONS
APPLICATION OF NANO- AND...
 CONCLUSION
 ESSENTIALS
 References
 
Function as a Diagnostic Imaging Agent
The imaging capability of nano- and microparticles involves the construction of particles with use of imaging contrast agents, such as paramagnetic or superparamagnetic metals for magnetic resonance (MR) imaging, optically active compounds for optical imaging, or gases for ultrasonographic (US) imaging. For example, encapsulation of paramagnetic gadolinium into polymeric microspheres enables detection of the microspheres at MR imaging (Fig 1) (15). The multiple micropores of the polymeric microsphere wall allow exchanges between gadolinium atoms and free water, which thus creates MR imaging signals at the targets (15,16). Another example is the use of nanoshells as optical imaging contrast agents. Nanoshells offer several advantages relative to conventional imaging agents, including more favorable optical scattering properties, enhanced biocompatibility, reduced susceptibility to chemical and thermal denaturation, and the ability to conjugate antibodies or other targeting moieties of interest to enable molecular-specific optical imaging (14).


Figure 1A
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  		Figure 1a: (a) Electron microscopic image of polymeric microspheres. Multiple micropores on the wall of polymeric microspheres allow exchange between interior (encapsulated) MR contrast agents and exterior free water, generating MR signals. (Reprinted, with permission, from reference 16.) (b) Polymeric microspheres encapsulated with gadolinium (gadopentetate dimeglumine) at 0.5 and 0.25 mol/L solution and saline. The gadolinium microspheres are aggregated in a pellet at the tube bottom after centrifugation. (c) Subsequent in vitro T1-weighted MR image shows hyperintense signals produced by gadolinium microspheres; no such signal is detected from saline. (Reprinted, with permission, from reference 15.)

 

Figure 1B
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  		Figure 1b: (a) Electron microscopic image of polymeric microspheres. Multiple micropores on the wall of polymeric microspheres allow exchange between interior (encapsulated) MR contrast agents and exterior free water, generating MR signals. (Reprinted, with permission, from reference 16.) (b) Polymeric microspheres encapsulated with gadolinium (gadopentetate dimeglumine) at 0.5 and 0.25 mol/L solution and saline. The gadolinium microspheres are aggregated in a pellet at the tube bottom after centrifugation. (c) Subsequent in vitro T1-weighted MR image shows hyperintense signals produced by gadolinium microspheres; no such signal is detected from saline. (Reprinted, with permission, from reference 15.)

 

Figure 1C
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  		Figure 1c: (a) Electron microscopic image of polymeric microspheres. Multiple micropores on the wall of polymeric microspheres allow exchange between interior (encapsulated) MR contrast agents and exterior free water, generating MR signals. (Reprinted, with permission, from reference 16.) (b) Polymeric microspheres encapsulated with gadolinium (gadopentetate dimeglumine) at 0.5 and 0.25 mol/L solution and saline. The gadolinium microspheres are aggregated in a pellet at the tube bottom after centrifugation. (c) Subsequent in vitro T1-weighted MR image shows hyperintense signals produced by gadolinium microspheres; no such signal is detected from saline. (Reprinted, with permission, from reference 15.)

 
As US contrast agents, microbubbles have been already used in clinical practice for many years. The clinical application of microbubbles includes microbubble-based US imaging of liver to detect early hepatocellular carcinoma, microbubble-enhanced echocardiography to visualize myocardial perfusion, and microbubble-mediated functional examination of vesicoureteric reflux in children (6). In addition, since certain materials for construction of particles can reflect and scatter the ultrasound wave, the nano- and microparticles constructed with such echogenic materials can be directly detected at US with no need to incorporate contrast agents.

Function as a Target-specific Probe or Tracer
To implement this function, the physical and chemical properties of nano- and microparticles, usually their surfaces, need to be modified with target ligands. These ligands can be monoclonal antibodies or their fragments, peptides, small molecular peptidomimetics (small proteinlike chains that contain both natural and non-natural amino acids), vitamins, or aptamers (small molecules that can bind to another molecule) (17). Particles that function as target-specific imaging probes or tracers are based on the mechanism of ligand-molecule binding, that is, the specific interaction of ligands with their corresponding molecules of the targets (such as receptors expressed on cell surfaces) to form an antigen-antibody pairlike complex. The specific ligand-molecule binding allows the imaging-detachable ligand-conjugated particles to be highly localized at the site of interest. Thus, once the target-specific imaging particles reach a certain level, the particle-delineated target can be visualized with imaging. Configuration of multivalent ligands (or mixture ligands) is desirable to maintain the particle-target interaction and reduce "off rates," which thus permits the success of target-specific imaging within a sufficient time window after administration of target-specific imaging particles. In certain circumstances, such as liver MR imaging with superparamagnetic iron oxide particles, liver-specific imaging can be achieved with no surface modification of the particles because superparamagnetic iron oxide particles are primarily taken up by the Kupffer cells of the liver, among other types of cells (18).

Function as a Therapeutic Carrier
The ability of target-specific nano- and microparticles to carry therapeutic agents (such as drugs, genes, or proteins) is essential for the application of nanotechnology in modern medicine. Therapeutic agents can be attached to the surface of a target-specific imaging particle, incorporated into its structure, or encapsulated within the core of a hollow agent (19). The importance of combining therapeutics with a target-specific nano- or microparticle is the capability to concentrate high doses of therapeutics at the targets while minimizing the systemic toxicity, which, therefore, efficiently activates the intracellular metabolic processes to create subsequent biologic environment changes, that is, target-specific therapy (20). The proposed mechanisms for drug or gene release from the particles to the target cells include diffusion, particle fusion and internalization into cells, component (lipid-lipid) exchanges, or some combination of these mechanisms (17).

Some authors suggest that an ideal nanoparticle should have (a) biocompatibility, (b) a sufficiently long intravascular half-life to allow for repeated passage and interactions, (c) the ability to conjugate ligands on the surface in multivalent configuration, (d) the ability to have functional groups for high-affinity surface metal chelation or radiolabeling for imaging, and (e) the capability to have both imaging and therapeutic agents incorporated in the same particle (5).

The "three-in-one" functions—imaging, targeting, and transport—are the characteristics of nano- and microparticles (Fig 2). By combining each of the three functions of particles, one can generate (a) target-specific molecular imaging for early diagnosis of diseases, (b) target-specific therapy for efficient treatment of diseases, and (c) imaging-guided target-specific therapy for further enhancement of target particle-based treatment of diseases (Fig 3).


Figure 2
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  		Figure 2: Diagram of microbubble constructed for drug delivery. Gas-filled microspheres can be designed so that their interior is loaded with drugs and gas. A stabilizing material, in this case a lipid, surrounds the perfluorocarbon bubble. Drugs can be incorporated alone, or if insoluble, in water, or in an oil layer. The microsphere can be targeted to specific tissue by incorporating protein ligands on the surface. The microbubble is capable of three functions: visualization at US, site-specific targeting, and drug transportation. (Reprinted, with permission, from reference 6.)

 

Figure 3
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  		Figure 3: Diagram represents particle with three-in-one functions for imaging, targeting, and transport (carrier). Combination of the three functions enables generation of target-specific molecular imaging for early diagnosis, site-specific delivery of therapeutics for efficient treatment, and imaging-guided site-specific delivery of therapeutics for further enhanced treatment.

 

   APPLICATION OF NANO- AND MICROPARTICLES IN IMAGING OF CARDIOVASCULAR INTERVENTIONS
TOP
 ABSTRACT
 INTRODUCTION
 PARTICLES
 PARTICLE FUNCTIONS
 APPLICATION OF NANO- AND...
CONCLUSION
 ESSENTIALS
 References
 
Imaging of cardiovascular interventions should help address several issues pertinent to the success of cardiovascular interventional therapies, such as (a) monitoring the primary interventional procedure to assess desirable distribution and localization of delivered therapeutics at the targets, (b) enhancing the effectiveness of the delivered therapeutics to achieve a sufficient level of therapeutic effect at the targets, and (c) monitoring the function and functional period of the delivered therapeutics at the targets (21). The application of the three-in-one functions of nano- and microparticles, including imaging, targeting, and transport, has opened new avenues for using imaging to monitor, enhance, and track cardiovascular interventions.

Particle-mediated Imaging of Primary Gene and Drug Delivery
In clinical practice, during the delivery of therapeutics to the targets (the so-called primary delivery procedure), one needs to know how and where the delivered therapeutics distribute and locate within the targets. The combination of nanotechnology with routinely practiced, imaging-guided interventional approaches can ensure the success of primary interventional procedures. Recent attempts have been made to validate the feasibility of using US to monitor vascular gene delivery in animals (22). The development of this new technique involves production of echogenic gene-carrying particles. We recently encapsulated a surrogate marker gene, the green fluorescent protein (gfp) gene, into polymeric microspheres that were echogenic (ie, reflection of the ultrasound wave). With a catheter-based approach, the echogenic gfp-carrying particles were locally infused into the artery walls, while the infusion process was monitored with US. US scans displayed a hyperechogenic ring of the artery wall as the gfp-carrying particles entered the target. We subsequently compared US imaging of gfp-carrying particles with that of saline, gfp-carrying plasmid, and gfp-carrying lentivirus by using the same catheter-based local-delivery approach. Among these four agents, only gfp-carrying particles created echo signal changes in the target artery walls, which thus enabled assessment of the biodistribution and localization after administration of gfp-carrying particles into the targets (Fig 4). These experimental studies with animals confirm the potential usefulness of particles as imaging agents and therapeutic carriers in monitoring the success of primary-delivery procedures, the first key component for a successful vascular interventional gene and drug therapy.


Figure 4
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  		Figure 4: Transverse US scans of pig femoral arteries, A, before infusion and after infusion with, B, saline, C, gfp-carrying plasmid, D, gfp-carrying lentivirus, and, E, gfp-carrying microspheres (particles). Arrow = artery. Saline, gfp-carrying plasmid, and gfp-carrying lentivirus do not create echo signal changes, while gfp-carrying microspheres generate high echo-intense signals around entire vessel wall. US-based imaging of catheter-mediated vascular gene delivery enables assessment of distribution and location of genes and microspheres within target vessels.

 
A few studies (23,24) have also demonstrated the usefulness of combining drug-carrying nanoparticles with arterial stent placement to reduce in-stent restenosis. Simultaneous dual-loading of a drug and an imaging contrast agent represents another opportunity to use a particle-based imaging method to monitor primary stent placement procedures.

In addition to the application of nanotechnology to catheter-based gene and drug delivery, non–catheter-based nanoparticle imaging techniques such as tissue factor imaging may offer a noninvasive molecular imaging tool to monitor primary therapeutic delivery. Tissue factor imaging is based on the mechanism that biologic pathways or metabolic processes, which are activated by target particle–shuttled therapeutics, can be delineated and followed by using molecular imaging before, during, and after administration of these therapeutics (4,19). To this end, it is essential to explore the molecules of the targets, such as atherosclerotic plaques and ischemic myocardium, which should specifically interact with or be bound by the target particles with dual-loading of an imaging agent and a therapeutic.

Several molecules, such as endothelial interleukin-2, intercellular adhesion molecule–1, vascular cell adhesion molecule–1, fibrin, fibrinogen, IIb-IIa factors, {alpha}vß3-integrin, and myeloperoxidese, are expressed from vulnerable plaques and activated platelets. Thus, these molecules become the targets for tissue factor imaging (4,17,19,25,26). For example, the success of nanoparticle-targeted fibrin imaging, which is based on physiopathologic evidence of fibrin deposition, one of the earliest signs of plaque rupture or erosion and intraplaque hemorrhage, has been reported (27,28). Through systemic administration, the fibrin-specific nanoparticles accumulate at the site of arterial thrombi, which can then be detected at either US or MR imaging (29,30). Another example of target particle–based tissue factor imaging is molecular MR imaging of angiogenesis, which is based on the mechanism by which ligand-conjugated paramagnetic nanoparticles specifically target {alpha}vß3-integrin, a general marker of angiogenesis (5,31–33). The results of these studies have demonstrated the potential opportunities for the use of target-specific imaging particles to detect early events in diseases. For imaging of cardiovascular interventions, the combination of tissue factor imaging with the transport function of particles should enable us to not only generate target-specific imaging but also to shuttle specifically the therapeutics to the targets of interests, which will then enable the use of different imaging modalities to assess the distribution and location of therapeutics and/or particles after their primary target-specific delivery.

Particle-enhanced Gene and Drug Therapy
The efficient entry of genes or drugs into the target cells once they arrive at the target site is the second key component for the success of cardiovascular interventional therapy. Currently, in vivo transfection and transduction of genes in the vasculature are very low, approximately only 1% for nonviral gene-carrying vectors (34,35). Concerns over the safety and practicality of recombinant viral vectors in patients and the inefficiency of nonviral transfection techniques are the major hurdles for the clinical application of cardiovascular gene therapy (36). To address these problems, scientists have attempted to combine nanotechnology with the provision of physical energies, such as ultrasound, to increase the in vivo transfection and expression of transgenes. The primary particles used for this purpose are US microbubbles and liposomes.

US microbubbles can be used as cavitation nuclei for gene delivery (37–39). Once they enter the region of insonation, the gene-bearing microbubbles oscillate, collapse, and thereby, locally release the genes (Fig 5). Cavitation of microbubbles in capillary beds also increases capillary permeability, which further improves local access for the released genes (6). By using a low-frequency (usually 1–2-MHz) ultrasound probe with either a surface transducer or an endovascular transducer, some authors (40–42) have confirmed that microbubble-based US can enhance gene transfection and transduction in vitro and in vivo. For example, by focusing the ultrasound beam on the heart during intravenous injection of gene-carrying microbubbles, high levels of transgene expression in the insonated region of the myocardium were achieved (37). Another example of enhanced gene transfection and transduction is the success of US-mediated delivery of TIMP-3 plasmid DNA into saphenous vein grafts, which increased their luminal size and thus prevented their failure (43).


Figure 5
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  		Figure 5: Diagram of enhanced gene delivery with ultrasound and microbubbles. Presence of gas in gene-filled microbubble allows ultrasound energy to "pop" the bubble. An energetic wave is then created that allows genetic material to enter surrounding cells. (Reprinted, with permission, from reference 6.)

 
The exact mechanism for US-enhanced gene transfection is not yet clear, but is likely attributable to sonoporation (44). Sonoporation is the term used to describe the transient, nonlethal perforation of the cell membrane induced by the ultrasound shockwave, which reversibly and irreversibly disrupts the membranes of the cells through cavitation, reduces the thickness of the unstirred layer at the cell surface, and thereby facilitates the passage of genes and/or vectors across membranes. In addition, rapid vibration of microbubbles on the surface of the cells or rapid fluid movement at the sites of microbubble location during insonification (so-called microstreaming) perhaps further improves the effectiveness agent transfection by providing ultrasound energy at the targets (39,45). Some of the target sites such as the brain and solid tumors have unique physiologic barriers to the delivery of therapeutics, which may be overcome by using focused ultrasound combined with nanoparticles. Studies (46,47) demonstrate that the blood-brain barrier or vascular–endothelial cell barrier can be consistently opened with focused ultrasound exposure in the presence of echogenic microbubbles.

Functioning as a site-specific drug- or gene-carrying vehicle, the ligand-conjugated particles themselves allow directed tissue targeting that enables delivery of concentrated high doses of genes or drugs to the target, which thus enhances the effects of gene and drug therapies (48). For example, by conjugating intercellular adhesion molecule–1 onto echogenic liposomes, substantial transfection and higher expression of a reporter gene from human umbilical vein endothelial cells can be achieved (48). Other authors also report greater effectiveness of drugs (such as paclitaxel and doxorubicin) in inhibiting plaque angiogenesis and restenosis with site-specific nanoparticles (23,33,49). The liposome-enhanced approach primarily depends on the strength of the lipid exchange (or lipid mixing) and, thereafter, fusion and endocytosis. The emulsion-enhanced approach is highly dependent on the strength of the ligand-molecule pairs, which create close apposition between the emulsion vehicle and the targeted cell membrane.

Particle-based Imaging for Follow-up Gene Therapy
The third key component of imaging of cardiovascular interventions is to track the functionality of therapeutics at the targets to determine at what level the therapeutics affect the target and how long the therapeutics function at the targets. For cardiovascular gene therapy, it is not possible to use noninvasive methods to directly detect the transgenes, gene-carrying vectors, and even gene-expressed downstream products such as proteins and enzymes that constitute the receptors. Currently, the confirmation of successful gene transfection and expression depends mainly on different laboratory tests, such as histologic staining, immunoblotting, or in situ hybridization of harvested tissues obtained at either autopsy or biopsy.

Molecular imaging enables the delineation of cellular and/or molecular components and the biochemical signaling processes that result from gene expression. Thus, particle-based imaging should enable conclusive assurance of not only the success of primary transgene delivery procedures but also the biologic effects that are induced or activated by transgenes at the targets.

Use of molecular imaging to track transgene expression and function requires the construction of dual genes in a single vector, which should simultaneously express (a) an imaging reporter, such as gfp for optical imaging, and (b) a therapeutic, such as a vascular endothelial growth factor (VEGF) for promoting angiogenesis of the ischemic heart (50,51). After delivering the dual-gene vectors into the targets (such as the ischemic myocardium), gfp and VEGF genes express simultaneously two proteins, green fluorescent protein and VEGF, at the sites. Thus, indirect monitoring of VEGF function in the ischemic heart, for example, is possible by direct tracking of gfp under optical imaging, since two proteins are expressed from the same vector, a single plasmid, or a recombinant virus. To date, fluorescent molecules such as green fluorescent protein have been successfully expressed from different tissues and organs of various animal species, but this has not been tested in humans as yet. Thus, in its current state, the fluorescent molecule–mediated optical imaging technique has provided a useful noninvasive imaging tool for basic medical science.

Use of particle-based molecular imaging to track transgene expression and function requires two constructs: (a) a dual-gene vector that simultaneously expresses a cell surface receptor and a therapeutic protein at the target and (b) a targeted imaging particle (tracer) that specifically interacts, by means of its ligand-receptor pair, with the cell surface receptor overexpressed at the target. Thus, after simultaneous expression of both the cell surface receptor and the therapeutic protein, systemic delivery of the receptor-specific imaging particles should delineate the location of the expressed receptors, which thus enables indirect assessment of the function of the therapeutic genes.


   CONCLUSION
TOP
 ABSTRACT
 INTRODUCTION
 PARTICLES
 PARTICLE FUNCTIONS
 APPLICATION OF NANO- AND...
 CONCLUSION
ESSENTIALS
 References
 
Nano- and microparticles, with the three-in-one functions of imaging, targeting, and transporting, play a central role in nano- and microparticle-based imaging of cardiovascular interventions. While it is still in its developing phase, nano- and microparticle-based imaging of cardiovascular interventions has already presented the exciting potential to monitor primary interventional procedures for precise therapeutic delivery, enhance the effectiveness of delivered therapeutics, and monitor therapeutic efficiency after interventions performed to treat cardiovascular diseases. As refinements of nanotechniques continue with additional effort on their subsequent translation to clinical practice, the rapid growth of nanoscience and the application of nanotechnology in modern medicine are changing the field of imaging and imaging-guided interventions for cardiovascular diseases.


   ESSENTIALS
TOP
 ABSTRACT
 INTRODUCTION
 PARTICLES
 PARTICLE FUNCTIONS
 APPLICATION OF NANO- AND...
 CONCLUSION
 ESSENTIALS
References
 


   FOOTNOTES
 

Abbreviations: gfp = green fluorescent protein • VEGF = vascular endothelial growth factor


   References
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 ABSTRACT
 INTRODUCTION
 PARTICLES
 PARTICLE FUNCTIONS
 APPLICATION OF NANO- AND...
 CONCLUSION
 ESSENTIALS
 References
 

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