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Virtual Journal for Biomedical Optics

Virtual Journal for Biomedical Optics

| EXPLORING THE INTERFACE OF LIGHT AND BIOMEDICINE

  • Editor: Gregory W. Faris
  • Vol. 4, Iss. 2 — Feb. 10, 2009
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In-vivo fluorescence imaging of mammalian organs using charge-assembled mesocapsule constructs containing indocyanine green

Mohammad A. Yaseen, Jie Yu, Michael S. Wong, and Bahman Anvari  »View Author Affiliations


Optics Express, Vol. 16, Issue 25, pp. 20577-20587 (2008)
http://dx.doi.org/10.1364/OE.16.020577


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Abstract

Indocyanine green (ICG) is a fluorescent probe used in clinical imaging. However, its utility remains limited by optical instability, rapid circulation kinetics, and exclusive uptake by the liver. Using mesocapsule (MC) constructs to encapsulate ICG, we have developed a technology to stabilize ICG’s optical properties and alter its biodistribution. We present in vivo fluorescence images of mammalian organs to demonstrate the potential application of our ICG encapsulation technology for optical imaging of specific tissues.

© 2008 Optical Society of America

1. Introduction

Fluorescence imaging is actively pursued as a technology to better understand and treat physiological processes, and facilitate drug development [1

1. V. Ntziachristos and 33 (2006).

, 2

2. N. Beckmann, R. Kneuer, H.-U. Gremlich, H. Karmouty-Quintana, F.-X. Blé, and M. Müller, “In Vivo mouse imaging and spectroscopy in drug discovery,” NMR Biomed. 20, 154Z–185 (2007). [CrossRef] [PubMed]

]. One particular fluorescent probe of interest is indocyanine green (ICG), which has FDA approval for ophthalmic imaging, and assessment of cardiac output and hepatic function [3

3. M. L. J. Landsman, G. Kwant, G. A. Mook, and W. G. Zijlstra, “Light-absorbing properties, stability, and spectral stabilization of indocyanine green,” J. Appl. Physiol. 40, 575–583 (1976). [PubMed]

5

5. J. G. Webster, “Measurement of Flow and Volume of Blood,” in Medical Instrumentation: Application and Design, G. Webster, ed. (John Wiley & Sons, Inc, New York, 1998).

]. With negligible toxicity [6

6. T. Desmettre, J. M. Devoiselle, and S. Mordon, “Fluorescence Properties and Metabolic Features of Indocyanine Green (ICG) as Related to Angiography,” Surv. Ophthalmol. 45, 15–27 (2000). [CrossRef] [PubMed]

, 7

7. W. Holzer, M. Mauerer, A. Penzkofer, R. M. Szeimies, C. Abels, M. Landthaler, and W. Bäumler, “Photostability and thermal stability of indocyanine green,” J. Photochem. Photobiol. B 47, 155–164 (1998). [CrossRef]

], and absorption and fluorescence in the near-infrared (NIR) spectrum, ICG has prompted investigations in several tissue imaging and therapeutic applications [8

8. I. Roberts, P. Fallon, F. J. Kirkham, A. Lloyd-Thomas, C. Cooper, M. Eliot, and A. D. Edwards, “Estimation of cerbral blood flow with near infrared spectroscopy and indocyanine green,” Lancet 342, 1425–1425 (1993). [CrossRef] [PubMed]

15

15. J. V. Frangioni, “In vivo near-infrared fluorescence imaging,” Curr. Opin. Chem. Biol. 7, 626–634 (2003). [CrossRef] [PubMed]

].

While its fluorescence emission in the NIR bandwidth of 790–850 nm can allow for relatively deep optical imaging (on the order of a cm), ICG, currently administered in an aqueous solution, suffers from two major drawbacks: (1) unstable optical properties, with decreased absorption and fluorescence resultant from molecular degradation into leucoforms [7

7. W. Holzer, M. Mauerer, A. Penzkofer, R. M. Szeimies, C. Abels, M. Landthaler, and W. Bäumler, “Photostability and thermal stability of indocyanine green,” J. Photochem. Photobiol. B 47, 155–164 (1998). [CrossRef]

]; and (2) non-specific spatial distribution within the body, where after a bolus injection, its concentration within the blood plasma exponentially with a half-life of τ1/2=2-4 min [6

6. T. Desmettre, J. M. Devoiselle, and S. Mordon, “Fluorescence Properties and Metabolic Features of Indocyanine Green (ICG) as Related to Angiography,” Surv. Ophthalmol. 45, 15–27 (2000). [CrossRef] [PubMed]

]. ICG’s optical instability, rapid circulation kinetics, and exclusive uptake by the liver limit its utility for optical imaging applications.

To extend ICG’s utility for optically-mediated medical imaging applications, a number of investigators have developed nanometer size carrier particles as a method to stabilize ICG’s optical properties, potentially prolong its circulation kinetics, and control its tissue distribution. Several strategies have been reported to encapsulate ICG, including the use of phospholipid emulsions, poly-lactic co(glycolic)-acid (PLGA) particles, sol-gel matrices, and diblock copolymer micelles [16

16. S. Mordon, T. Desmettre, J.-M. Devoiselle, and V. Mitchell, “Selective Laser Photocoagulation of Blood Vessels in a Hamster Skin Flap Model Using a Specific ICG Formulation,” Lasers Surg. Med. 21, 365–373 (1997). [CrossRef] [PubMed]

21

21. V. Saxena, M. Sadoqi, and J. Shao, “Enhanced photo-stability, thermal-stability and aqueous-stability of indocyanine green in polymeric nanoparticulate systems,” J Photochem. Photobiol. B 74, 29–38 (2004). [CrossRef] [PubMed]

]. Among these technologies, ICG demonstrates improved optical stability and low cytotoxicity when encapsulated within the PLGA nanoparticles developed by Saxena et. al., diblock copolymer micelles developed by Rodriguez et. al, and sol gel PEBBLE matrices formulated by Kim et. al. Furthermore, encapsulation within PLGA nanoparticles also influences ICG’s in-vivo biodistribution, prolonging ICG’s residence time within the circulation and also depositing in larger amounts to organs including the heart, lungs, kidney, and spleen [22

22. V. Saxena, M. Sadoqi, and J. Shao, “Polymeric nanoparticulate delivery system for Indocyanine green: Biodistribution in healthy mice,” Int. J. Pharm. 308, 200–204 (2006). [CrossRef] [PubMed]

].

Fig. 1. Conceptual model of a mesocapsule containing ICG construct coated with nanoparticle micelles such as magnetite/polyacrylic acid composite, with cutaway provided to display the capsule interior. ICG resides within the positively charged polymer-salt aggregate core and the capsule shell.

In this investigation, we perform optical imaging of mammalian organs using our MC constructs, and demonstrate that constructs coated with polylysine or magnetite/polyacrylic acid (PAA) composite alter the biodistribution of ICG. Constructs coated with the magnetite/PAA composite accumulate within the lungs in amounts significantly different from polylysine coated constructs and free ICG. To our knowledge, this work is the first demonstration of any ICG encapsulation system for in vivo fluorescence imaging.

2. Materials and methods

2.1 Capsule preparation and characterization

We used either 50 nm diameter magnetite particles, or polylysine polymers (110 kDa) as our coating materials. The MCs which we refer to as Fe300 were coated with magnetite nanoparticles (NPs). The NPs measured 63 ± 20 nm in diameter and were themselves individually coated with polyacrylic acid (PAA), to potentially allow for surface conjugation of antibodies and other species to enhance target specificity. Polylysine coated MCs, which we refer to as PL100 system, were formed by adhesion of the polymer aggregate cores primarily through hydrogen bonding and electrostatic interaction between positively charged polylysine and negatively charged phosphate ions and ICG. Capsule sizes were measured using scanning electron microscopy, while surface charges were determined by phase analysis light scattering (PALS) in a ZetaPALS Zeta Potential Analyzer (Brookhaven Instruments Corporation).

2.2 In-vivo mouse imaging with MCs containing ICG

Female Swiss Webster mice (Charles River Laboratories) were utilized in this study under a protocol approved by the Institutional Animal Care and Use Committee at Rice University. All mice weighed between 20–25 g at the time of experiment. At least one day prior to experiment, hair was removed from the ventral side of each mouse using clippers and depilatory cream while under anesthesia by inhalation of isoflurane.

Whole body fluorescence images were acquired using a Maestro in-vivo fluorescence imaging system (Cambridge Research & Instrumentation, Inc., Woburn, MA). The system is equipped with a fiber-delivered 300 W xenon excitation lamp, and images can be acquired from λ=500-950 nm by a 1.3 megapixel CCD camera (Sony ICX285 CCD chip). In addition to standard excitation and emission filter sets, the Maestro system also contains a liquid crystal tunable filter (LCTF), which only transmits the emitted fluorescence light of a narrow spectral bandwidth (10 nm) to the camera. The peak wavelength of the LCTF can be rapidly switched within milliseconds with 1 nm precision. This allows the Maestro system to rapidly acquire an image stack, or cube, of fluorescence images, with each image consisting of light collected at a different fluorescence wavelength. Each pixel within the image cube therefore has an associated fluorescence spectrum. The software for the Maestro system contains several algorithms to process the spectral data cubes to remove undesired autofluorescence signal and generate overlaid images for multiple fluorophores.

A deep red excitation/emission filter set was used for our experiments (λex: 710–760 nm, λem > 750 nm). The LCTF was programmed to acquire image cubes from λ=790 nm to 900 nm with an increment of 10 nm per image. The camera was set to 100 ms exposure time with 2×2 binning. Each image cube required roughly 7 seconds to acquire.

During image acquisition, mice remained anesthetized by isoflurane inhalation, delivered continuously through a nosecone. Either ICG solution or MC preparations were administered to the mice through caudal vein injection at an ICG concentration of 2 mg/kg. Three mice were used for each capsule system. The mice were euthanized by cervical dislocation at 90 minutes post injection.

For each mouse, a control image cube was taken prior to injection to determine the influence of endogenous tissue autofluorescence. Image cubes were obtained from the mice at several time-points up to 90 minutes after injection. The mice remained under anesthesia for the first 30 minutes while image cubes were acquired at 5-minute intervals. The mice were allowed to recover from anesthesia after 30 minutes and briefly re-anesthetized for image acquisition at the later time-points.

Despite the difference in peak fluorescence intensity for each system (illustrated in Fig. 2), all ICG formulations were administered to the mice at the same ICG concentration (2 mg/kg). As native intestinal tissue demonstrates negligible autofluorescence relative to the signal from ICG solution and the MCs, no multispectral unmixing algorithms were necessary for these experiments.

The fluorescence images acquired at λem=820 nm were isolated from each image cube and analyzed using ImageJ software available from the National Institute of Health (Bethesda, MD). Images at this wavelength provided near maximal fluorescence signal for the MC systems. For each image, regions of interest (ROI) were identified corresponding to the heart and lungs region and prominent blood vessels such as the maxillary facial vein or femoral artery and veins on the leg. For each ROI, the mean projected intensity, Ī, was calculated as:

I̅=j=1mIjm
(1)

where Ij represents the pixel intensity at the jth pixel in a 2-dimensional ROI with a total of m pixels.

The Ī values were subsequently used to compute the target-to-background ratio (TBR), the signal to noise ratio (SNR), and image contrast (C) using MATLAB. These figures of merit are used frequently in medical imaging to evaluate image quality, and are determined by the following expressions [28

28. J. P. Houston, S. Ke, W. Wang, C. Li, and E. M. Sevick-Muraca, “Quality analysis of in vivo near-infrared fluorescence and conventional gamma images acquired using a dual labeled tumor targeting probe,” J. Biomed. Opt. 10, 054010 (2005). [CrossRef] [PubMed]

, 29

29. R. E. Coleman, C. M. Laymon, and T. G. Turkington, “FDG Imaging of Lung Nodules: A Phantom Study Comparing Spect, Camera-based PET, and Dedicated PET,” Radiology 210, 823 –838 (1999). [PubMed]

]:

SNR=I̅TI̅Bjm(IjBI̅B)2m
(2)
C=I̅TI̅BI̅B
(3)

where ĪT and ĪB represent the mean intensities (Ī) in a target ROI containing a total of m pixels (liver, heart and lungs, intestine, brain, and blood vessels), and background ROI, respectively.

2.3 Fluorescence imaging and ICG quantification of harvested tissues

Immediately following euthanasia (at 90 minutes post-injection), blood samples (100 µl) and organs (heart, intestines, kidney, lungs, liver, and spleen) were harvested and imaged after sacrifice. Following the imaging experiments, the ICG was extracted from the plasma and organs using dimethyl sulfoxide (DMSO) and quantified by fluorescence measurements [22

22. V. Saxena, M. Sadoqi, and J. Shao, “Polymeric nanoparticulate delivery system for Indocyanine green: Biodistribution in healthy mice,” Int. J. Pharm. 308, 200–204 (2006). [CrossRef] [PubMed]

, 25

25. M. A. Yaseen, J. Yu, M. S. Wong, and B. Anvari, “Tissue Distribution of Encapsulated Indocyanine Green in Healthy Mice,” Ann. Biomed. Eng. In Review. [PubMed]

]. Succinctly, ICG was organically extracted from the tissues by first homogenizing the tissues or diluting blood samples with DMSO. Using a fluorimeter (Fluoromax 3, JY Horiba), ICG content was quantified by measuring the fluorescence profile of supernatant and comparing peak value (λ=820 nm) to a standard curve. The fluorimeter contained a 150 W xenon arc lamp, excitation and emission monochromators, and a photomultiplier tube with extended red sensitivity (R928P, Hammamatsu).

3. Results and discussion

3.1 MC characteristics

Salient physical properties for both MC systems are presented in table 1. Figure 2 displays the intrinsic fluorescence profiles of ICG solution and the two MC systems containing ICG obtained from liquid sample preparation in a microcentrifuge tube. All ICG formulations provide substantially more fluorescence signal than native intestinal tissue. Compared to ICG solution, MCs demonstrate lower fluorescence emission, and, in the case of the PL100 MCs, the fluorescence peak appears to shift downward by 5 nm from λ=830 to λ=825 nm.

Table 1. Physical properties of MC systems utilized for this study.

table-icon
View This Table

3.2 In-vivo imaging with MCs containing ICG

Figure 3 displays computed contrast (C) and signal to noise ratio (SNR) for regions of interest (ROI) that correspond anatomically to the heart and lungs (CHL and SNRHL, Figs. 3.a-b) and large prominent blood vessels, such as the maxillary facial vein or the femoral arteries and veins (CBlood and SNRBlood, Figs. 3.c-d). Horizontal, dashed lines are provided at SNR=1, indicating reported threshold levels above which features from a given ROI can be distinguished from the background ROI [30

30. H. Palmedo, H. Bender, F. Grünwald, P. Mallman, P. Zamora, D. Krebs, and H. J. Biersack, “Comparison of fluorine-18 fluorodeoxyglucose positron emission tomography and technetium-99m methoxyisobutylisonitrile scintimammography in the detection of breast tumors,” Eur. J. Nucl. Med. 24, 1138–1145 (1997). [PubMed]

, 31

31. W. T. Phillips, “Delivery of gamma-imaging agents by liposomes,” Adv. Drug. Delivery Rev. 37, 13–32 (1999). [CrossRef]

].

Fig. 2. Fluorescence spectral profiles measured by Maestro in vivo imaging system. For comparison, the autofluorescence profile, taken from the intestinal region of interest (ROI) of an image from a non-injected mouse image, is also provided. The profiles are normalized to the fluorescence peak of free ICG solution.

The data in Fig. 3 indicate that all three ICG formulations allow for the distinction of the heart and lungs ROI from the background for up to 30 minutes after injection. Features within both the blood ROI and brain ROI can be distinguished for at least 30 minutes after injection using the PL100 MC system For up to 60 minutes, the PL100 MC system demonstrates substantially higher CBlood and SNRBlood than the ICG.

Fig. 3. Computed contrast (C) and signal to noise ratio (SNR) for ROIs corresponding to heart and lungs (a and b) and the bloodstream (c and d). Data are provided as means ± standard deviation for ICG solution, Fe300 MCs, and PL100 MCs (n=3)
Fig. 4. Single frame excerpt from a time-sequence video displaying false-color fluorescence images of mice injected with ICG solution (left), PL100 MCs (center), and Fe300 MCs (right) at various timepoints (Media 1). The featured images were acquired at t=20 min. post injection.

Figure 4 displays a single frame from a video of false-color fluorescence intensity representations for animals injected with either ICG solution or one of our MC systems at different post-injection time-points (see Media 1). In all images, the greatest amount of signal arises from the liver. This is consistent with findings from other studies [32

32. R. Gref, Y. Minamitake, M. T. Peracchia, V. Trubetskoy, V. Torchilin, and R. Langer, “Biodegradable Long-Circulating Polymeric Nanospheres,” Science 263, 1600–1603 (1994). [CrossRef] [PubMed]

], where it has been shown that the liver takes up the majority of ICG and other exogenous agents. At early time-points, however, other features, such as the brain and large superficial blood vessels can still be identified without further image manipulation. Initially (at t=5 min), the ubiquitous fluorescence signal is considerably stronger for the ICG solution. This is most likely attributable to the stronger fluorescence intensity of ICG compared to the MC systems.

Early on, high fluorescence signal can be detected from the mouse brain, thorax, and extremities for ICG solution and both capsule formulations. For both ICG solution and the Fe300 MCs, the fluorescence from these regions drops precipitously over time. In both cases, after 30 min, the signal has diminished considerably, and no features apart from the liver can be easily distinguished from the background. For the PL100 MCs, however, significant fluorescence signal can still be seen from the brain and thorax up to 30 minutes after injection. The false color images presented in the time sequence video suggest that PL100 MCs reside within the vasculature for a greater length of time when compared to ICG solution or other capsule systems tested in our earlier tissue distribution investigations [25

25. M. A. Yaseen, J. Yu, M. S. Wong, and B. Anvari, “Tissue Distribution of Encapsulated Indocyanine Green in Healthy Mice,” Ann. Biomed. Eng. In Review. [PubMed]

].

Figure 5 shows the grayscale fluorescence intensity collected from the harvested organs and blood 90 minutes post injection. For all ICG formulations, the majority of the fluorescence signal comes from the liver and the intestines. The bright fluorescence signal from the intestine in Fig. 5, when compared to the liver, is of particular interest. The high fluorescence signal within the intestines at 90 minutes is possibly attributable to the secretion of bile from the liver into the intestines. This assumption is consistent with the later frames of the time sequence video (see Media 1), in which the signal from the intestines continues to increase in brightness, suggesting that bile containing ICG is deposited there from the liver.

For the in-vivo image in Fig. 4, three factors may account for the lower fluorescence signal from the intestines. First, the images presented in Fig. 4 were acquired at an earlier time-point (20 minutes post-injection), when less ICG and bile had been secreted to the intestines from the liver. Second, from the ventral side, the liver is closer to the tissue surface, and therefore, excitation and emission light, to and from the liver, respectively, experience less scattering and attenuation. Lastly, due to liver being a highly vascularized organ, greater amount of various ICG formulations may have been transported to the liver, leading to a more intense fluorescence signal when compared to the intestines.

Fig. 5. Fluorescence images of harvested organs from mice injected with different ICG formulations. Animals were sacrificed at 90 minutes post-injection. For each formulation, ICG accumulated in large amounts within the intestine and liver, resulting in strong fluorescence signal. Both organs can be clearly identified at the bottom of each image (intestines on the left and liver on the right) in (b). Dashed circles correspond to locations of the harvested heart (H), lungs (L), kidney (K), spleen (S), and blood sample (B).

A slight amount of fluorescent signal could be detected within the kidneys for each formulation, but negligible fluorescence was observed from the heart, spleen, or blood. In the case of Fe300 MCs, the lungs generated a significant signal. Small bright spots can be observed on the lungs, suggesting that the MCs were compartmentalized to certain regions within the lung. No substantial signal was seen in the lungs in the case of ICG solution or the PL100 MCs.

Fig. 6. ICG quantification of harvested organs from mice injected with different ICG formulations. Animals were sacrificed at 90 minutes post-injection.

Figure 6 displays the ICG content extracted from the harvested blood and organs at 90 minutes post injection. For all 3 ICG formulations, the largest fractions of ICG remained in the liver and intestines. For the Fe300 MCs, however, the lungs and liver both had comparable amounts of ICG. Further investigation is necessary to determine why, despite containing as much ICG as the liver, the lungs cannot be clearly identified in the fluorescence images using Fe300 MCs. We suspect, though, that the diminished fluorescence signal from the lungs is a consequence of light attenuation by overlying muscle and ribcage tissue.

For these MC systems, the capsules’ coating demonstrates a pronounced influence on the biodistribution and circulation kinetics. PL100 MCs circulate in the vasculature for up to one hour after injection before being taken up by the liver, while Fe300 MCs are removed from the bloodstream more rapidly than the PL100 MCs by the lungs and liver.

To efficiently deliver exogenous agents such as nanoparticles (NPs) to specific targeted sites, particle surfaces must be engineered to reduce their uptake by macrophages, a reaction from the body’s natural defense system against bacteria and foreign particulate matter. Phagocytosis of foreign pathogens and particles by macrophages is facilitated by plasma proteins and antibodies referred to as opsonins. Upon entry of NPs into the bloodstream, opsonins including immunoglobulins (Ig) IgG and IgM, and complement proteins such as C3, C4, and C5, readily adsorb to particle surfaces and mediate the recognition of the particles by macrophages, a process referred to as opsonization. Additionally, other plasma proteins such as albumin, fibronectin, and apolipoprotein E have also been shown to adsorb to NP surfaces and behave like opsonins by mediating phagocytic response by macrophages. In the case of bacteria, opsonization occurs when specific domains of the opsonin recognize and bind to receptor proteins on the bacteria membrane surface. Although the adsorption mechanism for NPs is not well understood, reports indicate that opsonins first encounter NPs by Brownian motion and rapidly adsorb to NP surfaces by means of attractive forces such as van der Waals, electrostatic, or hydrophobic/hydrophilic interactions. The opsonization process is known to occur within seconds after injection. Receptors located on macrophage surfaces, specific to opsonins and activated complement protein byproducts such as C3b and iC3b, allow for fast recognition and phagocytosis of opsonized NPs [33

33. D. E. Owens III and N. A. Peppas, “Opsonization, biodistribution, and pharmacokinetics of polymeric nanoparticles,” Int J. Pharm. 307, 93–102 (2006). [CrossRef]

41

41. R. Gref, M. Lück, P. Quellec, M. Marchland, E. Dellacherie, S. Harnisch, T. Blunk, and R. H. Müller, “‘Stealth’ corona-core nanoparticles surface modified by polyethylene glycol (PEG): influences of the corona (PEG chain length and surface density) and of the core composition on phagocytic uptake and plasma protein adsorption,” Colloids Surf. B Biointerfaces 18, 301–313 (2000). [CrossRef] [PubMed]

].

Various methods to shield NPs from opsonization and phagocytosis, thereby prolonging their circulation times have been reported. These methods include coating the particles with hydrophilic, branched polymers including PEG and poloxamers that minimize interactions with NPs and opsonins [32

32. R. Gref, Y. Minamitake, M. T. Peracchia, V. Trubetskoy, V. Torchilin, and R. Langer, “Biodegradable Long-Circulating Polymeric Nanospheres,” Science 263, 1600–1603 (1994). [CrossRef] [PubMed]

, 38

38. S. M. Moghimi and J. Szebeni, “Stealth liposomes and long circulating nanoparticles: critical issues in pharmacokinetics, opsonization and protein-binding properties,” Prog. Lipid Res. 42, 463–478 (2003). [CrossRef] [PubMed]

, 42

42. V. P. Torchilin and V. S. Trubetskoy, “Which polymers can make nanoparticulate drug carriers long-circulating?,” Adv. Drug Delivery Rev. 16, 141–155 (1995). [CrossRef]

44

44. G. Storm, S. O. Belliot, T. Daemen, and D. D. Lasic, “Surface modification of nanoparticles to oppose uptake by the mononuclear phagocyte system,” Adv. Drug Delivery Rev. 17, 31–48 (1995). [CrossRef]

]. Through the covalent attachment of these polymers to the NP surface, interactions between NPs and opsonin proteins are sterically hindered. These flexible, hydrophilic, branched polymers form a cloud around the particle, reducing, although not eliminating, the prospect of phagocytosis [38

38. S. M. Moghimi and J. Szebeni, “Stealth liposomes and long circulating nanoparticles: critical issues in pharmacokinetics, opsonization and protein-binding properties,” Prog. Lipid Res. 42, 463–478 (2003). [CrossRef] [PubMed]

]. The polylysine polymer used to coat the PL100 MCs is not highly branched and presumably does not provide substantial steric hindrance for the MCs from opsonins. The increased residence time of PL100 MCs within the bloodstream is likely attributable to their zeta potential (-0.4 mV). The near neutral surface charge reduces the electrostatic interaction between the MCs and plasma membranes of endothelial cells. This is consistent with other reports of longer circulating neutral particles [34

34. S.-D. Li and L. Huang, “Pharmacokinetics and Biodistribution of Nanoparticles,” Mol. Pharm. 5, 496–504 (2008). [CrossRef] [PubMed]

, 45

45. Q. le Masne de Chermont, C. Chanéac, J. Seguin, F. Pellé, S. Maîtrejean, J.-P. Jolivet, D. Gourier, M. Bessodes, and D. Scherman, “Nanoprobes with near-infrared persistent luminescence for in vivo imaging,” Proc. Natl. Acad. Sci. U. S. A. 104, 9266–9271 (2007). [CrossRef] [PubMed]

]. We continue to develop methods to covalently attach branched polymers such as PEG to our MC surfaces to further extend circulation time, facilitating preferential targeting of specific tissues and organs.

Several investigators have reported the development of nanoparticles that demonstrate sensitivity to both optical and magnetic stimulation [46

46. O. m, C. Sun, J. Gunn, N. Kohler, P. Gabikian, D. Lee, N. Bhattarai, R. Ellenbogen, R. Sze, A. Hallahan, J. Olson, and M. Zhang, “Optical and MRI Multifunctional Nanoprobe for Targeting Gliomas,” Nano Lett. 5, 1003–1008 (2005). [CrossRef]

48

48. J. Kim, S. Park, J. E. Lee, S. M. Jin, J. H. Lee, I. S. Lee, I. Yang, J.-S. Kim, S. K. Kim, M. H. Cho, and T. Hyeon, “Designed Fabrication of Multifunctional Magnetic Gold Nanoshells and Their Application to Magnetic Resonance Imaging and Photothermal Therapy,” Angew. Chem. Int. Ed. Engl. 45, 7754–7758 (2006). [CrossRef] [PubMed]

]. Like these multifunctional particles, our Fe300 MCs are useful for several applications such as magnetic hyperthermia, magnetic resonance imaging, magnetic resonance spectroscopy, fiber guided laser scanning fluorescence microscopy, fiber-guided laser thermotherapy, and laser bronchoscopy [49

49. A. N. Mathur and P. N. Mathur, “Lasers in Interventional Pulmonology,” in Biomedical Photonics Handbook, T. Vo-Dinh, ed. (CRC Press, Boca Raton, 2003), pp. 41-41–41-17.

]. In particular, as the Fe300 MCs deposit considerably within the lungs, the Fe300 MCs may be an effective optical probe for multimodal imaging and treatment of pulmonary conditions.

4. Conclusion

Our charge-assembled MC systems containing ICG are effective contrast agents for fluorescence imaging. The capsules fluoresce strongly in the NIR region, allowing for the imaging of deeply situated tissue structures without the undesired influence of tissue autofluorescence. The coating influences the circulation time and tissue distribution of the capsules. A coating of superparamagnetic magnetite NPs, which themselves are coated with PAA, gives rise to a negatively charged capsule system that is readily taken up by the lungs. A coating of positively charged polylysine capsules gives rise to a neutrally charged MC system with prolonged circulation time in the bloodstream. Future investigations will further explore the MCs’ potential for molecular imaging of tumors and mammalian organs, including the covalent attachment of branched, dendritic polymer coatings and antibody conjugation for increased target specificity.

Acknowledgments

This work was supported by a grant from the National Institutes of Health under grant No GMO 8362. It was also supported by the Student Research Award from the American Society for Laser Medicine and Surgery. We also wish to thank Darnell Roblyer and Jiantang Sun for their valuable discussions and guidance with the MAESTRO imaging system, respectively.

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T. Fischer, I. Gemeinhardt, S. Wagner, D. V. Stieglitz, J. Schnorr, K.-G. A. Hermann, B. Ebert, D. Petzelt, R. MacDonald, K. Licha, M. Schirner, V. Krenn, T. Kamradt, and M. Taupitz, “Assessment of Unspecific Near-Infrared Dyes in Laser-Induced Fluorescence Imaging of Experimental Arthritis,” Acad. Radiol. 13, 4–13 (2006). [CrossRef] [PubMed]

12.

A. N. Pande, R. N. Kohler, E. Aikawa, R. Weissleider, and F. A. Jaffer, “Detection of macrophage activity in atherosclerosis in vivo using multichannel, high-resolution laser scanning fluorescence microscopy,” J. Biomed. Opt. 11, 021009 (2006). [CrossRef] [PubMed]

13.

E. Tanaka, H. S. Choi, H. Fujii, M. G. Bawendi, and J. V. Frangioni, “Image-guided oncologic surgery using invisible light: Completed pre-clinical development for sentinel lymph node mapping,” Ann. Surg. Oncol. 13, 1671–1681 (2006). [CrossRef] [PubMed]

14.

F. Ogata, R. Azuma, M. Kikuchi, I. Koshima, and Y. Morimoto, “Novel lymphography using indocyanine green dye for near-infrared fluorescence labeling,” Ann. Plast. Surg. 58, 652–655 (2007). [CrossRef] [PubMed]

15.

J. V. Frangioni, “In vivo near-infrared fluorescence imaging,” Curr. Opin. Chem. Biol. 7, 626–634 (2003). [CrossRef] [PubMed]

16.

S. Mordon, T. Desmettre, J.-M. Devoiselle, and V. Mitchell, “Selective Laser Photocoagulation of Blood Vessels in a Hamster Skin Flap Model Using a Specific ICG Formulation,” Lasers Surg. Med. 21, 365–373 (1997). [CrossRef] [PubMed]

17.

V. Saxena, M. Sadoqi, and J. Shao, “Indocyanine green-loaded biodegradable nanoparticles: preparation, physicochemical characterization and in vitro release,” Int. J. Pharm. 278, 293–301 (2004). [CrossRef] [PubMed]

18.

G. Kim, S.-W. Huang, K. C. Day, M. O’Donnell, R. R. Agayan, M. A. Day, R. Kopelman, and S. Ashkenazi, “Indocyanine-green-embedded PEBBLEs as a contrast agent for photoacoustic imaging,” J. Biomed. Opt. 12, 044020 (2007). [CrossRef] [PubMed]

19.

V. B. Rodriguez, S. M. Henry, A. S. Hoffman, P. S. Stayton, X. Li, and S. H. Pun, “Encapsulation and stabilization of indocyanine green within poly(styrene-alt-maleic anhydride) block-poly(styrene) micelles for near-infrared imaging,” J. Biomed. Opt. 13, 014025 (2008). [CrossRef] [PubMed]

20.

A. J. Gomes, L. O. Lunardi, J. M. Marchetti, C. N. Lunardi, and A. C. Tedesco, “Indocyanine Green Nanoparticles Useful for Photomedicine,” Photomed. Laser Surg. 34, 514–521 (2006). [CrossRef]

21.

V. Saxena, M. Sadoqi, and J. Shao, “Enhanced photo-stability, thermal-stability and aqueous-stability of indocyanine green in polymeric nanoparticulate systems,” J Photochem. Photobiol. B 74, 29–38 (2004). [CrossRef] [PubMed]

22.

V. Saxena, M. Sadoqi, and J. Shao, “Polymeric nanoparticulate delivery system for Indocyanine green: Biodistribution in healthy mice,” Int. J. Pharm. 308, 200–204 (2006). [CrossRef] [PubMed]

23.

J. Yu, M. A. Yaseen, B. Anvari, and M. S. Wong, “Synthesis of Near-Infrared-Absorbing Nanoparticle-Assembled Capsules,” Chem. Mater. 19, 1277–1284 (2007). [CrossRef]

24.

R. K. Rana, V. S. Murthy, J. Yu, and M. S. Wong, “Nanoparticle Self-Assembly of Heirarchically Ordered Microcapsule Structures,” Adv. Mater. 17, 1145–1150 (2005). [CrossRef]

25.

M. A. Yaseen, J. Yu, M. S. Wong, and B. Anvari, “Tissue Distribution of Encapsulated Indocyanine Green in Healthy Mice,” Ann. Biomed. Eng. In Review. [PubMed]

26.

M. A. Yaseen, J. Yu, M. S. Wong, and B. Anvari, “Stability assessment of indocyanine green within dextran-coated mesocapsules by absorbance spectroscopy,” J. Biomed. Opt. 12, 064031 (2007). [CrossRef]

27.

M. A. Yaseen, J. Yu, M. S. Wong, and B. Anvari, “Laser-Induced Heating of Dextran-Coated Mesocapsules Containing Indocyanine Green,” Biotechnol. Prog. 23, 1431–1440 (2007). [CrossRef] [PubMed]

28.

J. P. Houston, S. Ke, W. Wang, C. Li, and E. M. Sevick-Muraca, “Quality analysis of in vivo near-infrared fluorescence and conventional gamma images acquired using a dual labeled tumor targeting probe,” J. Biomed. Opt. 10, 054010 (2005). [CrossRef] [PubMed]

29.

R. E. Coleman, C. M. Laymon, and T. G. Turkington, “FDG Imaging of Lung Nodules: A Phantom Study Comparing Spect, Camera-based PET, and Dedicated PET,” Radiology 210, 823 –838 (1999). [PubMed]

30.

H. Palmedo, H. Bender, F. Grünwald, P. Mallman, P. Zamora, D. Krebs, and H. J. Biersack, “Comparison of fluorine-18 fluorodeoxyglucose positron emission tomography and technetium-99m methoxyisobutylisonitrile scintimammography in the detection of breast tumors,” Eur. J. Nucl. Med. 24, 1138–1145 (1997). [PubMed]

31.

W. T. Phillips, “Delivery of gamma-imaging agents by liposomes,” Adv. Drug. Delivery Rev. 37, 13–32 (1999). [CrossRef]

32.

R. Gref, Y. Minamitake, M. T. Peracchia, V. Trubetskoy, V. Torchilin, and R. Langer, “Biodegradable Long-Circulating Polymeric Nanospheres,” Science 263, 1600–1603 (1994). [CrossRef] [PubMed]

33.

D. E. Owens III and N. A. Peppas, “Opsonization, biodistribution, and pharmacokinetics of polymeric nanoparticles,” Int J. Pharm. 307, 93–102 (2006). [CrossRef]

34.

S.-D. Li and L. Huang, “Pharmacokinetics and Biodistribution of Nanoparticles,” Mol. Pharm. 5, 496–504 (2008). [CrossRef] [PubMed]

35.

F. Alexis, E. Pridgen, L. K. Molnar, and O. C. Farokhzad, “Factors Affecting the Clearance and Biodistribution of Polymeric Nanoparticles,” Mol. Pharm. 5, 505–515 (2008). [CrossRef] [PubMed]

36.

J.-C. Leroux, F. De Jaeghere, B. Anner, E. Doelker, and R. Gurny, “An investigation on the role of plasma and serum opsonins on the internalization of biodegradable poly(D,L-lactic acid) nanoparticles by human monocytes,” Life Sci. 57, 695–703 (1995). [CrossRef] [PubMed]

37.

M. T. Peracchia, S. Harnisch, H. Pinto-Alphandary, A. Gulik, J. C. Dedieu, D. Desmaële, J. d’Angelo, R. H. Müller, and P. Couvreur, “Visualization of in vitro protein-rejecting properties of PEGylated stealth ® polycyanoacrylate nanoparticles,” Biomaterials 20, 1269–1275 (1999). [CrossRef] [PubMed]

38.

S. M. Moghimi and J. Szebeni, “Stealth liposomes and long circulating nanoparticles: critical issues in pharmacokinetics, opsonization and protein-binding properties,” Prog. Lipid Res. 42, 463–478 (2003). [CrossRef] [PubMed]

39.

R. Gref, A. Domb, P. Quellec, T. Blunk, R. H. Muller, J. M. Verbavatz, and R. Langer, “The controlled intravenous delivery of drugs using PEG-coated sterically stabilized nanospheres,” Adv. Drug. Delivery Rev. 16, 215–233 (1995). [CrossRef]

40.

S. C. Semple, A. Chonn, and P. R. Cullis, “Interactions of liposomes and lipid-based carrier systems with blood proteins: Relation to clearance behaviour in vivo,” Adv. Drug Delivery Rev. 32, 3–17 (1998). [CrossRef]

41.

R. Gref, M. Lück, P. Quellec, M. Marchland, E. Dellacherie, S. Harnisch, T. Blunk, and R. H. Müller, “‘Stealth’ corona-core nanoparticles surface modified by polyethylene glycol (PEG): influences of the corona (PEG chain length and surface density) and of the core composition on phagocytic uptake and plasma protein adsorption,” Colloids Surf. B Biointerfaces 18, 301–313 (2000). [CrossRef] [PubMed]

42.

V. P. Torchilin and V. S. Trubetskoy, “Which polymers can make nanoparticulate drug carriers long-circulating?,” Adv. Drug Delivery Rev. 16, 141–155 (1995). [CrossRef]

43.

I. Brigger, C. Dubernet, and P. Couvreur, “Nanoparticles in cancer therapy and diagnosis,” Adv. Drug Delivery Rev. 54, 631–651 (2002). [CrossRef]

44.

G. Storm, S. O. Belliot, T. Daemen, and D. D. Lasic, “Surface modification of nanoparticles to oppose uptake by the mononuclear phagocyte system,” Adv. Drug Delivery Rev. 17, 31–48 (1995). [CrossRef]

45.

Q. le Masne de Chermont, C. Chanéac, J. Seguin, F. Pellé, S. Maîtrejean, J.-P. Jolivet, D. Gourier, M. Bessodes, and D. Scherman, “Nanoprobes with near-infrared persistent luminescence for in vivo imaging,” Proc. Natl. Acad. Sci. U. S. A. 104, 9266–9271 (2007). [CrossRef] [PubMed]

46.

O. m, C. Sun, J. Gunn, N. Kohler, P. Gabikian, D. Lee, N. Bhattarai, R. Ellenbogen, R. Sze, A. Hallahan, J. Olson, and M. Zhang, “Optical and MRI Multifunctional Nanoprobe for Targeting Gliomas,” Nano Lett. 5, 1003–1008 (2005). [CrossRef]

47.

L. Levy, Y. Sahoo, K. S. Kim, E. J. Bergey, and P. N. Prasad, “Nanochemistry: Synthesis and Characterization of Multifunctional Nanoclinics for Biological Applications,” Chem. Mater. 14, 3715–3721 (2002). [CrossRef]

48.

J. Kim, S. Park, J. E. Lee, S. M. Jin, J. H. Lee, I. S. Lee, I. Yang, J.-S. Kim, S. K. Kim, M. H. Cho, and T. Hyeon, “Designed Fabrication of Multifunctional Magnetic Gold Nanoshells and Their Application to Magnetic Resonance Imaging and Photothermal Therapy,” Angew. Chem. Int. Ed. Engl. 45, 7754–7758 (2006). [CrossRef] [PubMed]

49.

A. N. Mathur and P. N. Mathur, “Lasers in Interventional Pulmonology,” in Biomedical Photonics Handbook, T. Vo-Dinh, ed. (CRC Press, Boca Raton, 2003), pp. 41-41–41-17.

OCIS Codes
(170.3880) Medical optics and biotechnology : Medical and biological imaging
(170.6280) Medical optics and biotechnology : Spectroscopy, fluorescence and luminescence
(170.2655) Medical optics and biotechnology : Functional monitoring and imaging

ToC Category:
Medical Optics and Biotechnology

History
Original Manuscript: October 14, 2008
Revised Manuscript: November 20, 2008
Manuscript Accepted: November 25, 2008
Published: November 26, 2008

Virtual Issues
Vol. 4, Iss. 2 Virtual Journal for Biomedical Optics

Citation
Mohammad A. Yaseen, Jie Yu, Michael S. Wong, and Bahman Anvari, "In-vivo fluorescence imaging of mammalian organs using charge-assembled mesocapsule constructs containing indocyanine green," Opt. Express 16, 20577-20587 (2008)
http://www.opticsinfobase.org/vjbo/abstract.cfm?URI=oe-16-25-20577


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References

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  12. A. N. Pande, R. N. Kohler, E. Aikawa, R. Weissleider, and F. A. Jaffer, "Detection of macrophage activity in atherosclerosis in vivo using multichannel, high-resolution laser scanning fluorescence microscopy," J. Biomed. Opt. 11, 021009 (2006). [CrossRef] [PubMed]
  13. E. Tanaka, H. S. Choi, H. Fujii, M. G. Bawendi, and J. V. Frangioni, "Image-guided oncologic surgery using invisible light: Completed pre-clinical development for sentinel lymph node mapping," Ann. Surg. Oncol. 13, 1671-1681 (2006). [CrossRef] [PubMed]
  14. F. Ogata, R. Azuma, M. Kikuchi, I. Koshima, and Y. Morimoto, "Novel lymphography using indocyanine green dye for near-infrared fluorescence labeling," Ann. Plast. Surg. 58, 652-655 (2007). [CrossRef] [PubMed]
  15. J. V. Frangioni, "In vivo near-infrared fluorescence imaging," Curr. Opin. Chem. Biol. 7, 626-634 (2003). [CrossRef] [PubMed]
  16. S. Mordon, T. Desmettre, J.-M. Devoiselle, and V. Mitchell, "Selective Laser Photocoagulation of Blood Vessels in a Hamster Skin Flap Model Using a Specific ICG Formulation," Lasers Surg. Med. 21, 365-373 (1997). [CrossRef] [PubMed]
  17. V. Saxena, M. Sadoqi, and J. Shao, "Indocyanine green-loaded biodegradable nanoparticles: preparation, physicochemical characterization and in vitro release," Int. J. Pharm. 278, 293-301 (2004). [CrossRef] [PubMed]
  18. G. Kim, S.-W. Huang, K. C. Day, M. O'Donnell, R. R. Agayan, M. A. Day, R. Kopelman, and S. Ashkenazi, "Indocyanine-green-embedded PEBBLEs as a contrast agent for photoacoustic imaging," J. Biomed. Opt. 12, 044020 (2007). [CrossRef] [PubMed]
  19. V. B. Rodriguez, S. M. Henry, A. S. Hoffman, P. S. Stayton, X. Li, and S. H. Pun, "Encapsulation and stabilization of indocyanine green within poly(styrene-alt-maleic anhydride) block-poly(styrene) micelles for near-infrared imaging," J. Biomed. Opt. 13, 014025 (2008). [CrossRef] [PubMed]
  20. A. J. Gomes, L. O. Lunardi, J. M. Marchetti, C. N. Lunardi, and A. C. Tedesco, "Indocyanine Green Nanoparticles Useful for Photomedicine," Photomed. Laser Surg. 34, 514-521 (2006). [CrossRef]
  21. V. Saxena, M. Sadoqi, and J. Shao, "Enhanced photo-stability, thermal-stability and aqueous-stability of indocyanine green in polymeric nanoparticulate systems," J. Photochem. Photobiol. B 74, 29-38 (2004). [CrossRef] [PubMed]
  22. V. Saxena, M. Sadoqi, and J. Shao, "Polymeric nanoparticulate delivery system for Indocyanine green: Biodistribution in healthy mice," Int. J. Pharm. 308, 200-204 (2006). [CrossRef] [PubMed]
  23. J. Yu, M. A. Yaseen, B. Anvari, and M. S. Wong, "Synthesis of Near-Infrared-Absorbing Nanoparticle-Assembled Capsules," Chem. Mater. 19, 1277-1284 (2007). [CrossRef]
  24. R. K. Rana, V. S. Murthy, J. Yu, and M. S. Wong, "Nanoparticle Self-Assembly of Heirarchically Ordered Microcapsule Structures," Adv. Mater. 17, 1145-1150 (2005). [CrossRef]
  25. M. A. Yaseen, J. Yu, M. S. Wong, and B. Anvari, "Tissue Distribution of Encapsulated Indocyanine Green in Healthy Mice," submitted toAnn. Biomed. Eng. [PubMed]
  26. M. A. Yaseen, J. Yu, M. S. Wong, and B. Anvari, "Stability assessment of indocyanine green within dextran-coated mesocapsules by absorbance spectroscopy," J. Biomed. Opt. 12, 064031 (2007). [CrossRef]
  27. M. A. Yaseen, J. Yu, M. S. Wong, and B. Anvari, "Laser-Induced Heating of Dextran-Coated Mesocapsules Containing Indocyanine Green," Biotechnol. Prog. 23, 1431-1440 (2007). [CrossRef] [PubMed]
  28. J. P. Houston, S. Ke, W. Wang, C. Li, and E. M. Sevick-Muraca, "Quality analysis of in vivo near-infrared fluorescence and conventional gamma images acquired using a dual labeled tumor targeting probe," J. Biomed. Opt. 10, 054010 (2005). [CrossRef] [PubMed]
  29. R. E. Coleman, C. M. Laymon, and T. G. Turkington, "FDG Imaging of Lung Nodules: A Phantom Study Comparing Spect, Camera-based PET, and Dedicated PET," Radiology 210, 823 -838 (1999). [PubMed]
  30. H. Palmedo, H. Bender, F. Grünwald, P. Mallman, P. Zamora, D. Krebs, and H. J. Biersack, "Comparison of fluorine-18 fluorodeoxyglucose positron emission tomography and technetium-99m methoxyisobutylisonitrile scintimammography in the detection of breast tumors," Eur. J. Nucl. Med. 24, 1138-1145 (1997). [PubMed]
  31. W. T. Phillips, "Delivery of gamma-imaging agents by liposomes," Adv. Drug. Delivery Rev. 37, 13-32 (1999). [CrossRef]
  32. R. Gref, Y. Minamitake, M. T. Peracchia, V. Trubetskoy, V. Torchilin, and R. Langer, "Biodegradable Long-Circulating Polymeric Nanospheres," Science 263, 1600-1603 (1994). [CrossRef] [PubMed]
  33. D. E. OwensIII and N. A. Peppas, "Opsonization, biodistribution, and pharmacokinetics of polymeric nanoparticles," Int J. Pharm. 307, 93-102 (2006). [CrossRef]
  34. S.-D. Li and L. Huang, "Pharmacokinetics and Biodistribution of Nanoparticles," Mol. Pharm. 5, 496-504 (2008). [CrossRef] [PubMed]
  35. F. Alexis, E. Pridgen, L. K. Molnar, and O. C. Farokhzad, "Factors Affecting the Clearance and Biodistribution of Polymeric Nanoparticles," Mol. Pharm. 5, 505-515 (2008). [CrossRef] [PubMed]
  36. J.-C. Leroux, F. De Jaeghere, B. Anner, E. Doelker, and R. Gurny, "An investigation on the role of plasma and serum opsonins on the internalization of biodegradable poly(D,L-lactic acid) nanoparticles by human monocytes," Life Sci. 57, 695-703 (1995). [CrossRef] [PubMed]
  37. M. T. Peracchia, S. Harnisch, H. Pinto-Alphandary, A. Gulik, J. C. Dedieu, D. Desmaële, J. d'Angelo, R. H. Müller, and P. Couvreur, "Visualization of in vitro protein-rejecting properties of PEGylated stealth ® polycyanoacrylate nanoparticles," Biomaterials 20, 1269-1275 (1999). [CrossRef] [PubMed]
  38. S. M. Moghimi and J. Szebeni, "Stealth liposomes and long circulating nanoparticles: critical issues in pharmacokinetics, opsonization and protein-binding properties," Prog. Lipid Res. 42, 463-478 (2003). [CrossRef] [PubMed]
  39. R. Gref, A. Domb, P. Quellec, T. Blunk, R. H. Muller, J. M. Verbavatz, and R. Langer, "The controlled intravenous delivery of drugs using PEG-coated sterically stabilized nanospheres," Adv. Drug. Delivery Rev. 16, 215-233 (1995). [CrossRef]
  40. S. C. Semple, A. Chonn, and P. R. Cullis, "Interactions of liposomes and lipid-based carrier systems with blood proteins: Relation to clearance behaviour in vivo," Adv. Drug Delivery Rev. 32, 3-17 (1998). [CrossRef]
  41. R. Gref, M. Lück, P. Quellec, M. Marchland, E. Dellacherie, S. Harnisch, T. Blunk, and R. H. Müller, "'Stealth' corona-core nanoparticles surface modified by polyethylene glycol (PEG): influences of the corona (PEG chain length and surface density) and of the core composition on phagocytic uptake and plasma protein adsorption," Colloids Surf. B Biointerfaces 18, 301-313 (2000). [CrossRef] [PubMed]
  42. V. P. Torchilin and V. S. Trubetskoy, "Which polymers can make nanoparticulate drug carriers long-circulating?," Adv. Drug Delivery Rev. 16, 141-155 (1995). [CrossRef]
  43. I. Brigger, C. Dubernet, and P. Couvreur, "Nanoparticles in cancer therapy and diagnosis," Adv. Drug Delivery Rev. 54, 631-651 (2002). [CrossRef]
  44. G. Storm, S. O. Belliot, T. Daemen, and D. D. Lasic, "Surface modification of nanoparticles to oppose uptake by the mononuclear phagocyte system," Adv. Drug Delivery Rev. 17, 31-48 (1995). [CrossRef]
  45. Q. le Masne de Chermont, C. Chanéac, J. Seguin, F. Pellé, S. Maîtrejean, J.-P. Jolivet, D. Gourier, M. Bessodes, and D. Scherman, "Nanoprobes with near-infrared persistent luminescence for in vivo imaging," Proc. Natl. Acad. Sci. U. S. A. 104, 9266-9271 (2007). [CrossRef] [PubMed]
  46. O. Veiseh, C. Sun, J. Gunn, N. Kohler, P. Gabikian, D. Lee, N. Bhattarai, R. Ellenbogen, R. Sze, A. Hallahan, J. Olson, and M. Zhang, "Optical and MRI Multifunctional Nanoprobe for Targeting Gliomas," Nano Lett. 5, 1003-1008 (2005). [CrossRef]
  47. L. Levy, Y. Sahoo, K. S. Kim, E. J. Bergey, and P. N. Prasad, "Nanochemistry: Synthesis and Characterization of Multifunctional Nanoclinics for Biological Applications," Chem. Mater. 14, 3715-3721 (2002). [CrossRef]
  48. J. Kim, S. Park, J. E. Lee, S. M. Jin, J. H. Lee, I. S. Lee, I. Yang, J.-S. Kim, S. K. Kim, M. H. Cho, and T. Hyeon, "Designed Fabrication of Multifunctional Magnetic Gold Nanoshells and Their Application to Magnetic Resonance Imaging and Photothermal Therapy," Angew. Chem. Int. Ed. Engl. 45, 7754-7758 (2006). [CrossRef] [PubMed]
  49. A. N. Mathur, and P. N. Mathur, "Lasers in Interventional Pulmonology," in Biomedical Photonics Handbook, T. Vo-Dinh, ed. (CRC Press, Boca Raton, 2003), pp. 41-41 - 41-17.

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