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In Vivo Tumor Vasculature Targeted PET/NIRF Imaging with TRC105(Fab)-Conjugated, Dual-Labeled Mesoporous Silica Nanoparticles
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In Vivo Tumor Vasculature Targeted PET/NIRF Imaging with TRC105(Fab)-Conjugated, Dual-Labeled Mesoporous Silica Nanoparticles
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† Department of Radiology, University of Wisconsin—Madison, Madison, Wisconsin 53792, United States
‡ Materials Science Program, University of Wisconsin—Madison, Madison, Wisconsin 53706, United States
§ Department of Medical Physics, University of Wisconsin—Madison, Madison, Wisconsin 53705, United States
∥ TRACON Pharmaceuticals, Inc., San Diego, California 92122, United States
⊥ University of Wisconsin Carbone Cancer Center, Madison, Wisconsin 53792, United States
*E-mail: [email protected]. Address: Departments of Radiology and Medical Physics, University of Wisconsin—Madison, Room 7137, 1111 Highland Avenue, Madison, Wisconsin 53705−2275, United States.
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Molecular Pharmaceutics

Cite this: Mol. Pharmaceutics 2014, 11, 11, 4007–4014
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https://doi.org/10.1021/mp500306k
Published June 17, 2014

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Abstract

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Multifunctional mesoporous silica nanoparticles (MSN) with well-integrated multimodality imaging properties have generated increasing research interest in the past decade. However, limited progress has been made in developing MSN-based multimodality imaging agents to image tumors. We describe the successful conjugation of, copper-64 (64Cu, t1/2 = 12.7 h), 800CW (a near-infrared fluorescence [NIRF] dye), and TRC105 (a human/murine chimeric IgG1 monoclonal antibody) to the surface of MSN via well-developed surface engineering procedures, resulting in a dual-labeled MSN for in vivo targeted positron emission tomography (PET) imaging/NIRF imaging of the tumor vasculature. Pharmacokinetics and tumor targeting efficacy/specificity in 4T1 murine breast tumor-bearing mice were thoroughly investigated through various in vitro, in vivo, and ex vivo experiments. Dual-labeled MSN is an attractive candidate for future cancer theranostics.

Copyright © 2014 American Chemical Society

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SPECIAL ISSUE

This article is part of the Positron Emission Tomography: State of the Art special issue.

Introduction

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Vasculature targeting of tumor angiogenesis can be done based on biomarkers on the surface of tumor endothelial cells and does not require nanoparticle extravasation. (1) Vasculature targeted ligands, including vascular endothelial growth factor (VEGF) and arginine–glycine–aspartic acid (RGD) peptides, have been conjugated to the surface of different functional nanoparticles, including but not limited to, quantum dots (QDs), (2) single-walled carbon nanotubes (SWNTs), (3) and nanographene oxide (GO), (4, 5) for enhanced tumor targeted imaging and drug delivery.
TRC105 (a human/murine chimeric IgG1 monoclonal antibody) is a promising vasculature targeting moiety, (6) which binds to both human and murine CD105 (endoglin), a vascular-specific marker for tumor angiogenesis. (7, 8) Using TRC105 antibody and its fragments (i.e., TRC105(Fab) or F(ab′)2), we reported the first positron emission tomography (PET) imaging of CD105 expression in cancer, (9, 10) demonstrating the potential of CD105 for cancer-targeted imaging and therapy.
Fluorescence imaging, especially near-infrared fluorescence (NIRF) imaging, is economical and highly sensitive in certain scenarios. However, it is not quantitative in nature. (11) PET imaging, in contrast, has superb tissue penetration of signal, high sensitivity, and quantitative evaluation of the in vivo biodistribution. (12) The combination of PET with NIRF may provide more complementary information than either single modality alone and has attracted increasing interests recently. (13-20) For example, to mitigate the qualitative nature of QDs optical imaging, copper-64 (64Cu, t1/2 = 12.7 h) labeled QDs have been developed for in vivo PET/NIRF targeted dual-modality imaging using RGD peptides as the targeting ligands. (13)
Mesoporous silica nanoparticle (MSN) possesses many attractive properties and have been intensively investigated as a novel and biocompatible drug delivery system. (21-24) Although MSN itself emits no light, many strategies have been developed for engineering fluorescent MSN that can be tracked by optical imaging. For example, fluorescent dyes with varied excitation/emission combinations have been chemically linked to the surface or loaded into the matrix of MSN for studying the dynamic distribution of MSN in vivo. (25, 26) Moreover, optical nanocrystals, including QDs (27) and upconversion nanoparticles, (28) have also been encapsulated into MSN for imaging deeper tissues. Efforts have focused on the design of various fluorescent MSNs for in vivo cancer imaging, but little progress has been made with respect to in vivo tumor targeted imaging of the functionalized MSN.
Herein, using TRC105 (Fab) vascular targeting moiety as the targeting ligand, we report the first example of 64Cu (a PET tracer) and 800CW (a NIRF dye) labeled MSN for PET/NIRF dual-modality imaging of the tumor vasculature. Pharmacokinetics and tumor targeting efficacy/specificity in 4T1 murine breast tumor-bearing mice were thoroughly investigated through various in vitro, in vivo, and ex vivo experiments. Our dual-labeled MSN could become a promising candidate for future image-guided drug delivery and targeted cancer therapy.

Experimental Section

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Materials

TRC105 was provided by TRACON Pharmaceuticals Inc. (San Diego, CA). PD-10 columns were purchased from GE Healthcare (Piscataway, NJ). IR Dye 800CW-NHS (NHS denotes N-hydroxysuccinimide) ester was acquired from LI-COR Biosciences Co. (Lincoln, NE). SCM-PEG5k-Mal was obtained from Creative PEGworks. NOTA-SCN (i.e., 2-S-(4-isothiocyanatobenzyl)-1,4,7-triazacyclononane-1,4,7-triacetic acid) was acquired from Macrocyclics, Inc. (Dallas, TX). NHS-fluorescein, Chelex 100 resin (50–100 mesh), tetraethyl orthosilicate (TEOS), ammonia (NH3·H2O), triethylamine (TEA), 3-aminopropyl)triethoxysilane (APS), dimethyl sulfoxide, cetyltrimethylammonium chloride (CTAC, 25 wt %), and Kaiser test kit were purchased from Sigma-Aldrich (St. Louis, MO). Traut’s reagent (2-Iminothiolane·HCl) and Ellman’s reagent (5,5′-dithiobis(2-nitrobenzoic acid) or DTNB) were purchased from Fisher Scientific. Water and all buffers were of Millipore grade and pretreated with Chelex 100 resin to ensure that the aqueous solution was free of heavy metals. All chemicals were used as received without further purification.

Generation of TRC105(Fab)

Procedures for the synthesis of TRC105(Fab) were the same as we reported previously. (29) Typically, TRC105 (2 mg/mL) was digested out in a reaction buffer (20 mM sodium phosphate monobasic, 10 mM disodium ethylenediaminetetraacetic acid [EDTA], and 80 mM cysteine hydrochloride) for 4 h at 37 °C, with immobilized papain/TRC105 at a weight ratio of 1:40. Afterward, the reaction mixture was centrifuged at 5000g for 1 min to remove the immobilized papain. The supernatant was purified by size exclusion column chromatography on a Sephadex G-75 column to yield TRC105(Fab), using phosphate-buffered saline (PBS) as the mobile phase.
For the thiolation of TRC105(Fab), in 700 μL (1.5 mg/mL) of TRC105(Fab) was added 50 μL (2 mg/mL) of Traut’s reagent and adjusted the pH to 8.0 using 0.1 M Na2CO3. The mixture was kept shaking for 2 h at room temperature. As-synthesized TRC105(Fab)-SH was purified using PD-10 columns with PBS as the mobile phase. Fraction from 3.0 to 4.0 mL was collected and concentrated using a 10 k filter at 5000 rpm for 15 min. The final concentration of TRC105(Fab)-SH was found to be about 1.7 mg/mL (∼300 μL).

Synthesis of MSN

Procedures for the synthesis of ∼80 nm sized MSN were the same as we reported previously. (30) In a typical synthesis, CTAC (2 g) and TEA (20 mg) were dissolved in 20 mL of high Q water and stirred at room temperature for 1 h. Afterward, 1.0 mL of TEOS was added rapidly and the resulting mixture was stirred for 1 h at 95 °C in a water bath. The mixture was then cooled down, collected by centrifugation, and washed with water and ethanol to remove residual reactants. Subsequently, the product was extracted for 24 h with a 1 wt% solution of NaCl in methanol at room temperature to remove the template CTAC. This process was carried out for at least three times to ensure complete removal of CTAC.
For amino group modification, as-synthesized MSN was first dispersed in 20 mL of absolute ethanol, followed by addition of 1 mL of APS. The system was sealed and kept at 86–90 °C in a water bath for 48 h. Afterward, the mixture was centrifuged and washed with ethanol for several times to remove the residual APS. The MSN-NH2 could be well-dispersed in water, and the concentration of −NH2 groups (nmol/mL) was measured using a Kaiser test kit.

Synthesis of NOTA-MSN-800CW-PEG-TRC105(Fab)

To conjugated MSN with 800CW, 2 nmol of 800CW-NHS ester was mixed with MSN-NH2 (with ∼100 nmol of −NH2 groups) and reacted for 2 h at room temperature (pH 8.5–9.0) to form MSN-800CW-NH2. Then, NOTA-SCN (∼53 nmol) in dimethyl sulfoxide was allowed to react with MSN-800CW-NH2 at pH 8.5 to obtain NOTA-MSN-800CW-NH2. Afterward, 2 mg (400 nmol) of SCM-PEG5k-Mal was added and reacted for another 2 h, resulting in NOTA-MSN-800CW-PEG-Mal. NOTA-MSN-800CW-PEG-TRC105(Fab) could be obtained by reacting TRC105(Fab)-SH with NOTA-MSN-800CW-PEG-Mal at room temperature for overnight. The final sample was kept at 4 °C before 64Cu labeling. Note, both “NOTA” and “PEG” were omitted from the acronyms of the final nanoconjugates for clarity considerations in the following sections.

Flow Cytometry

Cells were first harvested and suspended in cold PBS with 2% bovine serum albumin at a concentration of 5 × 106 cells/mL and then incubated with fluorescein conjugated MSN-800CW-TRC105(Fab) (targeted group) or fluorescein conjugated MSN-800CW (non-targeted group) for 30 min at room temperature. The cells were washed three times with cold PBS and centrifuged for 5 min. Afterward, the cells were washed and analyzed using a BD FACSCalibur four-color analysis cytometer, which is equipped with 488 and 633 nm lasers (Becton-Dickinson, San Jose, CA) and FlowJo analysis software (Tree Star, Ashland, OR). A “blocking” experiment was also performed in cells incubated with the same amount of fluorescein conjugated MSN-800CW-TRC105(Fab), where 500 μg/mL of unconjugated TRC105 was added to evaluate the CD105 specificity of fluorescein conjugated MSN-800CW-TRC105(Fab).

Radiolabeling with 64Cu

64CuCl2 (74–148 MBq) was diluted in 300 μL of 0.1 M sodium acetate buffer (pH 6.5) and added to MSN-800CW-TRC105(Fab) or MSN-800CW. Note, all MSN nanoconjugates were already conjugated with NOTA. The reaction was allowed to proceed at 37 °C for 30 min with constant stirring. 64Cu-MSN-800CW-TRC105(Fab) and 64Cu-800CW-MSN were purified using PD-10 columns with PBS as the mobile phase. The radioactivity fractions (typically between 3.5 and 4.5 mL) were collected for further in vivo imaging experiments. After 6 mL of PBS, the unreacted 64Cu started to elute from the column.

4T1 Murine Breast Cancer Model

All animal studies were conducted under a protocol approved by the University of Wisconsin Institutional Animal Care and Use Committee. To generate the 4T1 tumor model, 4–5 week old female BALB/c mice were purchased from Harlan (Indianapolis, IN, USA), and tumors were established by subcutaneously injecting 2 × 106 cells, suspended in 100 μL of 1:1 mixture of RPMI 1640 and Matrigel (BD Biosciences, Franklin Lakes, NJ, USA), into the front flank of mice. The tumor sizes were monitored every other day, and the animals were subjected to in vivo experiments when the tumor diameter reached 5–8 mm.

PET/NIRF Imaging and Biodistribution Studies

PET scans at various time points postinjection (pi) using a microPET/microCT Inveon rodent model scanner (Siemens Medical Solutions USA, Inc.), image reconstruction, and region-of-interest (ROI) analysis of the PET data were performed similarly to that described previously. (31) Quantitative PET data were presented as percentage injected dose per gram of tissue (%ID/g). Tumor-bearing mice were each injected with 5–10 MBq of 64Cu-MSN-800CW-TRC105(Fab) or 64Cu-MSN-800CW via tail vein before serial PET scans. Another group of three 4T1 tumor-bearing mice were each injected with 1 mg of unlabeled TRC105 at 1 h before 64Cu-MSN-800CW-TRC105(Fab) administration to evaluate the CD105 specificity of 64Cu-MSN-800CW-TRC105(Fab) in vivo (i.e., blocking experiment).
After the last PET scans at 48 h pi, biodistribution studies were carried out to confirm that the %ID/g values based on PET imaging truly represented the radioactivity distribution in tumor-bearing mice. Mice were euthanized, and blood, 4T1 tumor, and major organs/tissues were collected and wet-weighed. The radioactivity in the tissue was measured using a gamma-counter and presented as %ID/g (mean ± SD).
For in vivo NIRF imaging, each 4T1 tumor-bearing mouse was injected with MSN-800CW-TRC105(Fab) (targeted group) with the amount of 800CW estimated to be ∼400 pmol. The mouse was then imaged using an IVIS spectrum in vivo imaging system (Ex = 745 nm, Em = 800 nm) at 4 h pi. For non-targeted and blocking groups, mice were injected with MSN-800CW and MSN-800CW-TRC105(Fab) (together with 1 mg blocking dose of free TRC105), respectively, with equal amount of 800CW dyes.

Results and Discussion

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Synthesis and Characterizations of Thiolated TRC105(Fab)

Thiolated TRC105(Fab), i.e., TRC105(Fab)-SH, was generated following our previous reported procedures with an addition thiolation step (Figure 1a). (29) After papain digestion of full TRC105 antibody, a Sephadex G 75 column was used to separate TRC105(Fab) from other components in the reaction mixture. Sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) was then used to confirm the successful generation of TRC105(Fab), where the disappearance of the TRC105 band (∼148 kDa, lane 2 in Figure 1b) and the appearance of pure TRC105(Fab) band (∼47.5 kDa, lane 3 in Figure 1b) were shown. Traut’s reagent was later used for the thiolation of TRC105(Fab), forming TRC105(Fab)-SH. The presence of −SH groups was further confirmed by using Ellman’s reagent. Taken together, these results indicate the complete digestion of TRC105 after papain treatment to yield high purity TRC105(Fab) and the successful thiolation of TRC105(Fab) to form TRC105(Fab)-SH for further bioconjugations.

Figure 1

Figure 1. Synthesis and characterization of TRC105(Fab). (a) Schematic illustration showing the generation of TRC105(Fab) and its thiolation. (b) SDS-PAGE of molecular weight markers (lane 1), intact TRC105 antibody (lane 2), and TRC105(Fab) after purification on the Sephadex G-75 column (lane 3).

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Synthesis and Characterizations of 64Cu-MSN-800CW-TRC105(Fab)

Multiple steps of surface engineering were required for the synthesis 64Cu-MSN-800CW-TRC105(Fab), as shown in Scheme 1. As-synthesized uniform MSN (1) was first functionalized with amino groups (−NH2) with (3-aminopropyl)triethoxysilane (APS), to form MSN-NH2 (2), leaving amino groups on the surface for further conjugation. Successful −NH2 modification was confirmed by ninhydrin testing (Supportiong Information Figure S1). The desired amount of NIRF dyes (800CW-NHS ester) and NOTA-SCN (a 64Cu chelator) and were then reacted with MSN-NH2 at pH 8.5–9 to produce NOTA-MSN-800CW-NH2 (3). Afterward, the heterobifunctional succinimidyl carboxy methyl ester-poly ethylene glycol(5 kDa)-maleimide (SCM-PEG5k-Mal) was used to generate NOTA-MSN-800CW-PEG-Mal (4), which was then reacted with TRC105(Fab)-SH to yield NOTA-MSN-800CW-PEG-TRC105(Fab) (5). Lastly, the NOTA-MSN-800CW-PEG-TRC105(Fab) was labeled with 64Cu to form the 64Cu-NOTA-MSN-800CW-PEG-TRC105(Fab) nanoconjugate (6), abbreviated as 64Cu-MSN-800CW-TRC105(Fab). Because all the MSN nanoconjugates will contain the same NOTA and PEG chains (5 kDa), both “NOTA” and “PEG” were omitted from the acronyms of the final nanoconjugates for clarity.

Scheme 1

Scheme 1. Schematic Illustration of the Synthesis of 64Cu-MSN-800CW-TRC105(Fab)a
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Scheme aUniform MSN nanoparticle (1) was first modified with −NH2 groups with APS to form MSN-NH2 (2). As-synthesized MSN-NH2 was then subjected to 800CW and NOTA conjugation to yield NOTA-MSN-800CW-NH2 (3). Afterwards, PEGylation step was introduced to render the stability of NOTA-MSN-800CW-PEG-Mal (4) in PBS, at the same time adding maleimide groups. NOTA-MSN-800CW-PEG-TRC105(Fab) (5) could be obtained by reacting TRC105(Fab)-SH with 4 at room temperature. 64Cu-labeling was performed in the last step to generate 64Cu-NOTA-MSN-800CW-PEG-TRC105(Fab) (6), short for 64Cu-MSN-800CW-TRC105(Fab).

Figure 2a shows the representative transmission electron microscopy (TEM) image of ∼80 nm sized uniform MSN, which was synthesized following as described. (30) No obvious changes in the morphology of MSN were observed after multistep surface modifications, as evidenced by TEM image of MSN-800CW-TRC105(Fab) (Figure 2b). Successful conjugation of 800CW to MSN was confirmed by the NIRF imaging of MSN-800CW-TRC105(Fab) (inset in Figure 2b) using the IVIS spectrum in vivo imaging system (Ex = 745 nm, Em = 800 nm). Dynamic light scattering (DLS) and ζ potential measurements indicated the final Z-average size and surface charge of MSN-800CW-TRC105(Fab) to be 175.3 ± 9.7 nm and −3.25 ± 0.8 mV (pH 7.4, PBS), respectively.

Figure 2

Figure 2. Synthesis and characterization of MSN and MSN-800CW-TRC105(Fab). TEM images of (a) pure MSN, (b) MSN-800CW-TRC105(Fab). Insets in (a) and (b) show the schemes of MSN and MSN-800CW-TRC105(Fab). An optical image of MSN-800CW-TRC105(Fab) acquired from IVIS spectrum in vivo imaging system (Ex = 745 nm, Em = 800 nm) is also shown in the upper right portion of (b).

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In Vitro CD105 Targeting of MSN-800CW-TRC105(Fab)

Previously, we have demonstrated that fluorescein conjugated TRC105(Fab) binds with high avidity and specificity to human umbilical vein endothelial cells (HUVECs), (29) indicating that papain digestion does not affect antigen recognition. To assess CD105 targeting efficiency of MSN nanoconjugates, a flow cytometry study using HUVECs was also performed after NHS-fluorescein was conjugated to the surface of nanoparticles. Flow cytometry results (Figure 3) indicated that incubation with fluorescein conjugated MSN-800CW-TRC105(Fab) significantly enhanced the mean fluorescence intensity of HUVECs, compared to fluorescein conjugated MSN-800CW. The specificity of in vitro CD105 targeting with MSN-800CW-TRC105(Fab) was confirmed in the blocking study, where only background level uptake of MSN-800CW-TRC105(Fab) was observed after blocking HUVECs with a large dose of free TRC105 (500 μg/mL).

Figure 3

Figure 3. Flow cytometry analysis of MSN nanoconjugates in HUVECs (CD105 positive) after 30 min incubation and subsequent washing. Targeted group: fluorescein conjugated MSN-800CW-TRC105(Fab). Non-targeted group: fluorescein conjugated MSN-800CW. Blocking group: fluorescein conjugated MSN-800CW-TRC105(Fab) with a blocking dose of TRC105 (500 μg/mL).

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In Vivo PET/NIRF Dual Modal CD105-Targeted Imaging of 64Cu-MSN-800CW-TRC105(Fab)

For in vivo tumor targeted PET imaging, both MSN-800CW-TRC105(Fab) and MSN-800CW were labeled with 64Cu for in vivo imaging and biodistribution studies. As-synthesized 64Cu-MSN-800CW-TRC105(Fab) (targeted group) and 64Cu-MSN-800CW (non-targeted group) were purified using PD-10 columns with PBS as the mobile phase. The radioactivity fractions (typically elute between 3.0 and 4.0 mL) were collected for in vivo experiments. Unreacted 64Cu eluted from the column by the 6 mL fractions.
In vivo tumor targeted imaging was carried out in 4T1 murine breast tumor-bearing mice, which express a high level of CD105 on the tumor neovasculature. (7, 8) Each mouse was intravenously (iv) injected with 5–10 MBq of 64Cu-MSN-800CW-TRC105(Fab) or MSN-800CW-TRC105(Fab) (had ∼400 pmol of dyes) for PET/NIRF imaging to show in vivo biodistribution pattern as well as tumor accumulation (Figures 4, 5 and 6). Non-targeted and blocking groups were also included to assess the targeting specificity of dual-labeled MSN nanoconjugates. Quantitative data obtained from ROI analysis of these PET images are also shown in Supporting Information Table S1–S3.

Figure 4

Figure 4. Serial coronal PET images of 4T1 tumor-bearing mice at different time points postinjection of (a) 64Cu-MSN-800CW-TRC105(Fab), (b) 64Cu-MSN-800CW, and (c) 64Cu-MSN-800CW-TRC105(Fab) with a blocking dose of TRC105 (1 mg/mouse). Tumors are indicated by yellow arrowheads.

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Figure 5

Figure 5. In vivo NIRF imaging of 4T1 tumor-bearing mice at 4 h postinjection. (a) Targeted group, 64Cu-MSN-800CW-TRC105(Fab); (b) non-targeted group, 64Cu-MSN-800CW; (c) blocking group, 64Cu-MSN-800CW-TRC105(Fab) with a blocking dose of TRC105 (1 mg/mouse). Tumors are indicated by yellow arrowheads. Each mouse was iv injected with MSN nanoconjugates with equal amounts of 800CW dyes (∼400 pmol). All images were acquired by using IVIS spectrum in vivo imaging system (Ex = 745 nm, Em = 800 nm).

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Figure 6

Figure 6. Quantitative analysis of the PET data. (a) Time–activity curve of the liver, 4T1 tumor, blood, and muscle upon iv injection of 64Cu-MSN-800CW-TRC105(Fab) (targeted group, n = 3). (b) Time–activity curve of tumor-to-muscle (T/M), tumor-to-blood (T/B), and tumor-to-liver (T/L) ratios from the same targeted group (n = 3). (c) Comparison of 4T1 tumor uptake among the three groups. The differences between 4T1 tumor uptake of 64Cu-MSN-800CW-TRC105(Fab) and the two control groups were statistically significant (**P < 0.01) in all cases. (d) Biodistribution of three groups in 4T1 tumor-bearing mice at the end of the PET scans at 48 h pi (n = 3).

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The accumulation of 64Cu-MSN-800CW-TRC105(Fab) in the 4T1 tumor was clearly demonstrated in PET imaging and was found to be 5.4 ± 0.2%ID/g at 4 h pi, as shown in Figures 4a and 6a and Supporting Information Table S1 (n = 3). In contrast, the 4T1 tumor uptake of 64Cu-MSN-800CW was found to be ∼2%ID/g at all of the time points examined (n = 3; Figure 4b, Supporting Information Figure S2a and Table S2), indicating that TRC105(Fab) conjugation was required for enhanced tumor accumulation of 64Cu-MSN-800CW-TRC105(Fab) in vivo. To further confirm the CD105 targeting specificity of 64Cu-MSN-800CW-TRC105(Fab), blocking studies were performed. The administration of a blocking dose (1 mg/mouse) of free TRC105 at 1 h before 64Cu-MSN-800CW-TRC105(Fab) injection significantly reduced tumor uptake to 2.3 ± 0.2%ID/g at 4 h pi (n = 3, Figure 4c, Supporting Information Figure S2b and Table S3), demonstrating the CD105 specific targeting of 64Cu-MSN-800CW-TRC105(Fab) in vivo. Figure 6c further summarizes the comparison of 4T1 tumor uptake of three groups at different time points. 64Cu-MSN-800CW-TRC105(Fab) showed the highest tumor uptake throughout the study period.
In vivo NIRF imaging was used to further confirm the enhanced accumulation of MSN-800CW-TRC105(Fab). Different MSN nanoconjugates which contained equal amounts of dyes (∼400 pmol) were injected intravenously into 4T1 tumor-bearing mice. In vivo NIRF images that were generated at 4 h pi (when the nanoparticles showed the highest tumor accumulation based on the PET imaging, shown in Figure 4a) were acquired and are shown in Figure 5. A significantly stronger signal from the targeted group was observed compared to the non-targeted and blocking groups, indicating the successful detection by NIRF imaging of MSN-800CW-TRC105(Fab) nanoconjugates. Notably, the liver and spleen were the major organs for the accumulation of MSN-800CW-TRC105(Fab). However, due to the difference in scattering behaviors and depth, only 800CW emission signalsfrom xenograft 4T1 tumor on the surface of mouse skin were detected by the IVIS spectrum in vivo imaging system. Taken together, these data demonstrated the CD105 specificity of dual-modality PET/NIRF targeted imaging using 64Cu-MSN-800CW-TRC105(Fab) in vivo.
The conjugate 64Cu-MSN-800CW-TRC105(Fab) also improved tumor-to-muscle (T/M) biodistribution ratios. As shown in Figure 6b, T/M value of the targeted group was estimated to be 5.2 ± 0.2 at 0.5 h pi and increased up to 7.3 ± 1.1 at 4 h pi, which was significantly higher than that of non-targeted and blocking groups (Supporting Information Figure S2c,d and Table S4–S6). Similar to other TRC105-conjugated nanoparticles, (4, 5, 30) besides tumor accumulation, most of the 64Cu-MSN-800CW-TRC105(Fab) nanoconjugates were cleared by the reticuloendothelial system (RES) with liver uptake found to be 23.2 ± 3.5%ID/g at 0.5 h pi, decreasing gradually to 9.2 ± 0.6%ID/g by 48 h pi (n = 3; Figures 4a and 6a, and Supporting Information Table S1), which was validated by the ex vivo biodistribution study (Figure 6d). Similar trends were also observed in the non-targeted and blocking groups (Supporting Information Figure S2a,b and Table S2–S3).

Conclusion

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In conclusion, we report the in vivo tumor vasculature targeted PET/NIRF dual-modality imaging using well-functionalized 64Cu-MSN-800CW-TRC105(Fab) nanoconjugates. Pharmacokinetics and tumor targeting efficacy/specificity in 4T1 murine breast tumor-bearing mice were thoroughly investigated through various in vitro, in vivo, and ex vivo experiments. Vascular targeting led to ∼2-fold enhancement of tumor accumulation over passive targeting alone. Other targeting ligands could also be conjugated to MSN for further improvement of tumor accumulation in vivo. Given the presence of tunable pore size and larger surface area that could accommodate therapeutic agents, as-designed 64Cu-MSN-800CW-TRC105(Fab) could be employed as both imaging and therapeutic agents.

Supporting Information

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Ninhydrin testing, tables of PET region-of-interest quantifications, quantitative analysis of PET imaging data from non-targeted and blocking groups. This material is available free of charge via the Internet at http://pubs.acs.org.

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Author Information

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  • Corresponding Author
    • Weibo Cai - Department of Radiology, University of Wisconsin—Madison, Madison, Wisconsin 53792, United States;  Materials Science Program, University of Wisconsin—Madison, Madison, Wisconsin 53706, United States;  Department of Medical Physics, University of Wisconsin—Madison, Madison, Wisconsin 53705, United States;  University of Wisconsin Carbone Cancer Center, Madison, Wisconsin 53792, United States;  Email: [email protected]
  • Authors
    • Feng Chen - Department of Radiology, University of Wisconsin—Madison, Madison, Wisconsin 53792, United States
    • Tapas R. Nayak - Department of Radiology, University of Wisconsin—Madison, Madison, Wisconsin 53792, United States
    • Shreya Goel - Materials Science Program, University of Wisconsin—Madison, Madison, Wisconsin 53706, United States
    • Hector F. Valdovinos - Department of Medical Physics, University of Wisconsin—Madison, Madison, Wisconsin 53705, United States
    • Hao Hong - Department of Radiology, University of Wisconsin—Madison, Madison, Wisconsin 53792, United States;  Materials Science Program, University of Wisconsin—Madison, Madison, Wisconsin 53706, United States;  Department of Medical Physics, University of Wisconsin—Madison, Madison, Wisconsin 53705, United States;  TRACON Pharmaceuticals, Inc., San Diego, California 92122, United States;  University of Wisconsin Carbone Cancer Center, Madison, Wisconsin 53792, United States
    • Charles P. Theuer - Department of Radiology, University of Wisconsin—Madison, Madison, Wisconsin 53792, United States;  TRACON Pharmaceuticals, Inc., San Diego, California 92122, United States
    • Todd E. Barnhart - Department of Medical Physics, University of Wisconsin—Madison, Madison, Wisconsin 53705, United States
  • Notes
    The authors declare the following competing financial interest(s): Charles P. Theuer is an employee of TRACON. The other authors declare no competing financial interest..

Acknowledgment

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This work is supported, in part, by the University of Wisconsin—Madison, the National Institutes of Health (NIBIB/NCI 1R01CA169365, P30CA014520), the Department of Defense (W81XWH-11-1-0644), and the American Cancer Society (125246-RSG-13-099-01-CCE).

References

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This article references 31 other publications.

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    Herein we demonstrate that nanographene can be specifically directed to the tumor neovasculature in vivo through targeting of CD105 (i.e., endoglin), a vascular marker for tumor angiogenesis. The covalently functionalized nanographene oxide (GO) exhibited excellent stability and target specificity. Pharmacokinetics and tumor targeting efficacy of the GO conjugates were investigated with serial noninvasive positron emission tomog. imaging and biodistribution studies, which were validated by in vitro, in vivo, and ex vivo expts. The incorporation of an active targeting ligand (TRC105, a monoclonal antibody that binds to CD105) led to significantly improved tumor uptake of functionalized GO, which was specific for the neovasculature with little extravasation, warranting future investigation of these GO conjugates for cancer-targeted drug delivery and/or photothermal therapy to enhance therapeutic efficacy. Since poor extravasation is a major hurdle for nanomaterial-based tumor targeting in vivo, this study also establishes CD105 as a promising vascular target for future cancer nanomedicine.
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    The objective of this study was to characterize the in vitro and in vivo properties of the F(ab')2 fragment of TRC105, a human/murine chimeric IgG1 monoclonal antibody that binds with high avidity to human and murine CD105 (i.e., endoglin), and investigate its potential for positron emission tomog. (PET) imaging of tumor angiogenesis after 61/64Cu-labeling. TRC105-F(ab')2 of high purity was produced by pepsin digestion of TRC105, which was confirmed by SDS-PAGE, HPLC anal., and mass spectrometry. 61/64Cu-labeling of NOTA-TRC105-F(ab')2 (NOTA denotes 1,4,7-triazacyclononane-1,4,7-triacetic acid) was achieved with yields of >75% (specific activity: ∼115 GBq/μmol). PET imaging revealed rapid tumor uptake of 64Cu-NOTA-TRC105-F(ab')2 in the 4T1 murine breast cancer model (5.8 ± 0.8, 7.6 ± 0.6, 5.6 ± 0.4, 5.0 ± 0.6, and 3.8 ± 0.7% ID/g at 0.5, 3, 16, 24, and 48 h postinjection resp.; n = 4). Since tumor uptake peaked at 3 h postinjection, 61Cu-NOTA-TRC105-F(ab')2 also gave good tumor contrast at 3 and 8 h postinjection. CD105 specificity of the tracers was confirmed by blocking studies and histopathol. In conclusion, the use of a F(ab')2 fragment led to more rapid tumor uptake (which peaked at 3 h postinjection) than radiolabeled intact antibody (which often peaked after 24 h postinjection), which may allow for same day immunoPET imaging in future clin. studies.
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    A key challenge for improving the efficacy of passive drug delivery to tumor sites by a nanocarrier is to limit reticuloendothelial system uptake and to maximize the enhanced permeability and retention effect. We demonstrate that size redn. and surface functionalization of mesoporous silica nanoparticles (MSNP) with a polyethyleneimine-polyethylene glycol copolymer reduces particle opsonization while enhancing the passive delivery of monodispersed, 50 nm doxorubicin-laden MSNP to a human squamous carcinoma xenograft in nude mice after i.v. injection. Using near-IR fluorescence imaging and elemental Si anal., we demonstrate passive accumulation of ∼ 12% of the tail vein-injected particle load at the tumor site, where there is effective cellular uptake and the delivery of doxorubicin to KB-31 cells. This was accompanied by the induction of apoptosis and an enhanced rate of tumor shrinking compared to free doxorubicin. The improved drug delivery was accompanied by a significant redn. in systemic side effects such as animal wt. loss as well as reduced liver and renal injury. These results demonstrate that it is possible to achieve effective passive tumor targeting by MSNP size redn. as well as by introducing steric hindrance and electrostatic repulsion through coating with a copolymer. Further endowment of this multifunctional drug delivery platform with targeting ligands and nanovalves may further enhance cell-specific targeting and on-demand release.
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    Pan, L.; He, Q.; Liu, J.; Chen, Y.; Ma, M.; Zhang, L.; Shi, J. Nuclear-Targeted Drug Delivery of TAT Peptide-Conjugated Monodisperse Mesoporous Silica Nanoparticles J. Am. Chem. Soc. 2012, 134, 5722– 5725
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    Nuclear-Targeted Drug Delivery of TAT Peptide-Conjugated Monodisperse Mesoporous Silica Nanoparticles
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    Journal of the American Chemical Society (2012), 134 (13), 5722-5725CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
    Most present nanodrug delivery systems have been developed to target cancer cells but rarely nuclei. However, nuclear-targeted drug delivery is expected to kill cancer cells more directly and efficiently. In this work, TAT peptide has been employed to conjugate onto mesoporous silica nanoparticles (MSNs-TAT) with high payload for nuclear-targeted drug delivery for the first time. Monodispersed MSNs-TAT of varied particle sizes have been synthesized to investigate the effects of particle size and TAT conjugation on the nuclear membrane penetrability of MSNs. MSNs-TAT with a diam. of 50 nm or smaller can efficiently target the nucleus and deliver the active anticancer drug doxorubicin (DOX) into the targeted nucleus, killing these cancer cells with much enhanced efficiencies. This study may provide an effective strategy for the design and development of cell-nuclear-targeted drug delivery.
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    Functionalized Silica Nanoparticles: A Platform for Fluorescence Imaging at the Cell and Small Animal Levels
    Wang, Kemin; He, Xiaoxiao; Yang, XiaoHai; Shi, Hui
    Accounts of Chemical Research (2013), 46 (7), 1367-1376CODEN: ACHRE4; ISSN:0001-4842. (American Chemical Society)
    A review. Going in vivo, including living cells and the whole body, is very important for gaining a better understanding of the mystery of life and requires specialized imaging techniques. The diversity, compn., and temporal-spatial variation of life activities from cells to the whole body require the anal. techniques to be fast-response, noninvasive, highly sensitive, and stable, in situ and in real-time. Functionalized nanoparticle-based fluorescence imaging techniques have the potential to meet such needs through real-time and noninvasive visualization of biol. events in vivo. Functionalized silica nanoparticles (SiNPs) doped with fluorescent dyes appear to be an ideal and flexible platform for developing fluorescence imaging techniques used in living cells and the whole body. The authors can select and incorporate different dyes inside the silica matrix either noncovalently or covalently. These form the functionalized hybrid SiNPs, which support multiplex labeling and ratiometric sensing in living systems. Since the silica matrix protects dyes from outside quenching and degrading factors, this enhances the photostability and biocompatibility of the SiNP-based probes. This makes them ideal for real-time and long-time tracking. One nanoparticle can encapsulate large nos. of dye mols., which amplifies their optical signal and temporal-spatial resoln. response. Integrating fluorescent dye-doped SiNPs with targeting ligands using various surface modification techniques can greatly improve selective recognition. Along with the endocytosis, functionalized SiNPs can be efficiently internalized into cells for noninvasive localization, assessment, and monitoring. These unique characteristics of functionalized SiNPs substantially support their applications in fluorescence imaging in vivo. In this Account, the authors summarize their efforts to develop functionalized dye-doped SiNPs for fluorescence imaging at the cell and small animal levels. The authors first discuss how to design and construct various functionalized dye-doped SiNPs. Then the authors describe their properties and imaging applications in cell surface receptor recognition, intracellular labeling, tracking, sensing, and controlled release. Addnl., the authors demonstrated the promising application of dye-doped SiNPs as contrast imaging agents for in vivo fluorescence imaging in small animals. The authors expect these functionalized dye-doped SiNPs to open new opportunities for biol. and medical research and applications.
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    Advanced Functional Materials (2009), 19 (2), 215-222CODEN: AFMDC6; ISSN:1616-301X. (Wiley-VCH Verlag GmbH & Co. KGaA)
    The characterization of near-IR (NIR) mesoporous silica nanoparticles (MSN) suitable for in vivo optical imaging with high efficiency is presented. Trimethylammonium groups modified MSN (MSN-TA) with the av. size of 50-100 nm was synthesized with incorporation of the TA groups into the framework of MSN. It was further adsorbed with indocyanine green (ICG) by electrostatic attraction to render MSN-TA-ICG as an efficient NIR contrast agent for in vivo optical imaging. The studies in stability of MSN-TA-ICG against pH indicated the bonding is stable over the range from acidic to physiol. pH. The in vivo biodistribution of MSN-TA-ICG in anesthetized rat demonstrated a rather strong and stable fluorescence of MSN-TA-ICG that prominent in the organ of liver. Transmission electron microscopy (TEM) imaging and elemental anal. of silicon further manifested the phys. and quant. residences of MSN-TA-ICG in major organs. This is the first report of MSN functionalized with NIR-ICG capable of optical imaging in vivo.
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    Controlled Synthesis of Uniform and Monodisperse Upconversion Core/Mesoporous Silica Shell Nanocomposites for Bimodal Imaging
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    Chemistry - A European Journal (2012), 18 (8), 2335-2341, S2335/1-S2335/5CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)
    Here the authors report the design and controlled synthesis of monodisperse and precisely size-controllable UCNP@mSiO2 nanocomposites smaller than 50 nm by directly coating a mesoporous silica shell (mSiO2) on upconversion nanocrystals NaYF4:Tm/Yb/Gd (UCNPs), which can be used as near-IR fluorescence and magnetic resonance imaging (MRI) agents and a platform for drug delivery as well. Some key steps such as transferring hydrophobic UCNPs to the water phase by using cetyltrimethylammonium bromide (CTAB), removal of the excess amt. of CTAB, and temp.-controlled ultrasonication treatment should be adopted and carefully monitored to obtain uniform upconversion core/mesoporous silica shell nanocomposites. The excellent performance of the core-shell-structured nanocomposite in near-IR fluorescence and magnetic resonance imaging was also demonstrated.
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    Zhang, Y.; Hong, H.; Orbay, H.; Valdovinos, H. F.; Nayak, T. R.; Theuer, C. P.; Barnhart, T. E.; Cai, W. Pet Imaging of CD105/Endoglin Expression with a (6)(1)/(6)(4)Cu-Labeled Fab Antibody Fragment Eur. J. Nucl. Med. Mol. Imaging 2013, 40, 759– 767
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    PET imaging of CD105/endoglin expression with a 61/64Cu-labeled Fab antibody fragment
    Zhang, Yin; Hong, Hao; Orbay, Hakan; Valdovinos, Hector F.; Nayak, Tapas R.; Theuer, Charles P.; Barnhart, Todd E.; Cai, Weibo
    European Journal of Nuclear Medicine and Molecular Imaging (2013), 40 (5), 759-767CODEN: EJNMA6; ISSN:1619-7070. (Springer)
    Purpose: The goal of this study was to generate and characterize the Fab fragment of TRC105, a monoclonal antibody that binds with high affinity to human and murine CD105 (i.e., endoglin), and investigate its potential for PET imaging of tumor angiogenesis in a small-animal model after 61/64Cu labeling. Methods: TRC105-Fab was generated by enzymic papain digestion. The integrity and CD105 binding affinity of TRC105-Fab was evaluated before NOTA (1,4,7-triazacyclononane-1,4,7-triacetic acid) conjugation and 61/64Cu labeling. Serial PET imaging and biodistribution studies were carried out in the syngeneic 4T1 murine breast cancer model to quantify tumor targeting efficiency and normal organ distribution of 61/64Cu-NOTA-TRC105-Fab. Blocking studies with unlabeled TRC105 were performed to confirm CD105 specificity of the tracer in vivo. Immunofluorescence staining was also conducted to correlate tracer uptake in the tumor and normal tissues with CD105 expression. Results TRC105-Fab was produced with high purity through papain digestion of TRC105, as confirmed by SDS-PAGE, HPLC anal., and mass spectrometry. 61/64Cu labeling of NOTA-TRC105-Fab was achieved with about 50 % yield (specific activity about 44 GBq/μmol). PET imaging revealed rapid uptake of 64Cu-NOTA-TRC105-Fab in the 4T1 tumor (3.6 ± 0.4, 4.2 ± 0.5, 4.9 ± 0.3, 4.4 ± 0.7, and 4.6 ± 0.8 %ID/g at 0.5, 2, 5, 16, and 24 h after injection, resp.; n = 4). Since tumor uptake peaked soon after tracer injection, 61Cu-labeled TRC105-Fab was also able to provide tumor contrast at 3 and 8 h after injection. CD105 specificity of the tracer was confirmed with blocking studies and histol. examn. Conclusion: We report PET imaging of CD105 expression using 61/64Cu-NOTA-TRC105-Fab, which exhibited prominent and target-specific uptake in the 4T1 tumor. The use of a Fab fragment led to much faster tumor uptake (which peaked at a few hours after tracer injection) compared to radiolabeled intact antibody, which may be translated into same-day immunoPET imaging for clin. investigation.
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    Chen, F.; Hong, H.; Zhang, Y.; Valdovinos, H. F.; Shi, S.; Kwon, G. S.; Theuer, C. P.; Barnhart, T. E.; Cai, W. In Vivo Tumor Targeting and Image-Guided Drug Delivery with Antibody-Conjugated, Radiolabeled Mesoporous Silica Nanoparticles ACS Nano 2013, 7, 9027– 9039
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    Orbay, H.; Zhang, Y.; Valdovinos, H. F.; Song, G.; Hernandez, R.; Theuer, C. P.; Hacker, T. A.; Nickles, R. J.; Cai, W. Positron Emission Tomography Imaging of CD105 Expression in a Rat Myocardial Infarction Model with (64)Cu-Nota-TRC105 Am. J. Nucl. Med. Mol. Imaging 2013, 4, 1– 9
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    31
    Positron emission tomography imaging of CD105 expression in a rat myocardial infarction model with (64)Cu-NOTA-TRC105
    Orbay Hakan; Zhang Yin; Valdovinos Hector F; Hernandez Reinier; Nickles Robert J; Song Guoqing; Hacker Timothy A; Theuer Charles P; Cai Weibo
    American journal of nuclear medicine and molecular imaging (2013), 4 (1), 1-9 ISSN:.
    Biological changes following myocardial infarction (MI) lead to increased secretion of angiogenic factors that subsequently stimulate the formation of new blood vessels as a compensatory mechanism to reverse ischemia. The goal of this study was to assess the role of CD105 expression during MI-induced angiogenesis by positron emission tomography (PET) imaging using (64)Cu-labeled TRC105, an anti-CD105 monoclonal antibody. MI was induced by ligation of the left anterior descending (LAD) artery in female rats. Echocardiography and (18)F-fluoro-2-deoxy-D-glucose ((18)F-FDG) PET scans were performed on post-operative day 3 to confirm the presence of MI in the infarct group and intact heart in the sham group, respectively. Ischemia-induced angiogenesis was non-invasively monitored with (64)Cu-NOTA-TRC105 (an extensively validated PET tracer in our previous studies) PET on post-operative days 3, 10, and 17. Tracer uptake in the infarct zone was highest on day 3 following MI, which was significantly higher than that in the sham group (1.41 ± 0.45 %ID/g vs 0.57 ± 0.07 %ID/g; n=3, p<0.05). Subsequently, tracer uptake in the infarct zone decreased over time to the background level on day 17, whereas tracer uptake in the heart of sham rats remained low at all time points examined. Histopathology documented increased CD105 expression following MI, which corroborated in vivo findings. This study indicated that PET imaging of CD105 can be a useful tool for MI-related research, which can potentially improve MI patient management in the future upon clinical translation of the optimized PET tracers.
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Cite this: Mol. Pharmaceutics 2014, 11, 11, 4007–4014
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  • Abstract

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    Figure 1

    Figure 1. Synthesis and characterization of TRC105(Fab). (a) Schematic illustration showing the generation of TRC105(Fab) and its thiolation. (b) SDS-PAGE of molecular weight markers (lane 1), intact TRC105 antibody (lane 2), and TRC105(Fab) after purification on the Sephadex G-75 column (lane 3).

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    Scheme 1

    Scheme 1. Schematic Illustration of the Synthesis of 64Cu-MSN-800CW-TRC105(Fab)a
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    Scheme aUniform MSN nanoparticle (1) was first modified with −NH2 groups with APS to form MSN-NH2 (2). As-synthesized MSN-NH2 was then subjected to 800CW and NOTA conjugation to yield NOTA-MSN-800CW-NH2 (3). Afterwards, PEGylation step was introduced to render the stability of NOTA-MSN-800CW-PEG-Mal (4) in PBS, at the same time adding maleimide groups. NOTA-MSN-800CW-PEG-TRC105(Fab) (5) could be obtained by reacting TRC105(Fab)-SH with 4 at room temperature. 64Cu-labeling was performed in the last step to generate 64Cu-NOTA-MSN-800CW-PEG-TRC105(Fab) (6), short for 64Cu-MSN-800CW-TRC105(Fab).

    Figure 2

    Figure 2. Synthesis and characterization of MSN and MSN-800CW-TRC105(Fab). TEM images of (a) pure MSN, (b) MSN-800CW-TRC105(Fab). Insets in (a) and (b) show the schemes of MSN and MSN-800CW-TRC105(Fab). An optical image of MSN-800CW-TRC105(Fab) acquired from IVIS spectrum in vivo imaging system (Ex = 745 nm, Em = 800 nm) is also shown in the upper right portion of (b).

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    Figure 3

    Figure 3. Flow cytometry analysis of MSN nanoconjugates in HUVECs (CD105 positive) after 30 min incubation and subsequent washing. Targeted group: fluorescein conjugated MSN-800CW-TRC105(Fab). Non-targeted group: fluorescein conjugated MSN-800CW. Blocking group: fluorescein conjugated MSN-800CW-TRC105(Fab) with a blocking dose of TRC105 (500 μg/mL).

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    Figure 4

    Figure 4. Serial coronal PET images of 4T1 tumor-bearing mice at different time points postinjection of (a) 64Cu-MSN-800CW-TRC105(Fab), (b) 64Cu-MSN-800CW, and (c) 64Cu-MSN-800CW-TRC105(Fab) with a blocking dose of TRC105 (1 mg/mouse). Tumors are indicated by yellow arrowheads.

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    Figure 5

    Figure 5. In vivo NIRF imaging of 4T1 tumor-bearing mice at 4 h postinjection. (a) Targeted group, 64Cu-MSN-800CW-TRC105(Fab); (b) non-targeted group, 64Cu-MSN-800CW; (c) blocking group, 64Cu-MSN-800CW-TRC105(Fab) with a blocking dose of TRC105 (1 mg/mouse). Tumors are indicated by yellow arrowheads. Each mouse was iv injected with MSN nanoconjugates with equal amounts of 800CW dyes (∼400 pmol). All images were acquired by using IVIS spectrum in vivo imaging system (Ex = 745 nm, Em = 800 nm).

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    Figure 6

    Figure 6. Quantitative analysis of the PET data. (a) Time–activity curve of the liver, 4T1 tumor, blood, and muscle upon iv injection of 64Cu-MSN-800CW-TRC105(Fab) (targeted group, n = 3). (b) Time–activity curve of tumor-to-muscle (T/M), tumor-to-blood (T/B), and tumor-to-liver (T/L) ratios from the same targeted group (n = 3). (c) Comparison of 4T1 tumor uptake among the three groups. The differences between 4T1 tumor uptake of 64Cu-MSN-800CW-TRC105(Fab) and the two control groups were statistically significant (**P < 0.01) in all cases. (d) Biodistribution of three groups in 4T1 tumor-bearing mice at the end of the PET scans at 48 h pi (n = 3).

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      Rosen, Lee S.; Hurwitz, Herbert I.; Wong, Michael K.; Goldman, Jonathan; Mendelson, David S.; Figg, William D.; Spencer, Shawn; Adams, Bonne J.; Alvarez, Delia; Seon, Ben K.; Theuer, Charles P.; Leigh, Bryan R.; Gordon, Michael S.
      Clinical Cancer Research (2012), 18 (17), 4820-4829CODEN: CCREF4; ISSN:1078-0432. (American Association for Cancer Research)
      Purpose: TRC105 is a chimeric IgG1 monoclonal antibody that binds CD105 (endoglin). This first-in-human, phase I, open-label study assessed safety, pharmacokinetics, and antitumor activity of TRC105 in patients with advanced refractory solid tumors. Patients and Methods: Patients received escalating doses of i.v. TRC105 until disease progression or unacceptable toxicity using a std. 3 + 3 phase I design. Results: Fifty patients were treated with escalating doses of TRC105. The max. tolerated dose (MTD) was exceeded at 15 mg/kg every week because of dose-limiting hypoproliferative anemia. TRC105 exposure increased with increasing dose, and continuous serum concns. that sat. CD105 receptors were maintained at 10 mg/kg weekly (the MTD) and 15 mg/kg every 2 wk. Common adverse events including anemia, telangiectasias, and infusion reactions reflected the mechanism of action of the drug. Antibodies to TRC105 were not detected in patients treated with TRC105 from Chinese hamster ovary cells being used in ongoing phase Ib and phase II studies. Stable disease or better was achieved in 21 of 45 evaluable patients (47%), including two ongoing responses at 48 and 18 mo. Conclusion: TRC105 was tolerated at 10 mg/kg every week and 15 mg/kg every 2 wk, with a safety profile that was distinct from that of VEGF inhibitors. Evidence of clin. activity was seen in a refractory patient population. Ongoing clin. trials are testing TRC105 in combination with chemotherapy and VEGF inhibitors and as a single agent in prostate, ovarian, bladder, breast, and hepatocellular cancer. Clin Cancer Res; 18(17); 4820-9. ©2012 AACR.
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    7. 7
      Seon, B. K.; Haba, A.; Matsuno, F.; Takahashi, N.; Tsujie, M.; She, X.; Harada, N.; Uneda, S.; Tsujie, T.; Toi, H.; Tsai, H.; Haruta, Y. Endoglin-Targeted Cancer Therapy Curr. Drug Delivery 2011, 8, 135– 143
      There is no corresponding record for this reference.
    8. 8
      Fonsatti, E.; Nicolay, H. J.; Altomonte, M.; Covre, A.; Maio, M. Targeting Cancer Vasculature Via Endoglin/CD105: A Novel Antibody-Based Diagnostic and Therapeutic Strategy in Solid Tumours Cardiovasc. Res. 2010, 86, 12– 19
      There is no corresponding record for this reference.
    9. 9
      Hong, H.; Yang, Y.; Zhang, Y.; Engle, J. W.; Barnhart, T. E.; Nickles, R. J.; Leigh, B. R.; Cai, W. Positron Emission Tomography Imaging of CD105 Expression During Tumor Angiogenesis Eur. J. Nucl. Med. Mol. Imaging 2011, 38, 1335– 1343
      9
      Positron emission tomography imaging of CD105 expression during tumor angiogenesis
      Hong, Hao; Yang, Yunan; Zhang, Yin; Engle, Jonathan W.; Barnhart, Todd E.; Nickles, Robert J.; Leigh, Bryan R.; Cai, Weibo
      European Journal of Nuclear Medicine and Molecular Imaging (2011), 38 (7), 1335-1343CODEN: EJNMA6; ISSN:1619-7070. (Springer)
      Purpose: Overexpression of CD105 (endoglin) correlates with poor prognosis in many solid tumor types. Tumor microvessel d. (MVD) assessed by CD105 staining is the current gold std. for evaluating tumor angiogenesis in the clinic. The goal of this study was to develop a positron emission tomog. (PET) tracer for imaging CD105 expression. Methods: TRC105, a chimeric anti-CD105 monoclonal antibody, was conjugated to 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) and labeled with 64Cu. FACS anal. and microscopy studies were performed to compare the CD105 binding affinity of TRC105 and DOTA-TRC105. PET imaging, biodistribution, blocking, and ex vivo histol. studies were performed on 4T1 murine breast tumor-bearing mice to evaluate the ability of 64Cu-DOTA-TRC105 to target tumor angiogenesis. Another chimeric antibody, cetuximab, was used as an isotype-matched control. Results: FACS anal. of human umbilical vein endothelial cells (HUVECs) revealed no difference in CD105 binding affinity between TRC105 and DOTA-TRC105, which was further validated by fluorescence microscopy. 64Cu labeling was achieved with high yield and specific activity. Serial PET imaging revealed that the 4T1 tumor uptake of the tracer was 8.0 ± 0.5, 10.4 ± 2.8, and 9.7 ± 1.8%ID/g at 4, 24, and 48 h post-injection, resp. (n = 3), higher than most organs at late time points which provided excellent tumor contrast. Biodistribution data as measured by gamma counting were consistent with the PET findings. Blocking expts., control studies with 64Cu-DOTA-cetuximab, as well as ex vivo histol. all confirmed the in vivo target specificity of 64Cu-DOTA-TRC105. Conclusion: This is the first successful PET imaging study of CD105 expression. Fast, prominent, persistent, and CD105-specific uptake of the tracer in the 4T1 tumor was obsd. Further studies are warranted and currently underway.
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    10. 10
      Hong, H.; Zhang, Y.; Orbay, H.; Valdovinos, H. F.; Nayak, T. R.; Bean, J.; Theuer, C. P.; Barnhart, T. E.; Cai, W. Positron Emission Tomography Imaging of Tumor Angiogenesis with a (61/64)Cu-Labeled F(ab′)(2) Antibody Fragment Mol. Pharm. 2013, 10, 709– 716
      10
      Positron Emission Tomography Imaging of Tumor Angiogenesis with a 61/64Cu-Labeled F(ab')2 Antibody Fragment
      Hong, Hao; Zhang, Yin; Orbay, Hakan; Valdovinos, Hector F.; Nayak, Tapas R.; Bean, Jero; Theuer, Charles P.; Barnhart, Todd E.; Cai, Weibo
      Molecular Pharmaceutics (2013), 10 (2), 709-716CODEN: MPOHBP; ISSN:1543-8384. (American Chemical Society)
      The objective of this study was to characterize the in vitro and in vivo properties of the F(ab')2 fragment of TRC105, a human/murine chimeric IgG1 monoclonal antibody that binds with high avidity to human and murine CD105 (i.e., endoglin), and investigate its potential for positron emission tomog. (PET) imaging of tumor angiogenesis after 61/64Cu-labeling. TRC105-F(ab')2 of high purity was produced by pepsin digestion of TRC105, which was confirmed by SDS-PAGE, HPLC anal., and mass spectrometry. 61/64Cu-labeling of NOTA-TRC105-F(ab')2 (NOTA denotes 1,4,7-triazacyclononane-1,4,7-triacetic acid) was achieved with yields of >75% (specific activity: ∼115 GBq/μmol). PET imaging revealed rapid tumor uptake of 64Cu-NOTA-TRC105-F(ab')2 in the 4T1 murine breast cancer model (5.8 ± 0.8, 7.6 ± 0.6, 5.6 ± 0.4, 5.0 ± 0.6, and 3.8 ± 0.7% ID/g at 0.5, 3, 16, 24, and 48 h postinjection resp.; n = 4). Since tumor uptake peaked at 3 h postinjection, 61Cu-NOTA-TRC105-F(ab')2 also gave good tumor contrast at 3 and 8 h postinjection. CD105 specificity of the tracers was confirmed by blocking studies and histopathol. In conclusion, the use of a F(ab')2 fragment led to more rapid tumor uptake (which peaked at 3 h postinjection) than radiolabeled intact antibody (which often peaked after 24 h postinjection), which may allow for same day immunoPET imaging in future clin. studies.
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    11. 11
      James, M. L.; Gambhir, S. S. A Molecular Imaging Primer: Modalities, Imaging Agents, and Applications Physiol. Rev. 2012, 92, 897– 965
      11
      A molecular imaging primer: modalities, imaging agents, and applications
      James, Michelle L.; Gambhir, Sanjiv S.
      Physiological Reviews (2012), 92 (2), 897-965CODEN: PHREA7; ISSN:0031-9333. (American Physiological Society)
      A review. Mol. imaging is revolutionizing the way we study the inner workings of the human body, diagnose diseases, approach drug design, and assess therapies. The field as a whole is making possible the visualization of complex biochem. processes involved in normal physiol. and disease states, in real time, in living cells, tissues, and intact subjects. In this review, we focus specifically on mol. imaging of intact living subjects. We provide a basic primer for those who are new to mol. imaging, and a resource for those involved in the field. We begin by describing classical mol. imaging techniques together with their key strengths and limitations, after which we introduce some of the latest emerging imaging modalities. We provide an overview of the main classes of mol. imaging agents (i.e., small mols., peptides, aptamers, engineered proteins, and nanoparticles) and cite examples of how mol. imaging is being applied in oncol., neuroscience, cardiol., gene therapy, cell tracking, and theranostics (therapy combined with diagnostics). A step-by-step guide to answering biol. and/or clin. questions using the tools of mol. imaging is also provided. We conclude by discussing the grand challenges of the field, its future directions, and enormous potential for further impacting how we approach research and medicine.
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    12. 12
      Gambhir, S. S. Molecular Imaging of Cancer with Positron Emission Tomography Nature Rev. Cancer 2002, 2, 683– 693
      12
      Molecular imaging of cancer with positron emission tomography
      Gambhir, Sanjiv Sam
      Nature Reviews Cancer (2002), 2 (9), 683-693CODEN: NRCAC4; ISSN:1474-175X. (Nature Publishing Group)
      A review. The imaging of specific mol. targets that are assocd. with cancer should allow earlier diagnosis and better management of oncol. patients. Positron emission tomog. (PET) is a highly sensitive non-invasive technol. that is ideally suited for pre-clin. and clin. imaging of cancer biol., in contrast to anatomical approaches. By using radiolabeled tracers, which are injected in non-pharmacol. doses, three-dimensional images can be reconstructed by a computer to show the concn. and location(s) of the tracer of interest. PET should become increasingly important in cancer imaging in the next decade.
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    13. 13
      Cai, W.; Chen, K.; Li, Z. B.; Gambhir, S. S.; Chen, X. Dual-Function Probe for PET and Near-Infrared Fluorescence Imaging of Tumor Vasculature J. Nucl. Med. 2007, 48, 1862– 1870
      There is no corresponding record for this reference.
    14. 14
      Chen, K.; Li, Z. B.; Wang, H.; Cai, W.; Chen, X. Dual-Modality Optical and Positron Emission Tomography Imaging of Vascular Endothelial Growth Factor Receptor on Tumor Vasculature Using Quantum Dots Eur. J. Nucl. Med. Mol. Imaging 2008, 35, 2235– 2244
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      Dual-modality optical and positron emission tomography imaging of vascular endothelial growth factor receptor on tumor vasculature using quantum dots
      Chen, Kai; Li, Zi-Bo; Wang, Hui; Cai, Weibo; Chen, Xiaoyuan
      European Journal of Nuclear Medicine and Molecular Imaging (2008), 35 (12), 2235-2244CODEN: EJNMA6; ISSN:1619-7070. (Springer)
      To date, the in vivo imaging of quantum dots (QDs) has been mostly qual. or semiquant. The development of a dual-function positron emission tomog. (PET)/near-IR fluorescence (NIRF) probe might allow the accurate assessment of the tumor-targeting efficacy of QDs. An amine-functionalized QD was conjugated with VEGF protein and DOTA chelator for VEGFR-targeted PET/NIRF imaging after 64Cu-labeling. The targeting efficacy of this dual functional probe was evaluated in vitro and in vivo through cell-binding assay, cell staining, in vivo optical/PET imaging, ex vivo optical/PET imaging, and histol. The DOTA-QD-VEGF exhibited VEGFR-specific binding in both cell-binding assay and cell staining expt. Both NIR fluorescence imaging and microPET showed VEGFR-specific delivery of conjugated DOTA-QD-VEGF nanoparticle and prominent reticuloendothelial system uptake. The U87MG tumor uptake of 64Cu-labeled DOTA-QD was less than one percentage injected dose per g (%ID/g), significantly lower than that of 64Cu-labeled DOTA-QD-VEGF (1.52 ± 0.6%ID/g, 2.81 ± 0.3%ID/g, 3.84 ± 0.4%ID/g, and 4.16 ± 0.5%ID/g at 1, 4, 16, and 24 h post injection, resp.; n = 3). Good correlation was also obsd. between the results measured by ex vivo PET and NIRF organ imaging. Histol. examn. revealed that DOTA-QD-VEGF primarily targets the tumor vasculature through a VEGF-VEGFR interaction. We have successfully developed a QD-based nanoprobe for dual PET and NIRF imaging of tumor VEGFR expression. The success of this bifunctional imaging approach may render higher degree of accuracy for the quant. targeted NIRF imaging in deep tissue.
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    15. 15
      Lee, J.; Lee, T. S.; Ryu, J.; Hong, S.; Kang, M.; Im, K.; Kang, J. H.; Lim, S. M.; Park, S.; Song, R. RGD Peptide-Conjugated Multimodal NaDdF4:Yb3+/Er3+ Nanophosphors for Upconversion Luminescence, MR, and PET Imaging of Tumor Angiogenesis J. Nucl. Med. 2013, 54, 96– 103
      There is no corresponding record for this reference.
    16. 16
      Sun, Y.; Yu, M.; Liang, S.; Zhang, Y.; Li, C.; Mou, T.; Yang, W.; Zhang, X.; Li, B.; Huang, C.; Li, F. Fluorine-18 Labeled Rare-Earth Nanoparticles for Positron Emission Tomography (PET) Imaging of Sentinel Lymph Node Biomaterials 2011, 32, 2999– 3007
      There is no corresponding record for this reference.
    17. 17
      Xie, J.; Chen, K.; Huang, J.; Lee, S.; Wang, J.; Gao, J.; Li, X.; Chen, X. PET/NIRF/MRI Triple Functional Iron Oxide Nanoparticles Biomaterials 2010, 31, 3016– 3022
      There is no corresponding record for this reference.
    18. 18
      Zhou, J.; Yu, M.; Sun, Y.; Zhang, X.; Zhu, X.; Wu, Z.; Wu, D.; Li, F. Fluorine-18-Labeled Gd3+/Yb3+/Er3+ Co-Doped NaYF4 Nanophosphors for Multimodality PET/MR/UCL Imaging Biomaterials 2011, 32, 1148– 1156
      There is no corresponding record for this reference.
    19. 19
      Huang, X.; Zhang, F.; Lee, S.; Swierczewska, M.; Kiesewetter, D. O.; Lang, L.; Zhang, G.; Zhu, L.; Gao, H.; Choi, H. S.; Niu, G.; Chen, X. Long-Term Multimodal Imaging of Tumor Draining Sentinel Lymph Nodes Using Mesoporous Silica-Based Nanoprobes Biomaterials 2012, 33, 4370– 4378
      There is no corresponding record for this reference.
    20. 20
      Zhang, Y.; Hong, H.; Engle, J. W.; Yang, Y.; Barnhart, T. E.; Cai, W. Positron Emission Tomography and Near-Infrared Fluorescence Imaging of Vascular Endothelial Growth Factor with Dual-Labeled Bevacizumab Am. J. Nucl. Med. Mol. Imaging 2012, 2, 1– 13
      20
      Positron emission tomography and near-infrared fluorescence imaging of vascular endothelial growth factor with dual-labeled bevacizumab
      Zhang, Yin; Hong, Hao; Engle, Jonathan W.; Yang, Yunan; Barnhart, Todd E.; Cai, Weibo
      American Journal of Nuclear Medicine and Molecular Imaging (2012), 2 (1), 1-13CODEN: AJNMAU; ISSN:2160-8407. (e-Century Publishing Corp.)
      The pivotal role of vascular endothelial growth factor (VEGF) in cancer is underscored by the approval of bevacizumab (Bev, a humanized anti-VEGF monoclonal antibody) for first line treatment of cancer patients. The aim of this study was to develop a dual-labeled Bev for both positron emission tomog. (PET) and near-IR fluorescence (NIRF) imaging of VEGF. Bev was conjugated to a NIRF dye (i.e. 800CW) and 2-S-(4-isothiocyanatobenzyl)-1,4,7-triazacyclononane-1,4,7-triacetic acid (p-SCN-Bn-NOTA) before 64Cu-labeling. Flow cytometry anal. of U87MG human glioblastoma cells revealed no difference in VEGF binding affinity/specificity between Bev and NOTA-Bev-800CW. 64Cu-labeling of NOTA-Bev-800CW was achieved with high yield. Serial PET imaging of U87MG tumor-bearing female nude mice revealed that tumor uptake of 64Cu-NOTA-Bev-800CW was 4.6 ± 0.7, 16.3 ± 1.6, 18.1 ± 1.4 and 20.7 ± 3.7 % ID/g at 4, 24, 48 and 72 h post-injection resp. (n = 4), corroborated by in vivo/ex vivo NIRF imaging and biodistribution studies. Tumor uptake as measured by ex vivo NIRF imaging had a good linear correlation with the % ID/g values obtained from PET (R2 = 0.93). Blocking expts. and histol. both confirmed the VEGF specificity of 64Cu-NOTA-Bev-800CW. The persistent, prominent, and VEGF-specific uptake of 64Cu-NOTA-Bev-800CW in the tumor, obsd. by both PET and NIRF imaging, warrants further investigation and future clin. translation of such Bev-based imaging agents.
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    21. 21
      Vallet-Regi, M.; Rámila, A.; del Real, R. P.; Pérez-Pariente, J. A New Property of Mcm-41: Drug Delivery System Chem. Mater. 2000, 13, 308– 311
      There is no corresponding record for this reference.
    22. 22
      Lu, J.; Liong, M.; Li, Z.; Zink, J. I.; Tamanoi, F. Biocompatibility, Biodistribution, and Drug-Delivery Efficiency of Mesoporous Silica Nanoparticles for Cancer Therapy in Animals Small 2010, 6, 1794– 1805
      There is no corresponding record for this reference.
    23. 23
      Meng, H.; Xue, M.; Xia, T.; Ji, Z.; Tarn, D. Y.; Zink, J. I.; Nel, A. E. Use of Size and a Copolymer Design Feature to Improve the Biodistribution and the Enhanced Permeability and Retention Effect of Doxorubicin-Loaded Mesoporous Silica Nanoparticles in a Murine Xenograft Tumor Model ACS Nano 2011, 5, 4131– 4144
      23
      Use of Size and a Copolymer Design Feature To Improve the Biodistribution and the Enhanced Permeability and Retention Effect of Doxorubicin-Loaded Mesoporous Silica Nanoparticles in a Murine Xenograft Tumor Model
      Meng, Huan; Xue, Min; Xia, Tian; Ji, Zhaoxia; Tarn, Derrick Y.; Zink, Jeffrey I.; Nel, Andre E.
      ACS Nano (2011), 5 (5), 4131-4144CODEN: ANCAC3; ISSN:1936-0851. (American Chemical Society)
      A key challenge for improving the efficacy of passive drug delivery to tumor sites by a nanocarrier is to limit reticuloendothelial system uptake and to maximize the enhanced permeability and retention effect. We demonstrate that size redn. and surface functionalization of mesoporous silica nanoparticles (MSNP) with a polyethyleneimine-polyethylene glycol copolymer reduces particle opsonization while enhancing the passive delivery of monodispersed, 50 nm doxorubicin-laden MSNP to a human squamous carcinoma xenograft in nude mice after i.v. injection. Using near-IR fluorescence imaging and elemental Si anal., we demonstrate passive accumulation of ∼ 12% of the tail vein-injected particle load at the tumor site, where there is effective cellular uptake and the delivery of doxorubicin to KB-31 cells. This was accompanied by the induction of apoptosis and an enhanced rate of tumor shrinking compared to free doxorubicin. The improved drug delivery was accompanied by a significant redn. in systemic side effects such as animal wt. loss as well as reduced liver and renal injury. These results demonstrate that it is possible to achieve effective passive tumor targeting by MSNP size redn. as well as by introducing steric hindrance and electrostatic repulsion through coating with a copolymer. Further endowment of this multifunctional drug delivery platform with targeting ligands and nanovalves may further enhance cell-specific targeting and on-demand release.
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    24. 24
      Pan, L.; He, Q.; Liu, J.; Chen, Y.; Ma, M.; Zhang, L.; Shi, J. Nuclear-Targeted Drug Delivery of TAT Peptide-Conjugated Monodisperse Mesoporous Silica Nanoparticles J. Am. Chem. Soc. 2012, 134, 5722– 5725
      24
      Nuclear-Targeted Drug Delivery of TAT Peptide-Conjugated Monodisperse Mesoporous Silica Nanoparticles
      Pan, Limin; He, Qianjun; Liu, Jianan; Chen, Yu; Ma, Ming; Zhang, Linlin; Shi, Jianlin
      Journal of the American Chemical Society (2012), 134 (13), 5722-5725CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
      Most present nanodrug delivery systems have been developed to target cancer cells but rarely nuclei. However, nuclear-targeted drug delivery is expected to kill cancer cells more directly and efficiently. In this work, TAT peptide has been employed to conjugate onto mesoporous silica nanoparticles (MSNs-TAT) with high payload for nuclear-targeted drug delivery for the first time. Monodispersed MSNs-TAT of varied particle sizes have been synthesized to investigate the effects of particle size and TAT conjugation on the nuclear membrane penetrability of MSNs. MSNs-TAT with a diam. of 50 nm or smaller can efficiently target the nucleus and deliver the active anticancer drug doxorubicin (DOX) into the targeted nucleus, killing these cancer cells with much enhanced efficiencies. This study may provide an effective strategy for the design and development of cell-nuclear-targeted drug delivery.
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    25. 25
      Wang, K.; He, X.; Yang, X.; Shi, H. Functionalized Silica Nanoparticles: A Platform for Fluorescence Imaging at the Cell and Small Animal Levels Acc. Chem. Res. 2013, 46, 1367– 1376
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      Functionalized Silica Nanoparticles: A Platform for Fluorescence Imaging at the Cell and Small Animal Levels
      Wang, Kemin; He, Xiaoxiao; Yang, XiaoHai; Shi, Hui
      Accounts of Chemical Research (2013), 46 (7), 1367-1376CODEN: ACHRE4; ISSN:0001-4842. (American Chemical Society)
      A review. Going in vivo, including living cells and the whole body, is very important for gaining a better understanding of the mystery of life and requires specialized imaging techniques. The diversity, compn., and temporal-spatial variation of life activities from cells to the whole body require the anal. techniques to be fast-response, noninvasive, highly sensitive, and stable, in situ and in real-time. Functionalized nanoparticle-based fluorescence imaging techniques have the potential to meet such needs through real-time and noninvasive visualization of biol. events in vivo. Functionalized silica nanoparticles (SiNPs) doped with fluorescent dyes appear to be an ideal and flexible platform for developing fluorescence imaging techniques used in living cells and the whole body. The authors can select and incorporate different dyes inside the silica matrix either noncovalently or covalently. These form the functionalized hybrid SiNPs, which support multiplex labeling and ratiometric sensing in living systems. Since the silica matrix protects dyes from outside quenching and degrading factors, this enhances the photostability and biocompatibility of the SiNP-based probes. This makes them ideal for real-time and long-time tracking. One nanoparticle can encapsulate large nos. of dye mols., which amplifies their optical signal and temporal-spatial resoln. response. Integrating fluorescent dye-doped SiNPs with targeting ligands using various surface modification techniques can greatly improve selective recognition. Along with the endocytosis, functionalized SiNPs can be efficiently internalized into cells for noninvasive localization, assessment, and monitoring. These unique characteristics of functionalized SiNPs substantially support their applications in fluorescence imaging in vivo. In this Account, the authors summarize their efforts to develop functionalized dye-doped SiNPs for fluorescence imaging at the cell and small animal levels. The authors first discuss how to design and construct various functionalized dye-doped SiNPs. Then the authors describe their properties and imaging applications in cell surface receptor recognition, intracellular labeling, tracking, sensing, and controlled release. Addnl., the authors demonstrated the promising application of dye-doped SiNPs as contrast imaging agents for in vivo fluorescence imaging in small animals. The authors expect these functionalized dye-doped SiNPs to open new opportunities for biol. and medical research and applications.
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    26. 26
      Lee, C. H.; Cheng, S. H.; Wang, Y. J.; Chen, Y. C.; Chen, N. T.; Souris, J.; Chen, C. T.; Mou, C. Y.; Yang, C. S.; Lo, L. W. Near-Infrared Mesoporous Silica Nanoparticles for Optical Imaging: Characterization and in Vivo Biodistribution Adv. Funct. Mater. 2009, 19, 215– 222
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      Near-infrared mesoporous silica nanoparticles for optical imaging: characterization and in vivo biodistribution
      Lee, Chia-Hung; Cheng, Shih-Hsun; Wang, Yu-Jing; Chen, Yu-Ching; Chen, Nai-Tzu; Souris, Jeffrey; Chen, Chin-Tu; Mou, Chung-Yuan; Yang, Chung-Shi; Lo, Leu-Wei
      Advanced Functional Materials (2009), 19 (2), 215-222CODEN: AFMDC6; ISSN:1616-301X. (Wiley-VCH Verlag GmbH & Co. KGaA)
      The characterization of near-IR (NIR) mesoporous silica nanoparticles (MSN) suitable for in vivo optical imaging with high efficiency is presented. Trimethylammonium groups modified MSN (MSN-TA) with the av. size of 50-100 nm was synthesized with incorporation of the TA groups into the framework of MSN. It was further adsorbed with indocyanine green (ICG) by electrostatic attraction to render MSN-TA-ICG as an efficient NIR contrast agent for in vivo optical imaging. The studies in stability of MSN-TA-ICG against pH indicated the bonding is stable over the range from acidic to physiol. pH. The in vivo biodistribution of MSN-TA-ICG in anesthetized rat demonstrated a rather strong and stable fluorescence of MSN-TA-ICG that prominent in the organ of liver. Transmission electron microscopy (TEM) imaging and elemental anal. of silicon further manifested the phys. and quant. residences of MSN-TA-ICG in major organs. This is the first report of MSN functionalized with NIR-ICG capable of optical imaging in vivo.
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    27. 27
      Pan, J.; Wan, D.; Gong, J. Pegylated Liposome Coated QDs/Mesoporous Silica Core–Shell Nanoparticles for Molecular Imaging Chem. Commun. 2011, 47, 3442– 3444
      There is no corresponding record for this reference.
    28. 28
      Liu, J.; Bu, W.; Zhang, S.; Chen, F.; Xing, H.; Pan, L.; Zhou, L.; Peng, W.; Shi, J. Controlled Synthesis of Uniform and Monodisperse Upconversion Core/Mesoporous Silica Shell Nanocomposites for Bimodal Imaging Chemistry 2012, 18, 2335– 2341
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      Controlled Synthesis of Uniform and Monodisperse Upconversion Core/Mesoporous Silica Shell Nanocomposites for Bimodal Imaging
      Liu, Jianan; Bu, Wenbo; Zhang, Shengjian; Chen, Feng; Xing, Huaiyong; Pan, Limin; Zhou, Liangping; Peng, Weijun; Shi, Jianlin
      Chemistry - A European Journal (2012), 18 (8), 2335-2341, S2335/1-S2335/5CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)
      Here the authors report the design and controlled synthesis of monodisperse and precisely size-controllable UCNP@mSiO2 nanocomposites smaller than 50 nm by directly coating a mesoporous silica shell (mSiO2) on upconversion nanocrystals NaYF4:Tm/Yb/Gd (UCNPs), which can be used as near-IR fluorescence and magnetic resonance imaging (MRI) agents and a platform for drug delivery as well. Some key steps such as transferring hydrophobic UCNPs to the water phase by using cetyltrimethylammonium bromide (CTAB), removal of the excess amt. of CTAB, and temp.-controlled ultrasonication treatment should be adopted and carefully monitored to obtain uniform upconversion core/mesoporous silica shell nanocomposites. The excellent performance of the core-shell-structured nanocomposite in near-IR fluorescence and magnetic resonance imaging was also demonstrated.
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    29. 29
      Zhang, Y.; Hong, H.; Orbay, H.; Valdovinos, H. F.; Nayak, T. R.; Theuer, C. P.; Barnhart, T. E.; Cai, W. Pet Imaging of CD105/Endoglin Expression with a (6)(1)/(6)(4)Cu-Labeled Fab Antibody Fragment Eur. J. Nucl. Med. Mol. Imaging 2013, 40, 759– 767
      29
      PET imaging of CD105/endoglin expression with a 61/64Cu-labeled Fab antibody fragment
      Zhang, Yin; Hong, Hao; Orbay, Hakan; Valdovinos, Hector F.; Nayak, Tapas R.; Theuer, Charles P.; Barnhart, Todd E.; Cai, Weibo
      European Journal of Nuclear Medicine and Molecular Imaging (2013), 40 (5), 759-767CODEN: EJNMA6; ISSN:1619-7070. (Springer)
      Purpose: The goal of this study was to generate and characterize the Fab fragment of TRC105, a monoclonal antibody that binds with high affinity to human and murine CD105 (i.e., endoglin), and investigate its potential for PET imaging of tumor angiogenesis in a small-animal model after 61/64Cu labeling. Methods: TRC105-Fab was generated by enzymic papain digestion. The integrity and CD105 binding affinity of TRC105-Fab was evaluated before NOTA (1,4,7-triazacyclononane-1,4,7-triacetic acid) conjugation and 61/64Cu labeling. Serial PET imaging and biodistribution studies were carried out in the syngeneic 4T1 murine breast cancer model to quantify tumor targeting efficiency and normal organ distribution of 61/64Cu-NOTA-TRC105-Fab. Blocking studies with unlabeled TRC105 were performed to confirm CD105 specificity of the tracer in vivo. Immunofluorescence staining was also conducted to correlate tracer uptake in the tumor and normal tissues with CD105 expression. Results TRC105-Fab was produced with high purity through papain digestion of TRC105, as confirmed by SDS-PAGE, HPLC anal., and mass spectrometry. 61/64Cu labeling of NOTA-TRC105-Fab was achieved with about 50 % yield (specific activity about 44 GBq/μmol). PET imaging revealed rapid uptake of 64Cu-NOTA-TRC105-Fab in the 4T1 tumor (3.6 ± 0.4, 4.2 ± 0.5, 4.9 ± 0.3, 4.4 ± 0.7, and 4.6 ± 0.8 %ID/g at 0.5, 2, 5, 16, and 24 h after injection, resp.; n = 4). Since tumor uptake peaked soon after tracer injection, 61Cu-labeled TRC105-Fab was also able to provide tumor contrast at 3 and 8 h after injection. CD105 specificity of the tracer was confirmed with blocking studies and histol. examn. Conclusion: We report PET imaging of CD105 expression using 61/64Cu-NOTA-TRC105-Fab, which exhibited prominent and target-specific uptake in the 4T1 tumor. The use of a Fab fragment led to much faster tumor uptake (which peaked at a few hours after tracer injection) compared to radiolabeled intact antibody, which may be translated into same-day immunoPET imaging for clin. investigation.
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    30. 30
      Chen, F.; Hong, H.; Zhang, Y.; Valdovinos, H. F.; Shi, S.; Kwon, G. S.; Theuer, C. P.; Barnhart, T. E.; Cai, W. In Vivo Tumor Targeting and Image-Guided Drug Delivery with Antibody-Conjugated, Radiolabeled Mesoporous Silica Nanoparticles ACS Nano 2013, 7, 9027– 9039
      There is no corresponding record for this reference.
    31. 31
      Orbay, H.; Zhang, Y.; Valdovinos, H. F.; Song, G.; Hernandez, R.; Theuer, C. P.; Hacker, T. A.; Nickles, R. J.; Cai, W. Positron Emission Tomography Imaging of CD105 Expression in a Rat Myocardial Infarction Model with (64)Cu-Nota-TRC105 Am. J. Nucl. Med. Mol. Imaging 2013, 4, 1– 9
      31
      Positron emission tomography imaging of CD105 expression in a rat myocardial infarction model with (64)Cu-NOTA-TRC105
      Orbay Hakan; Zhang Yin; Valdovinos Hector F; Hernandez Reinier; Nickles Robert J; Song Guoqing; Hacker Timothy A; Theuer Charles P; Cai Weibo
      American journal of nuclear medicine and molecular imaging (2013), 4 (1), 1-9 ISSN:.
      Biological changes following myocardial infarction (MI) lead to increased secretion of angiogenic factors that subsequently stimulate the formation of new blood vessels as a compensatory mechanism to reverse ischemia. The goal of this study was to assess the role of CD105 expression during MI-induced angiogenesis by positron emission tomography (PET) imaging using (64)Cu-labeled TRC105, an anti-CD105 monoclonal antibody. MI was induced by ligation of the left anterior descending (LAD) artery in female rats. Echocardiography and (18)F-fluoro-2-deoxy-D-glucose ((18)F-FDG) PET scans were performed on post-operative day 3 to confirm the presence of MI in the infarct group and intact heart in the sham group, respectively. Ischemia-induced angiogenesis was non-invasively monitored with (64)Cu-NOTA-TRC105 (an extensively validated PET tracer in our previous studies) PET on post-operative days 3, 10, and 17. Tracer uptake in the infarct zone was highest on day 3 following MI, which was significantly higher than that in the sham group (1.41 ± 0.45 %ID/g vs 0.57 ± 0.07 %ID/g; n=3, p<0.05). Subsequently, tracer uptake in the infarct zone decreased over time to the background level on day 17, whereas tracer uptake in the heart of sham rats remained low at all time points examined. Histopathology documented increased CD105 expression following MI, which corroborated in vivo findings. This study indicated that PET imaging of CD105 can be a useful tool for MI-related research, which can potentially improve MI patient management in the future upon clinical translation of the optimized PET tracers.
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  • Supporting Information

    Supporting Information

    Ninhydrin testing, tables of PET region-of-interest quantifications, quantitative analysis of PET imaging data from non-targeted and blocking groups. This material is available free of charge via the Internet at http://pubs.acs.org.


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