Gastrin-Releasing Peptide Receptor- and Prostate-Specific Membrane

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GRPR- and PSMA-specific ultra-small gold nanoparticles for characterization and diagnosis of prostate carcinoma via fluorescence imaging Marc Pretze, Andreas Hien, Matthias Raedle, Ralf Schirrmacher, Carmen Wängler, and Björn Wängler Bioconjugate Chem., Just Accepted Manuscript • DOI: 10.1021/acs.bioconjchem.8b00067 • Publication Date (Web): 15 Mar 2018 Downloaded from http://pubs.acs.org on March 16, 2018

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Bioconjugate Chemistry

GRPR- and PSMA-specific ultra-small gold nanoparticles for characterization and diagnosis of prostate carcinoma via fluorescence imaging Marc Pretze1*, Andreas Hien2, Matthias Rädle2, Ralf Schirrmacher3, Carmen Wängler4, and Björn Wängler1* 1

Molecular Imaging & Radiochemistry, Department of Clinical Radiology and Nuclear Medicine,

Medical Faculty Mannheim of Heidelberg University, Mannheim 68167, Germany 2

Institute of Process Control and Innovative Energy Conversion, Mannheim University of Applied

Sciences, Mannheim 68163, Germany 3

Oncologic Imaging, Department of Oncology, University of Alberta, Edmonton 6820, Alberta,

Canada 4

Biomedical Chemistry, Medical Faculty Mannheim of Heidelberg University, Mannheim 68167,

Germany

KEYWORDS GRPR, PSMA, gold nanoparticle, prostate cancer, fluorescence imaging, gallium-68

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ABSTRACT: Gold nanoparticles (AuNPs) have widely been used for 70 years in cancer treatment, but only in the last 15 years the focus has been on specific AuNPs with homogeneous size and shape for various areas in science. They constitute a perfect platform for multi-functionalization and therefore enable the enhancement of target affinity. Here we report on the development of tumor specific AuNPs as diagnostic tools intended for the detection of prostate cancer via fluorescence imaging and positron emission tomography (PET). The AuNPs were further evaluated in vitro and in vivo and exhibited favorable diagnostic properties concerning tumor cell uptake, biodistribution, clearance and tumor retention.

INTRODUCTION Gold nanoparticles (AuNPs) have been used for nearly 70 years for the therapy 1-3 and diagnosis 4 of different cancers. Early on, those colloidal solutions were unspecific and consisted of AuNPs of heterogeneous size distribution, restricting their use to interstitial brachytherapeutic applications 5. The development of methods for the synthesis of monodisperse AuNPs 6 followed by surfacemodification for enhanced stability and homogenization of AuNPs 7-9 paved the way for further functionalization 10. The high affinity of sulfur towards gold surfaces and the formation of stable and covalent Au-S bonds 11 enables a fast and facile functionalization of AuNPs with thiol-modified (bio)molecules. Although cytotoxic effects are known for citrate-capped AuNPs 12, 13-14, polyethylene glycol-containing (PEG)ylated AuNPs exhibit toxic effects only at high concentrations of >3 g/kg 4, 1516

. Furthermore, the PEGylation of the AuNPs leads to a higher bioavailability because the in vivo

formation of a protein corona around the AuNP is hindered 17-18. Therefore, more target-specific


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AuNPs could be developed and labeled with small-molecules 19, antibodies 20, peptides 21, natural products 22-23, radionuclides 24, and Magnetic Resonance Imaging (MRI) relevant metals 25. Thus, AuNPs represent a perfect platform for multimerization of target-specific effectors at their surface and modification for multimodal imaging techniques 26 as well as for theranostic purposes 27-31. Many approaches are based on a phenomenon typically known as ‘enhanced permeability and retention’ (EPR) due to passive extravasation of nanoparticles across the perforated vasculature of tumors 32.

In this work, we report on the functionalization of target-specific AuNPs for the diagnosis of different prostate cancers via near-infrared (NIR) fluorescence imaging. We show the straightforward synthesis and characterization of modified AuNPs with target-specific peptides (Bombesin(7-14) (BBN(7-14))

33-34

and the Lys-urea-Glu motif (LUG) 35) binding the gastrin-releasing peptide receptor (GRPR) and the prostate-specific membrane antigen (PSMA), respectively. The different AuNPs were tested for stability, avidity and cell association as well as fluorescence imaging in vitro. Furthermore, their biodistribution, tumor enrichment and imaging in vivo were evaluated.

RESULTS AND DISCUSSION

Synthesis The synthesis of AuNPs is based on the method of Brust and Schiffrin 7. Characterization of the resulting rubyred AuNP solutions was performed via DLS, EM, NMR and UV/Vis. Quantification of ligands per particle was performed with TGA (see SI Fig. S-3–6). Very small AuNPs with a PEG



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shell were synthesized with size distribution of 3 ± 2 nm in diameter (see SI). Next, a ligand exchange reaction was performed in order to introduce furan-protected thiol-selective maleimide moieties for the Michael addition of thiol-functionalized (bio-)molecules 36.

Shortly before further functionalization, the maleimide groups of the AuNPs were deprotected in dry DMSO for 2 h at 95°C. Next, the AuNPs were cooled to ambient temperature and further functionalization was performed in DMSO at ambient temperature. Figure 1 illustrates the whole synthesis and functionalization process for all AuNPs which were investigated in this study.

The purification of the particles was performed via dialysis against deionized water (visking cellulose tube with molecular weight cut-off of 14.000 Da, containing 50–100 mL reaction solution against 10 L deionized water; 1 h, 3h and 16 h). After purification, the AuNPs were lyophilized and stored at 4°C for several months. Despite the fact that AuNPs are already commercially available, the herein reported AuNPs exhibit a size distribution and surface-modification which is not yet available commercially.

Prior to further functionalization maleimide-AuNP 2a was freshly deprotected to 2b which was then reacted with thiol-EG-BBN(7-14) 5 or thiol-EG-LUG 6, followed by thiol-hexyl-SIDAG 3 for NIR detection or thiol-NODAGA 9 for radiolabeling yielding AuNPs 7, 8, 10, 11 and 12 (Fig 1). The dye is stable in vitro, exhibits very low photobleaching (50 nm) has no impact on the specific tumor-targeting properties of the nanoparticle 38-39, because the big nanoparticles exhibit slower kinetics and therefore the biodistribution is strongly influenced by the nanoparticle itself and not by the tumor vector. The herein reported ultra-small AuNP (80% confluency using 0.05% trypsin/EDTA solution. In contrast to PC3 and A431 cells, LNCaP cells were grown longer in well-plates before using them in in vitro assays (2 days instead of one) and washed more carefully, since they grow less adherent. Bradford assays were performed after uptake, internalization and avidity experiments. For cell uptake studies, Tris-Mn buffer was used (see SI for detailed recipe). Cells were seeded onto a 24 well plate 2–3 days prior to the experiment to obtain ~1.6 × 106 cells per well. Cells were incubated with [68Ga]AuNPs (4.3 MBq/well) for a maximum of 5 h at 37°C. Afterwards, cells were washed carefully 3 × with PBS and lysed 2 × with 1 M NaOH for 10 min at 37°C. The NaOH fractions were collected and measured in a gamma counter (2470 WIZARD2, Perkin Elmer). Internalization assay. Cells were seeded onto a 12 well plate 2–3 days prior to the experiment to reach ~2.4 × 106 cells per well. Cells were incubated with [68Ga]AuNPs (4.4 MBq/well) for 4– 5 h at 37°C with and without blocking substance (60 µg BBN(7-14)/well (M = 940 g/mol) or 24 µg EG-LUG (EG = ethylene glycol) 14 / well (M = 464 g/mol), ~1000 × excess each). After incubation, the cells were washed 3 × with PBS, incubated 2 × with glycine buffer (pH 2.8) for 5 minutes at 37°C and the supernatant fraction was collected for gamma counting. Finally, the cells were lysed 2 × with 1 M NaOH and the NaOH fractions were collected for gamma counting. For

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the different well sizes the recommended working volumes were used for incubation (2 mL for 12 well plate, 1 mL for 24 well plate). All cell experiments were performed in triplicate. Fluorescence microscopy. Cells were seeded onto coverslips for 2 days, then washed with PBS and incubated for 24 h at 37°C in 5% CO2 with the respective media containing different amounts of AuNPs (1–100 µg/mL). Afterwards, the cells were washed with PBS and incubated with CellMask Orange-solution (1X working solution) for 15 min at 37°C. Cells were fixed with 1:1 medium : 4% formaldehyde in PBS for 2 min at ambient temperature and then with 4% formaldehyde in PBS for 15 min at ambient temperature. Cells were then washed 3 × with PBS and coverslips were prepared onto an object plate with Sytox Green-solution (8.3 µM, 10 µL). Fluorescence microscopy was performed on a Leica TCS SP8 confocal microscope with lasers at λ = 488, 552 and 638 nm. Overlays of microscopies were generated using FIJI software (v1.50e). Avidity studies. The avidities of the GRPR-specific or PSMA-specific AuNPs were determined similar to Fischer et al. 53. In brief, cells were seeded on 12- or 24-well plates for two days. 125

Iod-Tyr4-Bombesin (125I-BBN) (~370 kBq, ~81 GBq/µmol) was purchased from Perkin Elmer

and 177Lu-PSMA-617 (~972 MBq, ~53.7 GBq/µmol) was obtained from University Medical Center Mainz. 125I-BBN (0.06 nM, 106.7 pg/mL) was added together with the GRPR-specific AuNP derivatives in medium in different concentrations (0.01–60 µg/mL). 177Lu-PSMA-617 (1 nM, 1.21 ng/mL) was added together with the PSMA-specific AuNP derivatives in medium in different concentrations (0.01–60 µg/mL). Cells were incubated with OptiMEM for 1 h at 37°C, washed 3× with PBS and lysed 2× with 1 M NaOH. The NaOH fractions were collected and measured in the gamma counter. IC50 values were determined using Origin 8.1 software.


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In vivo experiments. The experiments were performed with male SHO mice (Crl:SHOPrkdcscidHrhr) obtained from Charles River (approval number 35-9185.81/G-206/15). 4–5 × 106 cells (PC3 or LNCaP, unsieved) in sterile PBS (100 µL) were inoculated subcutaneously in the left thigh when the mice were 6–8 weeks old. Mouse health and tumor growth were checked daily until the tumor reached a diameter of 4–5 mm (2–3 weeks for PC3, up to 8–12 weeks for LNCaP 54). On the day of injection, the mice were 10–38 weeks old. AuNPs were then injected intravenously into the lateral tail vein and their distribution in vivo was controlled after 1, 3, 6, 24, 48 h and 72 h via optical imaging (In Vivo Xtreme, Bruker, Ettlingen). After the last time point, animals were sacrificed, the organs were harvested and measured ex vivo with the In Vivo Xtreme system. All injections and measurements with mice were performed under anesthesia (2– 3% isoflurane/O2, 2–3 mL/min).

ASSOCIATED CONTENT Supporting Information. The supplementary material contains synthesis data, electron microscopies (EM), dynamic light scattering (DLS), thermogravimetric analysis (TGA) measurements, confocal fluorescence microscopies, fluorescence imaging, NMR spectroscopy measurements, and ex vivo and in vivo data. The following files are available free of charge. Supporting information (PDF).

AUTHOR INFORMATION Corresponding Authors *E-mail: [email protected]. Phone: +49 621 383 6045.


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*E-mail: [email protected]. Phone: +49 621 383 5594. AUTHOR CONTRIBUTIONS The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript. FUNDING SOURCES This work was supported by the Research Campus M2OLIE funded by the German Federal Ministry of Education and Research (BMBF, Funding Code 13GW0091B and 13GW0091E) and the “Zentrales Innovationsprogramm Mittelstand des Bundesministeriums für Wirtschaft und Energie” (AiF Project GmbH, Funding Code KF2035759AK3 and KF3086202AK3). ACKNOWLEDGMENT We would like to thank Tobias Timmermann for measuring NMR spectra and Dr. Uwe Seibold for measuring MALDI-MS spectra and Dr. Mareike Roscher for fruitful discussion concerning the animal experiments. We like to thank Dr. Karsten Richter from the German Cancer Research Center (DKFZ) for measuring the EM. We also want to thank Prof. Dr. Wolfgang Schubert for using the TGA and Prof. Dr. Thorsten Röder for using the DLS at Mannheim University of Applied Sciences. We would like to thank Ms. Anne-Maria Suhr and Ms. Stephanie Riester for their technical assistance in the in vitro and in vivo experiments. ABBREVIATIONS AuNP, gold nanoparticle; CT, computer tomography; TEM, transmission electron microscopy; DLS, dynamic light scattering; TGA, thermogravimetric analysis; NMR, nuclear magnetic resonance spectroscopy; LUG, Lys-urea-Glu motif; BBN, bombesin; PSMA, prostate-specific membrane antigen.


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Gastrin-Releasing Peptide Receptor- and Prostate-Specific Membrane

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