Article Cite This: Bioconjugate Chem. XXXX, XXX, XXX−XXX
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F‑Radiolabeling and In Vivo Analysis of SiFA-Derivatized Polymeric Core−Shell Nanoparticles 18
Sheldon Berke,† Anne-Larissa Kampmann,†,‡ Melinda Wuest,† Justin J. Bailey,† Britta Glowacki,§ Frank Wuest,† Klaus Jurkschat,*,§ Ralf Weberskirch,*,‡ and Ralf Schirrmacher*,† †
Department of Oncology, University of Alberta, 6820 116 Street, Edmonton, Alberta T6G 2R3, Canada Department of Organic Chemistry and §Department of Inorganic Chemistry, Faculty for Chemistry and Chemical Biology, Technische Universität Dortmund, Otto-Hahn-Strasse 6, 44227 Dortmund, Germany
‡
S Supporting Information *
ABSTRACT: Nanoparticles represent the most widely studied drug delivery systems targeting cancer. Polymeric nanoparticles can be easily generated through a microemulsion polymerization. Herein, the synthesis, radiolabeling, and in vivo evaluation of nanoparticles (NPs) functionalized by an organosilicon fluoride acceptor (SiFA) are reported which can be radiolabeled without further chemical modifications. Four nanoparticles in the sub-100 nm range with distinct hydrodynamic diameters of 20 nm (NP1), 33 nm (NP2), 45 nm (NP3), and 72 nm (NP4), respectively, were synthesized under size-controlled conditions. The SiFA-labeling building block acted as an initiator for the polymerization of polymer P1. The nanoparticles were radiolabeled with fluorine-18 (18F) through simple isotopic exchange (IE) and analyzed in vivo in a murine mammary tumor model (EMT6). The facile 18F radiolabeling SiFA methodology, performed in ethanol under mild reaction conditions, gave radiochemical yields (RCYs) of 19−26% and specific activities (SA) of 0.2−0.3 GBq/mg. Based on preclinical PET analysis, the tumor uptake and clearance profiles were analyzed depending on particle size. The nanoparticle size of 33 nm showed the highest tumor accumulation of SUVmean 0.97 (= 4.4%ID/g) after 4 h p.i. through passive diffusion based on the Enhanced Permeability and Retention (EPR) effect. Overall, this approach exhibits a simple, robust, and reliable synthesis of 18F radiolabeled polymeric nanoparticles with a favorable in vivo evaluation profile. This approach represents a straightforward synthetically accessible alternative to produce radiolabeled nanoparticles without any further surface modification to attach a radioisotope.
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100−150 nm.16 There are some discrepancies in the literature regarding uptake levels of particles >100 nm over particles [18F]NP3 and 4 (Table 1). After 4 h p.i. resulting TMRs were therefore highest for [18F]NP1 and [18F]NP2 versus [18F]NP3 and [18F]NP4, respectively (also Table 1). In summary, comparing these four [18F]NPs, [18F]NP2 with a size of ∼33 nm appears to be the ideal candidate for EPR-mediated tumor uptake as demonstrated here for the EMT6 tumor model. Our findings fit well into the concept of Wittrup et al.44 and other studies with radiolabeled inorganic nanoparticles48 indicating that particle sizes of ∼20− 30 nm result in optimal tumor uptake through passive targeting in conjunction with sufficient renal and hepatobilary clearance parameters and optimal blood circulation time.
introducing a payload into the NP core to achieve EPRmediated PET guided drug delivery as well as enhancing the overall tumor uptake.
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EXPERIMENTAL PROCEDURES General. All chemicals were purchased from Sigma−Aldrich (Steinheim, Germany), Acros (Nidderau, Germany), or ABCR (Karlsruhe, Germany), and were used as received unless otherwise stated. (4-(Bromomethyl)phenyl)di-tert-butylfluorosilane (SiFA-Br, synthesized according to Jurkschat et al.39), 2methyl-2-oxazoline (MeOx), 2-heptyl-2-oxazoline (HepOx, synthesized according to Seeliger et al.49), 2-(5-pentyl-[(1,2,3triazol)-4-yl-methacrylat)]-2-oxazoline (PenOx, synthesized according to ten Brummelhuis et al.50), and acetonitrile (MeCN) for polymer preparation were dried by heating at reflux over CaH2 under a dry argon atmosphere and subsequent distillation prior to use. Dry solvents were purified using a purification system from M Braun Glovebox Technology PLC 800. The dialysis membranes were composed of regenerated cellulose from ZelluTrans/Roth V-Series with a MWCO = 1000. The NMR spectra were recorded on a Bruker Avance300 DP X (300.1 MHz) and 400 DR X (400.1 MHz) at 292 K or the spectra were measured on 500 MHz spectrometer AVANCE-III HDX-500 with 5 mm nitrogen cooled Prodigy H(C,N) probe from Bruker BioSpin GmbH or on a 400 MHz NMR spectrometer Nanobay AVANCE-III HD-400 with 5 mm BBFOsmart probe from Bruker BioSpin GmbH. The spectra were calibrated using the solvent signals (CDCl3 7.26 ppm). Size exclusion chromatography (SEC) was performed on a Viscotec GPCmax equipped with a refractive index (RI) detector (tempered to 55 °C) using a Tosoh TSKgel GMHHRM (1× precolumn +2× 5.0 μm pores) column set. N,NDimethylformamide was used as eluent (DMF + LiBr, 20 mmol) at a flow rate of 0.7 mL min−1 at 60 °C. GPC columns were calibrated with poly(styrene) standards (from Viscotec). Prior to each measurement, the samples were filtered through a 0.2 μm Teflon filter (VWR) to remove particles. Dynamic light scattering experiments were performed using a Malvern Zetasizer Nano S (ZEN 1600). A 4 mW He−Ne laser (633 nm wavelength) with a fixed detector angle of 173° was used for these measurements. About 1 mL of dust-free sample was transferred to a special light scattering cell. The experiments were carried out in water and methanol at 25 °C and were repeated five times. For further interpretation, we used the average number values of these five measurements. A 1.0 mg/ mL solution of NP in water was incubated on a copper grid for 30 s at room temperature and then stained with 2% phosphotungstic acid for 15 s. A Philips/FEI (Morgagni) 410 Transmission Electron Microscope with CCD camera was used to take the NP micrographs, with the assistance of the University of Alberta Department of Biological Sciences Microscopy Service Unit. Synthesis of Poly[SiFA-(2-methyl-2-oxazoline) 31block-{(2-heptyl-2-oxazoline)4-co-(2-pentynyl-2-oxazoline)5}-OH] (P1). In a Schlenk tube, 1000 μL 2-methyl-2oxazoline (MOx, 30 equiv), 129.8 mg SiFA-Br (1 equiv) and 5 mL dry acetonitrile were mixed under inert conditions (argon). The reaction mixture was stirred at 110 °C for 2.5 h. Then 265 μL 2-heptyl-2-oxazoline (4 equiv) and 215 μL 2-pentynyl-2oxazoline (4 equiv) was added simultaneously and heated at 120 °C for 6 h. At room temperature, 1 mL of a methanolic sodium hydroxide (pH 8) solution (as a terminating reagent) was added and the reaction mixture was stirred for 30 min at
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CONCLUSION We have synthesized four novel SiFA-functionalized polymeric core−shell nanoparticles NP1-NP4 of variable sizes in the sub100 nm range (20−72 nm) and developed a “green” radiolabeling methodology utilizing simple 18F-SiFA IE in ethanol, which allows for a straightforward radiolabeling of three out of four SiFA-NPs. In addition, in vivo analysis revealed optimal tumor uptake as well as high TMR for [18F]NP2 with a size of ∼33 nm. These results are very promising for developing NPs for functional molecular imaging and future NP-based targeted therapies. Additionally, this labeling approach without need for additional chemical modification is an excellent alternative to chelator-functionalized nanoparticle systems (e.g., to chelate 64Cu), where the chelator is attached post NP formation. Further research in the future will focus on D
DOI: 10.1021/acs.bioconjchem.7b00630 Bioconjugate Chem. XXXX, XXX, XXX−XXX
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Bioconjugate Chemistry room temperature. The solid residue was filtered off and the solvent was removed at reduced pressure. Then water was added and the crude product was dialyzed (MWCO = 1000) for 24 h and afterward lyophilized. The polymer was purified by reprecipitation in cold diethyl ether (3 × 200 mL). The precipitated polymer was removed by centrifugation and dried under high pressure. 1H NMR (500.13 MHz, CDCl3): δ (ppm) = 0.87 (s, 11H, CH3,HOx), 1.04 (s, 18H, C(CH3),SiFA), 1.29 (s, 30H, 4 × CH2,HOx), 1.59 (brs, 8H, CH2,HOx), 1.83 (brs, 10H, CH2,AOx), 2.06−2.13 (m, 102H, CH3,MOx, CH2,AOx), 2.25−2.60 (m, 25H), 3.40 (m, 160H, CH2−CH2,backbone), 4.53 (brs, 2H, CH2,SiFA), 7.17/7.62 (brs, 2H/2H, phenyl,SiFA). 29Si NMR (59.63 MHz, CDCl3): δ (ppm) = 11.61, 16.60 (2J(29Si−19F) = 298.74 Hz). 19F-NMR (282.4 MHz, CDCl3): δ (ppm) = −188.13. SEC: PDI = 1.08, Mn = 5500 g/mol. Nanoparticle Formation. NP1-NP4 were formed in a microemulsion polymerization process. 60 mg P1 was dissolved in 5 mL millipure water, then 30 μL (50 wt %, NP1), 60 μL (100 wt %, NP2), 90 μL (150 wt %, NP3) or 120 μL (200 wt %, NP4) HDDMA, 5 μL AIBN solution (50 mg/mL in 1,4dioxane), and 5 μL heptadecane were added. After 30 min degassing with argon, the mixture was sonicated for 5 min. The temperature was increased to 65 °C and kept overnight. After cooling the reaction mixture to ambient temperature, the solution was centrifuged for 30 min at 4400 rpm. The aqueous layer was taken and centrifuged again (30 min, 4400 rpm). The clear aqueous phase was lyophilized. The white solid thus obtained was dissolved in chloroform and precipitated by adding cold diethyl ether. After centrifugation, the white solid was dried in vacuo. Production of 18F. 18F was produced using a TR19/9 cyclotron (Advanced Cyclotron Systems Inc., Richmond, British Columbia, Canada) through the 18O(p,n)18F nuclear reaction with oxygen-18 enriched water (98%; 3.0 mL, Rotem; Germany). 18F containing water [1.151 GBq, 1.5 mL] was then passed through a Sep-Pak Light carbonate QMA cartridge (Waters) preconditioned with 15 mL of water. The cartridge was dried by airflow and a Kryptofix 222/K2CO3 solution (0.032 mmol, 12.0 mg of Kryptofix 222 and 12 μmol, 1.66 mg of K2CO3 in acetonitrile/water (96 μL/4 μL)) was passed through the QMA cartridge to elute trapped 18F into a 5.0 mL conical glass vial. The solvent was removed at 90 °C under reduced pressure and a stream of nitrogen gas. The residue was dried azeotropically with 1.0 mL of anhydrous acetonitrile under a stream of nitrogen gas. The procedure was done twice at 90 °C. For radiolabeling, the residues thus obtained were dissolved in ethanol (300 μL, for NP2-NP4) or acetonitrile (300 μL, for NP1). Radiosyntheses of [18F]NP1. NP1 (0.6 mg) was dissolved in acetonitrile (300 μL) and combined with 744 MBq of 18F in acetonitrile (0.18 mL). The reaction mixture was stirred for 20 min at rt. The progress of the reaction was monitored via paper chromatography (PC, SI Figure S4) with water as eluent. The reaction solution was spotted on PC strips in 2.0 μL aliquots and developed in a water elution chamber. The solvent was allowed to travel 8 cm across the PC strip and was dried under air flow. Once completely dry, the PC strips were analyzed via a gamma radioactivity single trace TLC scanner (18F RF: 1.0, [18F]NP1:0.0). Subsequently the reaction vial was opened and subjected to a nitrogen airflow. The solvent was evaporated at 80 °C for 5 min before being redissolved in a 50%/50% saline/ ethanol solution (100 μL). NAP-10 size exclusion columns were preconditioned with 20 mL of saline. The entire NP1 18F
labeling reaction solution was loaded onto the NAP-10 column and eluted with saline solution. [18F]NP1 eluted from 1.0 to 1.9 mL with a radioactivity of 169 MBq (RCY: 23%, nondecay corrected). An aliquot was taken in the elution range of 1.3 to 1.6 mL to produce a concentrated solution of 69 MBq in 300 μL. This product was then tested for purity via radio-TLC and used for in vivo animal studies. Radiosyntheses of [18F]NP2-NP4. NP ((NP2 (0.3 mg), NP3 (0.6 mg), or NP4 (0.3 mg)) was dissolved in ethanol (300 μL) and combined with 500−2000 MBq of 18F-fluoride solution in ethanol (100−300 mL). The reaction mixture was heated at 65 °C for 30 min and allowed to cool to rt for 5 min. The reaction progress was monitored via paper TLC with water as eluent. The reaction solution was spotted on paper TLC strips in 2.0 μL aliquots and developed in a water elution chamber. The solvent was allowed to travel 8 cm across TLC strip and then removed and dried. Once completely dry, TLC strips were assessed via gamma radioactivity single trace TLC scanner. (fluorine-18 RF: 1.0, 18F-NP: 0.0). NAP-10 columns were preconditioned with 20 mL of saline solution. The entire NP 18F labeling reaction solution was loaded onto the NAP-10 column and eluted with saline solution. [18F]NP eluted from 1.0 to 1.9 mL (for all NPs) with radiochemical yields ranging between 19% and 26% (nondecay corrected). An elution fraction was taken in the elution range of 1.2 to 1.6 mL to produce a concentrated solution of 80.4 MBq in 400 μL. This product was then tested for purity via radio-TLC and used for in vivo animal studies. In Vivo Experiments. All animal experiments were carried out in accordance with guidelines of the Canadian Council on Animal Care and were approved by the local Animal Ethics Committee of the Cross Cancer Institute, Edmonton. Normal female BALB/c mice (age 8−12 weeks) were obtained from Charles-River (Saint-Constant, Quebec, Canada). Mice were housed in ventilated cages and provided food and water ad libitum. Murine EMT6 cells (1 × 106 cells in 100 μL PBS) were injected into the upper left shoulder of 6−8 months old female BALB/c mice. Tumors were allowed to grow for 9−11 days reaching a size of ∼300−500 mm3. The animals were anesthetized through inhalation of isoflurane in 100% oxygen (gas flow, 1 L/min), and body temperature was maintained at 37 °C. Mice were immobilized in the prone position in the center of the field of view of an INVEON PET scanner (Siemens Preclinical Solutions, Knoxville, TN, USA). The amount of radioactivity present in the injection solution in a 0.5 mL syringe was determined with a dose calibrator (Atomlab 300, Biodex Medical Systems, Shirley, NY, USA), which was cross-calibrated with the scanner. [18F]-NP1 was injected into a total of 3 mice. Three PET scans with a duration of 20 min were performed at 1 h post injection (one of them as a dynamic scan over the entire 1 h) after injection of 5.05−5.98 MBq (50−70 μL saline). An additional 20 min static scan was done at 4 h p.i. Mice were under anesthesia for the first hour p.i. and awake between the first and the second scan. [18F]NP2, [18F]NP3, and [18F]NP4 were measured in a similar manner as described for [18F]NP1 with always one dynamic scan per radiolabeled nanoparticle over 1 h p.i. and additional static scans at 1 and 4 h p.i. The following radioactivity amounts were injected: [18F]NP2 3.44−4.55 MBq (110−180 μL saline; n = 4 mice), [18F]NP3 3.87−4.47 MBq (120−160 μL; n = 3 mice), and [18F]NP4 3.90−5.35 MBq (60−110 μL; n = 4 mice), respectively. Dynamic list mode data were sorted into sinograms with 54 time frames (10 × 2 s, 8 × 5 s, 6 × 10 s, E
DOI: 10.1021/acs.bioconjchem.7b00630 Bioconjugate Chem. XXXX, XXX, XXX−XXX
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6 × 20 s, 8 × 60 s, 10 × 120 s, 5 × 300 s). The frames as well as all static files were reconstructed using the maximum a posteriori (MAP) reconstruction mode. No correction for partial volume effects was performed. The image files were further processed using the ROVER v 2.0.51 software (ABX GmbH, Radeberg, Germany). Masks defining 3D regions of interest (ROI) were set and the ROIs were defined by thresholding. ROIs covered all visible tumor mass of the subcutaneous tumors, and the thresholds were defined by 50% of the maximum radioactivity uptake level for each EMT6 tumor in each animal. Mean standardized uptake values [SUVmean = (activity/mL tissue)/(injected activity/body weight), mL/kg] were calculated for each ROI. Time-activity curves (TAC) were generated from the dynamic scans. All semiquantified PET data are presented as means ± SEM from n experiments. Time-activity curves and bar graph diagrams were constructed using GraphPad Prism 4.0 (GraphPad Software). Statistical differences were tested by unpaired Student’s t test and were considered significant for p < 0.05.
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ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.bioconjchem.7b00630. Analytical data of polymer P1, DLS results of NP1−4 in methanol, TEM of NP2−3, RCYs, PET images and time activity curves of [18F]NP1−4 (PDF)
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Article
AUTHOR INFORMATION
Corresponding Authors
*E-mail:
[email protected]. Phone: +49(231) 755-3800. *E-mail:
[email protected]. Phone: +49(231) 755-3863. *E-mail:
[email protected]. Phone: +1(514) 398-8527. ORCID
Anne-Larissa Kampmann: 0000-0003-1235-3332 Ralf Schirrmacher: 0000-0002-7098-3036 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS This project was financially supported by NSERC, Natural Sciences and Engineering Research Council of Canada to R.S, and by DFG, German Research Foundation (KA 4766/1-1) to A.-L. K. and R.S. We thank Prof. Jonathan Veinot from the Faculty of Sciences (University of Alberta) and the Edmonton PET Center (Cross Cancer Institute) for their technical support. The authors also gratefully acknowledge Prof. Jörg C. Tiller (Department of Biochemical and Chemical Engineering, TU Dortmund) and Prof. Heinz Rehage for providing the DLS device.
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ABBREVIATIONS EPR, enhanced permeability and retention; IE, isotopic exchange; i.v., intravenously; PET, positron emission tomography; p.i., post injection; RCY, radiochemical yield; SA, specific activity; SUV, standardized uptake value; TMR, tumorto-muscle-ratio F
DOI: 10.1021/acs.bioconjchem.7b00630 Bioconjugate Chem. XXXX, XXX, XXX−XXX
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Bioconjugate Chemistry
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DOI: 10.1021/acs.bioconjchem.7b00630 Bioconjugate Chem. XXXX, XXX, XXX−XXX
