Combining Albumin-Binding Properties and Interaction with Pemetrexed to Improve the Tissue Distribution of Radiofolates
Abstract
:1. Introduction
2. Results
2.1. Biodistribution Studies
2.1.1. Biodistribution in KB and IGROV-1 Tumor-Bearing Mice
2.1.2. Tumor-to-Background Ratios
2.2. In Vivo SPECT/CT Experiments
2.2.1. SPECT/CT Imaging of KB Tumor-Bearing Mice
2.2.2. SPECT/CT Imaging of IGROV-1 Tumor-Bearing Mice
3. Discussion
4. Materials and Methods
4.1. Preparation of [177Lu]Folate
4.2. Cell Culture
4.3. In Vivo Studies
4.4. Biodistribution Studies
4.5. Statistics
4.6. SPECT/CT Studies
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
- Siegel, B.A.; Dehdashti, F.; Mutch, D.G.; Podoloff, D.A.; Wendt, R.; Sutton, G.P.; Burt, R.W.; Ellis, P.R.; Mathias, C.J.; Green, M.A.; et al. Evaluation of 111In-DTPA-folate as a receptor-targeted diagnostic agent for ovarian cancer: Initial clinical results. J. Nucl. Med. 2003, 44, 700–707. [Google Scholar] [PubMed]
- Fisher, R.E.; Siegel, B.A.; Edell, S.L.; Oyesiku, N.M.; Morgenstern, D.E.; Messmann, R.A.; Amato, R.J. Exploratory study of 99mTc-EC20 imaging for identifying patients with folate receptor-positive solid tumors. J. Nucl. Med. 2008, 49, 899–906. [Google Scholar] [CrossRef] [PubMed]
- Leamon, C.P.; Reddy, J.A. Folate-targeted chemotherapy. Adv. Drug Deliv. Rev. 2004, 56, 1127–1141. [Google Scholar] [CrossRef] [PubMed]
- Teng, L.; Xie, J.; Teng, L.; Lee, R.J. Clinical translation of folate receptor-targeted therapeutics. Exp. Opin. Drug Deliv. 2012, 9, 901–908. [Google Scholar] [CrossRef] [PubMed]
- Assaraf, Y.G.; Leamon, C.P.; Reddy, J.A. The folate receptor as a rational therapeutic target for personalized cancer treatment. Drug Resist. Update 2014, 17, 89–95. [Google Scholar] [CrossRef] [PubMed]
- Betzel, T.; Müller, C.; Groehn, V.; Müller, A.; Reber, J.; Fischer, C.R.; Krämer, S.D.; Schibli, R.; Ametamey, S.M. Radiosynthesis and preclinical evaluation of 3′-aza-2′-[18F]fluorofolic acid: A novel PET radiotracer for folate receptor targeting. Bioconjug. Chem. 2013, 24, 205–214. [Google Scholar] [CrossRef] [PubMed]
- Chen, Q.; Meng, X.; McQuade, P.; Rubins, D.; Lin, S.A.; Zeng, Z.; Haley, H.; Miller, P.; Gonzalez Trotter, D.; Low, P.S. Folate-PEG-NOTA-Al18F: A new folate based radiotracer for PET imaging of folate receptor-positive tumors. Mol. Pharm. 2017, 14, 4353–4361. [Google Scholar] [CrossRef] [PubMed]
- Parker, N.; Turk, M.J.; Westrick, E.; Lewis, J.D.; Low, P.S.; Leamon, C.P. Folate receptor expression in carcinomas and normal tissues determined by a quantitative radioligand binding assay. Anal. Biochem. 2005, 338, 284–293. [Google Scholar] [CrossRef] [PubMed]
- Müller, C.; Vlahov, I.R.; Santhapuram, H.K.; Leamon, C.P.; Schibli, R. Tumor targeting using 67Ga-DOTA-Bz-folate—investigations of methods to improve the tissue distribution of radiofolates. Nucl. Med. Biol. 2011, 38, 715–723. [Google Scholar] [CrossRef] [PubMed]
- Müller, C.; Schibli, R. Prospects in folate receptor-targeted radionuclide therapy. Front. Oncol. 2013, 3, 249. [Google Scholar] [CrossRef] [PubMed]
- Curtin, N.J.; Hughes, A.N. Pemetrexed disodium, a novel antifolate with multiple targets. Lancet Oncol 2001, 2, 298–306. [Google Scholar] [CrossRef]
- Müller, C.; Brühlmeier, M.; Schubiger, P.A.; Schibli, R. Effects of antifolate drugs on the cellular uptake of radiofolates in vitro and in vivo. J. Nucl. Med. 2006, 47, 2057–2064. [Google Scholar] [PubMed]
- Müller, C.; Schibli, R.; Forrer, F.; Krenning, E.P.; de Jong, M. Dose-dependent effects of (anti)folate preinjection on 99mTc-radiofolate uptake in tumors and kidneys. Nucl. Med. Biol. 2007, 34, 603–608. [Google Scholar] [CrossRef] [PubMed]
- Müller, C.; Reddy, J.A.; Leamon, C.P.; Schibli, R. Effects of the antifolates pemetrexed and CB3717 on the tissue distribution of 99mTc-EC20 in xenografted and syngeneic tumor-bearing mice. Mol. Pharm. 2010, 7, 597–604. [Google Scholar] [CrossRef] [PubMed]
- Müller, C.; Schibli, R.; Krenning, E.P.; de Jong, M. Pemetrexed improves tumor selectivity of 111In-DTPA-folate in mice with folate receptor-positive ovarian cancer. J. Nucl. Med. 2008, 49, 623–629. [Google Scholar] [CrossRef] [PubMed]
- Reber, J.; Struthers, H.; Betzel, T.; Hohn, A.; Schibli, R.; Müller, C. Radioiodinated folic acid conjugates: Evaluation of a valuable concept to improve tumor-to-background contrast. Mol. Pharm. 2012, 9, 1213–1221. [Google Scholar] [CrossRef] [PubMed]
- Fani, M.; Tamma, M.L.; Nicolas, G.P.; Lasri, E.; Medina, C.; Raynal, I.; Port, M.; Weber, W.A.; Maecke, H.R. In vivo imaging of folate receptor positive tumor xenografts using novel 68Ga-NODAGA-folate conjugates. Mol. Pharm. 2012, 9, 1136–1145. [Google Scholar] [CrossRef] [PubMed]
- Reber, J.; Haller, S.; Leamon, C.P.; Müller, C. 177Lu-EC0800 combined with the antifolate pemetrexed: Preclinical pilot study of folate receptor targeted radionuclide tumor therapy. Mol. Cancer Ther. 2013, 12, 2436–2445. [Google Scholar] [CrossRef] [PubMed]
- Bischof, M.; Weber, K.J.; Blatter, J.; Wannenmacher, M.; Latz, D. Interaction of pemetrexed disodium (alimta, multitargeted antifolate) and irradiation in vitro. Int. J. Rad. Oncol. Biol. Phys. 2002, 52, 1381–1388. [Google Scholar] [CrossRef]
- Bischof, M.; Huber, P.; Stoffregen, C.; Wannenmacher, M.; Weber, K.J. Radiosensitization by pemetrexed of human colon carcinoma cells in different cell cycle phases. Int. J. Rad. Oncol Biol. Phys. 2003, 57, 289–292. [Google Scholar] [CrossRef]
- Oleinick, N.L.; Biswas, T.; Patel, R.; Tao, M.; Patel, R.; Weeks, L.; Sharma, N.; Dowlati, A.; Gerson, S.L.; Fu, P.; et al. Radiosensitization of non-small-cell lung cancer cells and xenografts by the interactive effects of pemetrexed and methoxyamine. Radiother. Oncol. 2016, 121, 335–341. [Google Scholar] [CrossRef] [PubMed]
- Müller, C.; Mindt, T.L.; de Jong, M.; Schibli, R. Evaluation of a novel radiofolate in tumour-bearing mice: Promising prospects for folate-based radionuclide therapy. Eur. J. Nucl. Med. Mol. Imaging 2009, 36, 938–946. [Google Scholar] [CrossRef] [PubMed]
- Müller, C.; Struthers, H.; Winiger, C.; Zhernosekov, K.; Schibli, R. DOTA conjugate with an albumin-binding entity enables the first folic acid-targeted 177Lu-radionuclide tumor therapy in mice. J. Nucl. Med. 2013, 54, 124–131. [Google Scholar] [CrossRef] [PubMed]
- Siwowska, K.; Haller, S.; Bortoli, F.; Benešová, M.; Groehn, V.; Bernhardt, P.; Schibli, R.; Müller, C. Preclinical comparison of albumin-binding radiofolates: Impact of linker entities on the in vitro and in vivo properties. Mol. Pharm. 2017, 14, 523–532. [Google Scholar] [CrossRef] [PubMed]
- Siwowska, K.; Schmid, R.M.; Cohrs, S.; Schibli, R.; Müller, C. Folate receptor-positive gynecological cancer cells: In vitro and in vivo characterization. Pharmaceuticals 2017, 10, 72. [Google Scholar] [CrossRef] [PubMed]
Sample Availability: Samples of the compounds are not available. |
[177Lu]cm13 | ||||
---|---|---|---|---|
- | PMX (1) | - | PMX (1) | |
4 h p.i. | 4 h p.i. | 4 h p.i. | 4 h p.i. | |
Tissue | KB | KB | IGROV-1 | IGROV-1 |
n = 5 | n = 5 | n = 4 | n = 4 | |
Blood | 7.32 ± 0.85 | 9.13 ± 0.89 | 7.88 ± 1.70 | 10.8 ± 1.43 |
Lung | 4.33 ± 0.44 | 4.92 ± 0.39 | 4.47 ± 0.97 | 6.14 ± 0.97 |
Spleen | 1.51 ± 0.15 | 1.45 ± 0.06 | 1.74 ± 0.15 | 2.16 ± 0.45 |
Kidneys | 26.5 ± 1.20 | 15.8 ± 2.60 **** | 26.9 ± 2.90 | 16.9 ± 3.10 *** |
Stomach | 1.37 ± 0.35 | 1.41 ± 0.19 | 1.58 ± 0.47 | 1.83 ± 0.39 |
Intestines | 1.29 ± 0.42 | 1.38 ± 0.32 | 1.10 ± 0.18 | 1.12 ± 0.20 |
Liver | 3.88 ± 0.49 | 3.31 ± 0.43 | 3.27 ± 0.49 | 3.38 ± 0.56 |
Muscle | 1.92 ± 0.25 | 1.55 ± 0.28 | 1.17 ± 0.43 | 1.28 ± 0.38 |
Bone | 1.55 ± 0.10 | 1.67 ± 0.24 | 1.38 ± 0.30 | 1.57 ± 0.25 |
Tumor | 22.4 ± 4.50 | 17.6 ± 0.90 *** | 31.5 ± 5.60 | 29.2 ± 8.80 |
Salivary glands | 6.78 ± 0.57 | 5.84 ± 1.25 | 6.17 ± 0.49 | 6.18 ± 0.88 |
[177Lu]cm13 | ||||
---|---|---|---|---|
- | PMX (1) | PMX (2) | PMX (3) | |
24 h p.i. | 24 h p.i. | 24 h p.i. | 24 h p.i. | |
Tissue | KB | KB | KB | KB |
n = 4 | n = 5 | n = 4 | n = 4 | |
Blood | 1.28 ± 0.23 | 1.39 ± 0.14 | 1.37 ± 0.17 | 1.31 ± 0.14 |
Lung | 1.74 ± 0.45 | 1.69 ± 0.22 | 1.66 ± 0.15 | 1.60 ± 0.35 |
Spleen | 0.69 ± 0.14 | 0.79 ± 0.13 | 0.80 ± 0.13 | 0.72 ± 0.15 |
Kidneys | 30.9 ± 3.90 | 24.7 ± 5.70 ** | 21.8 ± 0.70 **** | 21.0 ± 4.70 **** |
Stomach | 0.77 ± 0.19 | 0.70 ± 0.20 | 0.80 ± 0.14 | 0.63 ± 0.21 |
Intestines | 0.27 ± 0.07 | 0.47 ± 0.14 | 0.30 ± 0.07 | 0.34 ± 0.06 |
Liver | 2.46 ± 0.16 | 1.91 ± 0.44 | 2.04 ± 0.57 | 2.05 ± 0.05 |
Muscle | 1.56 ± 0.10 | 1.31 ± 0.25 | 1.17 ± 0.20 | 1.50 ± 0.49 |
Bone | 1.09 ± 0.31 | 0.97 ± 0.15 | 0.85 ± 0.06 | 0.95 ± 0.16 |
Tumor | 18.6 ± 6.80 | 22.1 ± 3.60 | 22.4 ± 3.20 | 20.9 ± 5.10 |
Salivary glands | 4.18 ± 0.62 | 3.71 ± 0.33 | 3.39 ± 0.30 | 3.86 ± 0.44 |
[177Lu]cm13 | ||||
---|---|---|---|---|
- | PMX (1) | PMX (2) | PMX (3) | |
24 h p.i. | 24 h p.i. | 24 h p.i. | 24 h p.i. | |
Tissue | IGROV-1 | IGROV-1 | IGROV-1 | IGROV-1 |
n = 4 | n = 5 | n = 5 | n = 5 | |
Blood | 1.46 ± 0.19 | 1.97 ± 0.15 | 2.21 ± 0.29 | 2.08 ± 0.31 |
Lung | 1.88 ± 0.24 | 2.16 ± 0.23 | 2.23 ± 0.25 | 2.21 ± 0.33 |
Spleen | 0.92 ± 0.17 | 1.19 ± 0.26 | 1.26 ± 0.33 | 1.20 ± 0.30 |
Kidneys | 34.0 ± 2.00 | 26.2 ± 3.50 *** | 21.8 ± 2.00 **** | 20.8 ± 3.40 **** (4) |
Stomach | 0.69 ± 0.19 | 0.69 ± 0.31 | 0.78 ± 0.13 | 0.65 ± 0.17 |
Intestines | 0.49 ± 0.12 | 0.44 ± 0.08 | 0.48 ± 0.07 | 0.43 ± 0.14 |
Liver | 2.75 ± 0.57 | 2.47 ± 0.51 | 2.73 ± 0.65 | 2.41 ± 0.49 |
Muscle | 1.52 ± 0.19 | 1.36 ± 0.37 | 1.28 ± 0.52 | 1.28 ± 0.32 |
Bone | 0.95 ± 0.11 | 0.96 ± 0.12 | 1.02 ± 0.17 | 0.95 ± 0.10 |
Tumor | 37.7 ± 5.10 | 40.7 ± 9.00 | 38.6 ± 3.50 | 32.9 ± 5.30 (5) |
Salivary glands | 4.43 ± 0.63 | 4.28 ± 0.43 | 3.95 ± 1.03 | 3.77 ± 0.45 |
© 2018 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
Share and Cite
Müller, C.; Guzik, P.; Siwowska, K.; Cohrs, S.; Schmid, R.M.; Schibli, R. Combining Albumin-Binding Properties and Interaction with Pemetrexed to Improve the Tissue Distribution of Radiofolates. Molecules 2018, 23, 1465. https://doi.org/10.3390/molecules23061465
Müller C, Guzik P, Siwowska K, Cohrs S, Schmid RM, Schibli R. Combining Albumin-Binding Properties and Interaction with Pemetrexed to Improve the Tissue Distribution of Radiofolates. Molecules. 2018; 23(6):1465. https://doi.org/10.3390/molecules23061465
Chicago/Turabian StyleMüller, Cristina, Patrycja Guzik, Klaudia Siwowska, Susan Cohrs, Raffaella M. Schmid, and Roger Schibli. 2018. "Combining Albumin-Binding Properties and Interaction with Pemetrexed to Improve the Tissue Distribution of Radiofolates" Molecules 23, no. 6: 1465. https://doi.org/10.3390/molecules23061465