Amino modified metal-organic frameworks as pH-responsive nanoplatforms for safe delivery of camptothecin

[EN] MIL-100(Fe) and MIL-101(Fe) metal-organic frameworks (MOFs) are excellent vehicles for drug delivery systems (DDSs) due to their high biocompatibility and stability in physiological fluids, as well as their pore diameter in the mesoporous range. Although they are appropriate for the internal diffusion of 20-(S)-camptothecin (CPT), a strongly cytotoxic molecule with excellent antitumor activity, no stable delivery system has been proposed so far for this drug based in MOFs. We here present novel DDSs based in amine functionalized MIL-100(Fe) and MIL-101(Fe) nanoMOFs with covalently bonded CPT. These CPT nanoplatforms are able to incorporate almost 20% of this molecule and show high stability at physiological pH, with no non-specific release. Based on their surface charge, some of these CPT loaded nanoMOFs present improved cell internalization in in vitro experiments. Moreover, a strong response to acid pH is observed, with up to four fold drug discharge at pH 5, which boost intracellular release by endosomolytic activity. These novel DDSs will help to achieve safe delivery of the very cytotoxic CPT, allowing to reduce the therapeutic dose and minimizing drug secondary effects. (C) 2019 Elsevier Inc. All rights reserved.Financial support of the Spanish Ministry of Economy and Competitiveness (projects TEC2016-80976-R and SEV-2016-0683) is gratefully acknowledged. A.C.G. thanks the La Caixa Foundation for a Ph.D. scholarship. We fully appreciate the assistance of the Electron Microscopy Service of the Universitat Politecnica de Valencia.Cabrera-García, A.; Checa-Chavarria, E.; Rivero-Buceta, EM.; Moreno Manzano, V.; Fernandez Jover, E.; Botella Asuncion, P. (2019). Amino modified metal-organic frameworks as pH-responsive nanoplatforms for safe delivery of camptothecin. Journal of Colloid and Interface Science. 541:163-174. https://doi.org/10.1016/j.jcis.2019.01.042S16317454

Development of a Prodrug of Camptothecin for Enhanced Treatment of Glioblastoma Multiforme

[EN] A novel therapeutic approach for glioblastoma multiforme (GBM) therapy has been carried out through in vitro and in vivo testing by using the prodrug camptothecin-20-O-(5-aminolevulinate) (CPT-ALA). The incorporation of ALA to CPT may promote uptake of the cytotoxic molecule by glioblastoma cells where the heme synthesis pathway is active, improving the therapeutic action and reducing the side effects over healthy tissue. The antitumor properties of CPT-ALA have been tested on different GBM cell lines (U87, U251, and C6) as well as in an orthotopic GBM model in rat, where potential toxicity in central nervous system cells was analyzed. In vitro results indicated no significant differences in the cytotoxic effect over the different GBM cell lines for CPT and CPT-ALA, albeit cell mortality induced by CPT over normal cell lines was significantly higher than CPT-ALA. Moreover, intracranial GBM in rat was significantly reduced (30% volume) with 2 weeks of CPT-ALA treatment with no significant side effects or alterations to the well-being of the animals tested. 5-ALA moiety enhances CPT diffusion into tumors due to solubility improvement and its metabolic-based targeting, increasing the CPT cytotoxic effect on malignant cells while reducing CPT diffusion to other proliferative healthy tissue. We demonstrate that CPT-ALA blocks proliferation of GBM cells, reducing the infiltrative capacity of GBM and promoting the success of surgical removal, which improves life expectancy by reducing tumor recurrence.Financial support from Spanish Ministry of Economy and Competitiveness (Projects PID2019-111436RB-C21 and SEV2016-0683) and the Generalitat Valenciana (Project PROMETEO/2017/060) is gratefully acknowledged. We thank Prof. Luis Fernandez (Group of Structural Mechanics and Materials Modellings-GEMM, University of Zaragoza, Spain) for donation of human GBM cell lines. We are grateful to Dr. Lawrence Humphreys (CIBER-BBN) for critical reading of the manuscriptCheca-Chavarria, E.; Rivero-Buceta, EM.; Sanchez Martos, MA.; Martinez Navarrete, G.; Soto-Sanchez, C.; Botella Asuncion, P.; Fernandez Jover, E. (2021). Development of a Prodrug of Camptothecin for Enhanced Treatment of Glioblastoma Multiforme. Molecular Pharmaceutics. 18(4):1558-1572. https://doi.org/10.1021/acs.molpharmaceut.0c009681558157218

Engineered Contrast Agents in a Single Structure for T1-T2 Dual Magnetic Resonance Imaging

[EN] The development of contrast agents (CAs) for Magnetic Resonance Imaging (MRI) with T-1-T-2 dual-mode relaxivity requires the accurate assembly of T-1 and T-2 magnetic centers in a single structure. In this context, we have synthesized a novel hybrid material by monitoring the formation of Prussian Blue analogue Gd(H2O)(4)[Fe(CN)(6)] nanoparticles with tailored shape (from nanocrosses to nanorods) and size, and further protection with a thin and homogeneous silica coating through hydrolysis and polymerization of silicate at neutral pH. The resulting Gd(H2O)(4)[Fe(CN)(6)]@SiO2 magnetic nanoparticles are very stable in biological fluids. Interestingly, this combination of Gd and Fe magnetic centers closely packed in the crystalline network promotes a magnetic synergistic effect, which results in significant improvement of longitudinal relaxivity with regards to soluble Gd3+ chelates, whilst keeping the high transversal relaxivity inherent to the iron component. As a consequence, this material shows excellent activity as MRI CA, improving positive and negative contrasts in T-1- and T-2-weighted MR images, both in in vitro (e.g., phantom) and in vivo (e.g., Sprague-Dawley rats) models. In addition, this hybrid shows a high biosafety profile and has strong ability to incorporate organic molecules on the surface with variable functionality, displaying great potential for further clinical application.Financial support of the Spanish Ministry of Economy and Competitiveness (projects TEC2016-80976-R and SEV-2016-0683) is gratefully acknowledged. Dr E. M. Rivero thanks the Cursol Foundation for a post-doctoral scholarship. A. C. G. also thanks the La Caixa Foundation for a Ph.D. scholarship. We fully appreciate the assistance of the Electron Microscopy Service of the UPV and INSCANNER S.L.Cabrera-García, A.; Checa-Chavarria, E.; Pacheco-Torres, J.; Bernabeu-Sanz, A.; Vidal Moya, JA.; Rivero-Buceta, EM.; Sastre Navarro, GI.... (2018). Engineered Contrast Agents in a Single Structure for T1-T2 Dual Magnetic Resonance Imaging. Nanoscale. 10(14):6349-6360. https://doi.org/10.1039/c7nr07948fS634963601014Bolan, P. J., Nelson, M. T., Yee, D., & Garwood, M. (2005). Imaging in breast cancer: Magnetic resonance spectroscopy. Breast Cancer Research, 7(4). doi:10.1186/bcr1202Mitchell, R. E., Katz, M. H., McKiernan, J. M., & Benson, M. C. (2005). The evaluation and staging of clinically localized prostate cancer. Nature Clinical Practice Urology, 2(8), 356-357. doi:10.1038/ncpuro0260Colombo, M., Carregal-Romero, S., Casula, M. F., Gutiérrez, L., Morales, M. P., Böhm, I. B., … Parak, W. J. (2012). Biological applications of magnetic nanoparticles. Chemical Society Reviews, 41(11), 4306. doi:10.1039/c2cs15337hMi, P., Kokuryo, D., Cabral, H., Wu, H., Terada, Y., Saga, T., … Kataoka, K. (2016). A pH-activatable nanoparticle with signal-amplification capabilities for non-invasive imaging of tumour malignancy. Nature Nanotechnology, 11(8), 724-730. doi:10.1038/nnano.2016.72Cheng, W., Ping, Y., Zhang, Y., Chuang, K.-H., & Liu, Y. (2013). Magnetic Resonance Imaging (MRI) Contrast Agents for Tumor Diagnosis. Journal of Healthcare Engineering, 4(1), 23-46. doi:10.1260/2040-2295.4.1.23Lauffer, R. B. (1987). Paramagnetic metal complexes as water proton relaxation agents for NMR imaging: theory and design. Chemical Reviews, 87(5), 901-927. doi:10.1021/cr00081a003Caravan, P., Ellison, J. J., McMurry, T. J., & Lauffer, R. B. (1999). Gadolinium(III) Chelates as MRI Contrast Agents:  Structure, Dynamics, and Applications. Chemical Reviews, 99(9), 2293-2352. doi:10.1021/cr980440xDavis, M. E., Chen, Z., & Shin, D. M. (2008). Nanoparticle therapeutics: an emerging treatment modality for cancer. Nature Reviews Drug Discovery, 7(9), 771-782. doi:10.1038/nrd2614Lee, N., & Hyeon, T. (2012). Designed synthesis of uniformly sized iron oxide nanoparticles for efficient magnetic resonance imaging contrast agents. Chem. Soc. Rev., 41(7), 2575-2589. doi:10.1039/c1cs15248cHasebroock, K. M., & Serkova, N. J. (2009). Toxicity of MRI and CT contrast agents. Expert Opinion on Drug Metabolism & Toxicology, 5(4), 403-416. doi:10.1517/17425250902873796Khawaja, A. Z., Cassidy, D. B., Al Shakarchi, J., McGrogan, D. G., Inston, N. G., & Jones, R. G. (2015). Revisiting the risks of MRI with Gadolinium based contrast agents—review of literature and guidelines. Insights into Imaging, 6(5), 553-558. doi:10.1007/s13244-015-0420-2Lee, N., Yoo, D., Ling, D., Cho, M. H., Hyeon, T., & Cheon, J. (2015). Iron Oxide Based Nanoparticles for Multimodal Imaging and Magnetoresponsive Therapy. Chemical Reviews, 115(19), 10637-10689. doi:10.1021/acs.chemrev.5b00112Zhou, Z., Bai, R., Munasinghe, J., Shen, Z., Nie, L., & Chen, X. (2017). T1–T2 Dual-Modal Magnetic Resonance Imaging: From Molecular Basis to Contrast Agents. ACS Nano, 11(6), 5227-5232. doi:10.1021/acsnano.7b03075Shin, T.-H., Choi, Y., Kim, S., & Cheon, J. (2015). Recent advances in magnetic nanoparticle-based multi-modal imaging. Chemical Society Reviews, 44(14), 4501-4516. doi:10.1039/c4cs00345dBae, K. H., Kim, Y. B., Lee, Y., Hwang, J., Park, H., & Park, T. G. (2010). Bioinspired Synthesis and Characterization of Gadolinium-Labeled Magnetite Nanoparticles for Dual ContrastT1- andT2-Weighted Magnetic Resonance Imaging. Bioconjugate Chemistry, 21(3), 505-512. doi:10.1021/bc900424uPeng, Y.-K., Lui, C. N. P., Chen, Y.-W., Chou, S.-W., Raine, E., Chou, P.-T., … Tsang, S. C. E. (2017). Engineering of Single Magnetic Particle Carrier for Living Brain Cell Imaging: A Tunable T1-/T2-/Dual-Modal Contrast Agent for Magnetic Resonance Imaging Application. Chemistry of Materials, 29(10), 4411-4417. doi:10.1021/acs.chemmater.7b00884Choi, J., Lee, J.-H., Shin, T.-H., Song, H.-T., Kim, E. Y., & Cheon, J. (2010). Self-Confirming «AND» Logic Nanoparticles for Fault-Free MRI. Journal of the American Chemical Society, 132(32), 11015-11017. doi:10.1021/ja104503gShin, T.-H., Choi, J., Yun, S., Kim, I.-S., Song, H.-T., Kim, Y., … Cheon, J. (2014). T1andT2Dual-Mode MRI Contrast Agent for Enhancing Accuracy by Engineered Nanomaterials. ACS Nano, 8(4), 3393-3401. doi:10.1021/nn405977tCheng, K., Yang, M., Zhang, R., Qin, C., Su, X., & Cheng, Z. (2014). Hybrid Nanotrimers for Dual T1 and T2-Weighted Magnetic Resonance Imaging. ACS Nano, 8(10), 9884-9896. doi:10.1021/nn500188yZhou, Z., Huang, D., Bao, J., Chen, Q., Liu, G., Chen, Z., … Gao, J. (2012). A Synergistically EnhancedT1-T2Dual-Modal Contrast Agent. Advanced Materials, 24(46), 6223-6228. doi:10.1002/adma.201203169Huang, G., Li, H., Chen, J., Zhao, Z., Yang, L., Chi, X., … Gao, J. (2014). Tunable T1and T2contrast abilities of manganese-engineered iron oxide nanoparticles through size control. Nanoscale, 6(17), 10404. doi:10.1039/c4nr02680bPerrier, M., Kenouche, S., Long, J., Thangavel, K., Larionova, J., Goze-Bac, C., … Guari, Y. (2013). Investigation on NMR Relaxivity of Nano-Sized Cyano-Bridged Coordination Polymers. Inorganic Chemistry, 52(23), 13402-13414. doi:10.1021/ic401710jPerera, V. S., Yang, L. D., Hao, J., Chen, G., Erokwu, B. O., Flask, C. A., … Huang, S. D. (2014). Biocompatible Nanoparticles of KGd(H2O)2[Fe(CN)6]·H2O with Extremely HighT1-Weighted Relaxivity Owing to Two Water Molecules Directly Bound to the Gd(III) Center. Langmuir, 30(40), 12018-12026. doi:10.1021/la501985pCai, X., Gao, W., Ma, M., Wu, M., Zhang, L., Zheng, Y., … Shi, J. (2015). A Prussian Blue-Based Core-Shell Hollow-Structured Mesoporous Nanoparticle as a Smart Theranostic Agent with Ultrahigh pH-Responsive Longitudinal Relaxivity. Advanced Materials, 27(41), 6382-6389. doi:10.1002/adma.201503381Yang, L., Zhou, Z., Liu, H., Wu, C., Zhang, H., Huang, G., … Gao, J. (2015). Europium-engineered iron oxide nanocubes with high T1and T2contrast abilities for MRI in living subjects. Nanoscale, 7(15), 6843-6850. doi:10.1039/c5nr00774gCabrera-García, A., Vidal-Moya, A., Bernabeu, Á., Sánchez-González, J., Fernández, E., & Botella, P. (2015). Gd–Si oxide mesoporous nanoparticles with pre-formed morphology prepared from a Prussian blue analogue template. Dalton Transactions, 44(31), 14034-14041. doi:10.1039/c5dt01928aCabrera-García, A., Vidal-Moya, A., Bernabeu, Á., Pacheco-Torres, J., Checa-Chavarria, E., Fernández, E., & Botella, P. (2016). Gd-Si Oxide Nanoparticles as Contrast Agents in Magnetic Resonance Imaging. Nanomaterials, 6(6), 109. doi:10.3390/nano6060109Botella, P., Corma, A., & Quesada, M. (2012). Synthesis of ordered mesoporous silica templated with biocompatible surfactants and applications in controlled release of drugs. Journal of Materials Chemistry, 22(13), 6394. doi:10.1039/c2jm16291aMascharak, P. K. (1986). Convenient synthesis of tris(tetraethylammonium) hexacyanoferrate(III) and its use as an oxidant with tunable redox potential. Inorganic Chemistry, 25(3), 245-247. doi:10.1021/ic00223a001Clemments, A. M., Muniesa, C., Landry, C. C., & Botella, P. (2014). Effect of surface properties in protein corona development on mesoporous silica nanoparticles. RSC Adv., 4(55), 29134-29138. doi:10.1039/c4ra03277bOyane, A., Kim, H.-M., Furuya, T., Kokubo, T., Miyazaki, T., & Nakamura, T. (2003). Preparation and assessment of revised simulated body fluids. Journal of Biomedical Materials Research, 65A(2), 188-195. doi:10.1002/jbm.a.10482Blüml, S., Schad, L. R., Stepanow, B., & Lorenz, W. J. (1993). Spin-lattice relaxation time measurement by means of a TurboFLASH technique. Magnetic Resonance in Medicine, 30(3), 289-295. doi:10.1002/mrm.1910300304Hennig, J., & Friedburg, H. (1988). Clinical applications and methodological developments of the RARE technique. Magnetic Resonance Imaging, 6(4), 391-395. doi:10.1016/0730-725x(88)90475-4Hennig, J., Nauerth, A., & Friedburg, H. (1986). RARE imaging: A fast imaging method for clinical MR. Magnetic Resonance in Medicine, 3(6), 823-833. doi:10.1002/mrm.1910030602Yamada, M., & Yonekura, S. (2009). Nanometric Metal−Organic Framework of Ln[Fe(CN)6]: Morphological Analysis and Thermal Conversion Dynamics by Direct TEM Observation. The Journal of Physical Chemistry C, 113(52), 21531-21537. doi:10.1021/jp907180eNavarro, M. C., Pannunzio-Miner, E. V., Pagola, S., Gómez, M. I., & Carbonio, R. E. (2005). Structural refinement of Nd[Fe(CN)6]·4H2O and study of NdFeO3 obtained by its oxidative thermal decomposition at very low temperatures. Journal of Solid State Chemistry, 178(3), 847-854. doi:10.1016/j.jssc.2004.11.026Ding, Y., Chu, X., Hong, X., Zou, P., & Liu, Y. (2012). The infrared fingerprint signals of silica nanoparticles and its application in immunoassay. Applied Physics Letters, 100(1), 013701. doi:10.1063/1.3673549Botella, P., Abasolo, I., Fernández, Y., Muniesa, C., Miranda, S., Quesada, M., … Corma, A. (2011). Surface-modified silica nanoparticles for tumor-targeted delivery of camptothecin and its biological evaluation. Journal of Controlled Release, 156(2), 246-257. doi:10.1016/j.jconrel.2011.06.039Na, H. B., Lee, J. H., An, K., Park, Y. I., Park, M., Lee, I. S., … Hyeon, T. (2007). Development of aT1 Contrast Agent for Magnetic Resonance Imaging Using MnO Nanoparticles. Angewandte Chemie International Edition, 46(28), 5397-5401. doi:10.1002/anie.200604775Deng, Y., Li, E., Cheng, X., Zhu, J., Lu, S., Ge, C., … Pan, Y. (2016). Facile preparation of hybrid core–shell nanorods for photothermal and radiation combined therapy. Nanoscale, 8(7), 3895-3899. doi:10.1039/c5nr09102kBottrill, M., Kwok, L., & Long, N. J. (2006). Lanthanides in magnetic resonance imaging. Chemical Society Reviews, 35(6), 557. doi:10.1039/b516376pZhang, W., Martinelli, J., Peters, J. A., van Hengst, J. M. A., Bouwmeester, H., Kramer, E., … Djanashvili, K. (2017). Surface PEG Grafting Density Determines Magnetic Relaxation Properties of Gd-Loaded Porous Nanoparticles for MR Imaging Applications. ACS Applied Materials & Interfaces, 9(28), 23458-23465. doi:10.1021/acsami.7b05912Li, Y., Chen, T., Tan, W., & Talham, D. R. (2014). Size-Dependent MRI Relaxivity and Dual Imaging with Eu0.2Gd0.8PO4·H2O Nanoparticles. Langmuir, 30(20), 5873-5879. doi:10.1021/la500602xT. L. Riss , R. A.Moravec , A. L.Niles , S.Duellman , H. A.Benink , T. J.Worzella and L.Minor , Cell Viability Assays , in Assay Guidance Manual , Eli Lilly & Company and the National Center for Advancing Translational Sciences , Bethesda, MD , 2012Mahmoudi, M., Lynch, I., Ejtehadi, M. R., Monopoli, M. P., Bombelli, F. B., & Laurent, S. (2011). Protein−Nanoparticle Interactions: Opportunities and Challenges. Chemical Reviews, 111(9), 5610-5637. doi:10.1021/cr100440gLu, J., Liong, M., Li, Z., Zink, J. I., & Tamanoi, F. (2010). Biocompatibility, Biodistribution, and Drug-Delivery Efficiency of Mesoporous Silica Nanoparticles for Cancer Therapy in Animals. Small, 6(16), 1794-1805. doi:10.1002/smll.20100053

Engineered contrast agents in a single structure for: T1- T2 dual magnetic resonance imaging

The development of contrast agents (CAs) for Magnetic Resonance Imaging (MRI) with T1–T2 dual-mode relaxivity requires the accurate assembly of T1 and T2 magnetic centers in a single structure. In this context, we have synthesized a novel hybrid material by monitoring the formation of Prussian Blue analogue Gd(H2O)4[Fe(CN)6] nanoparticles with tailored shape (from nanocrosses to nanorods) and size, and further protection with a thin and homogeneous silica coating through hydrolysis and polymerization of silicate at neutral pH. The resulting Gd(H2O)4[Fe(CN)6]@SiO2 magnetic nanoparticles are very stable in biological fluids. Interestingly, this combination of Gd and Fe magnetic centers closely packed in the crystalline network promotes a magnetic synergistic effect, which results in significant improvement of longitudinal relaxivity with regards to soluble Gd3+ chelates, whilst keeping the high transversal relaxivity inherent to the iron component. As a consequence, this material shows excellent activity as MRI CA, improving positive and negative contrasts in T1- and T2-weighted MR images, both in in vitro (e.g., phantom) and in vivo (e.g., Sprague-Dawley rats) models. In addition, this hybrid shows a high biosafety profile and has strong ability to incorporate organic molecules on the surface with variable functionality, displaying great potential for further clinical application.Financial support of the Spanish Ministry of Economy and Competitiveness (projects TEC2016-80976-R and SEV-2016-0683) is gratefully acknowledged. Dr E. M. Rivero thanks the Cursol Foundation for a post-doctoral scholarship. A. C. G. also thanks the La Caixa Foundation for a Ph.D. scholarship.Peer reviewe