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The development of microenvironment-responsive nanoprobes has shown great promise for use in magnetic resonance imaging (MRI), with the advantage of significantly improved specificity and good biocompatibility. However, the clinical application of responsive probes is hampered by a lack of biological sensitivity for early molecular diagnostics and visualizing microenvionment of metabolism reprogramming in tumor progression. Here, we report on a dual-ratiometric magnetic resonance tunable (DMRT) nanoprobe designed by crosslinking different ratios of transferrin chelating gadolinium and superparamagnetic nanoparticles, complexed to a pH responsive biocompatible polymer. This dually activatable nanoprobe enables pH-dependent tumor microenvironment visualization, providing exceptional quantitative pathophysiological information in vitro and in vivo. When used in combination with dual-contrast enhancement triple subtraction imaging technique (DETSI), this smart nanoprobe guarantees the diagnosis of early-stage diseases. We envisage that this novel integrated nanoplatform will provide a new paradigm for the clinical translation of robust DMRT nanoprobes for early disease detection and staging, as well as microenvironment visualization and disease progression monitoring.


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Dual-ratiometric magnetic resonance tunable nanoprobe with acidic-microenvironment-responsive property to enhance the visualization of early tumor pathological changes

Show Author's information Rong Cao1,§Ning Tang2,§Yi Zhu1,§An Chen1Yumeng Li1,3Renbin Ge1Yuan Li2Zhongyi Huang4Jiajing Guo1Jiali Deng1,3Hongwei Lu5( )Ziwei Lu6( )Helen Forgham7Thomas P. Davis7Ruirui Qiao7( )Zhongling Wang1( )
Department of Radiology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China
School of food science, Nanjing Xiaozhuang University, Nanjing 211171, China
School of Health Science and Engineering, University of Shanghai for Science and Technology, Shanghai 200093, China
Department of Neurology, School of Medicine, New York University, New York 10016, USA
Department of Biomedical Engineering, College of Engineering, Shantou University, Shantou 515063, China
Department of Radiology, The First Affiliated Hospital of Soochow University, Suzhou 215006, China
Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, Brisbane QLD 4072, Australia

§ Rong Cao, Ning Tang, and Yi Zhu contributed equally to this work.

Abstract

The development of microenvironment-responsive nanoprobes has shown great promise for use in magnetic resonance imaging (MRI), with the advantage of significantly improved specificity and good biocompatibility. However, the clinical application of responsive probes is hampered by a lack of biological sensitivity for early molecular diagnostics and visualizing microenvionment of metabolism reprogramming in tumor progression. Here, we report on a dual-ratiometric magnetic resonance tunable (DMRT) nanoprobe designed by crosslinking different ratios of transferrin chelating gadolinium and superparamagnetic nanoparticles, complexed to a pH responsive biocompatible polymer. This dually activatable nanoprobe enables pH-dependent tumor microenvironment visualization, providing exceptional quantitative pathophysiological information in vitro and in vivo. When used in combination with dual-contrast enhancement triple subtraction imaging technique (DETSI), this smart nanoprobe guarantees the diagnosis of early-stage diseases. We envisage that this novel integrated nanoplatform will provide a new paradigm for the clinical translation of robust DMRT nanoprobes for early disease detection and staging, as well as microenvironment visualization and disease progression monitoring.

Keywords: early diagnosis, ratiometric nanoprobe, dually activatable, microenvironment visualization, pathological changes

References(41)

[1]

Pashayan, N.; Pharoah, P. D. P. The challenge of early detection in cancer. Science 2020, 368, 589–590.

[2]

Mac, Q. D.; Mathews, D. V.; Kahla, J. A.; Stoffers, C. M.; Delmas, O. M.; Holt, B. A.; Adams, A. B.; Kwong, G. A. Non-invasive early detection of acute transplant rejection via nanosensors of granzyme B activity. Nat. Biomed. Eng. 2019, 3, 281–291.

[3]

Lee, W.; Il An, G.; Park, H.; Sarkar, S.; Ha, Y. S.; Huynh, P. T.; Bhise, A.; Bhatt, N.; Ahn, H.; Pandya, D. N. et al. Imaging strategy that achieves ultrahigh contrast by utilizing differential esterase activity in organs: Application in early detection of pancreatic Cancer. ACS Nano 2021, 15, 17348–17360.

[4]

Masud, M. K.; Na, J.; Younus, M.; Hossain, M. S. A.; Bando, Y.; Shiddiky, M. J. A.; Yamauchi, Y. Superparamagnetic nanoarchitectures for disease-specific biomarker detection. Chem. Soc. Rev. 2019, 48, 5717–5751.

[5]

Wang, Z. L.; Qiao, R. R.; Tang, N.; Lu, Z. W.; Wang, H.; Zhang, Z. X.; Xue, X. D.; Huang, Z. Y.; Zhang, S. R.; Zhang, G. X. et al. Active targeting theranostic iron oxide nanoparticles for MRI and magnetic resonance-guided focused ultrasound ablation of lung cancer. Biomaterials 2017, 127, 25–35.

[6]

Chen, W.; Schilperoort, M.; Cao, Y. H.; Shi, J. J.; Tabas, I.; Tao, W. Macrophage-targeted nanomedicine for the diagnosis and treatment of atherosclerosis. Nat. Rev. Cardiol. 2022, 19, 228–249.

[7]

Feng, G. X.; Liu, J.; Liu, R. R.; Mao, D.; Tomczak, N.; Liu, B. Ultrasmall conjugated polymer nanoparticles with high specificity for targeted cancer cell imaging. Adv. Sci. (Weinh. ) 2017, 4, 1600407.

[8]

Liang, P. P.; Huang, X. Y.; Wang, Y.; Chen, D. P.; Ou, C. J.; Zhang, Q.; Shao, J. J.; Huang, W.; Dong, X. C. Tumor-microenvironment-responsive nanoconjugate for synergistic antivascular activity and phototherapy. ACS Nano 2018, 12, 11446–11457.

[9]

Knox, H. J.; Hedhli, J.; Kim, T. W.; Khalili, K.; Dobrucki, L. W.; Chan, J. A bioreducible N-oxide-based probe for photoacoustic imaging of hypoxia. Nat. Commun. 2017, 8, 1794.

[10]

Wang, Z. L.; Xue, X. D.; He, Y. X.; Lu, Z. W.; Jia, B.; Wu, H.; Yuan, Y.; Huang, Y. E.; Wang, H.; Lu, H. W. et al. Novel redox-responsive polymeric magnetosomes with tunable magnetic resonance property for in vivo drug release visualization and dual-modal cancer therapy. Adv. Funct. Mater. 2018, 28, 1802159.

[11]

Kulkarni, A.; Chandrasekar, V.; Natarajan, S. K.; Ramesh, A.; Pandey, P.; Nirgud, J.; Bhatnagar, H.; Ashok, D.; Ajay, A. K.; Sengupta, S. A designer self-assembled supramolecule amplifies macrophage immune responses against aggressive cancer. Nat. Biomed. Eng. 2018, 2, 589–599.

[12]

Zhou, Z. X.; Vázquez-González, M.; Willner, I. Stimuli-responsive metal-organic framework nanoparticles for controlled drug delivery and medical applications. Chem. Soc. Rev. 2021, 50, 4541–4563.

[13]

Wang, Y. G.; Zhou, K. J.; Huang, G.; Hensley, C.; Huang, X. N.; Ma, X. P.; Zhao, T.; Sumer, B. D.; DeBerardinis, R. J.; Gao, J. M. A nanoparticle-based strategy for the imaging of a broad range of tumours by nonlinear amplification of microenvironment signals. Nat. Mater. 2014, 13, 204–212.

[14]

Dou, C.; Li, J. M.; He, J.; Luo, F.; Yu, T.; Dai, Q. J.; Chen, Y. Q.; Xu, J. Z.; Yang, X. C.; Dong, S. W. Bone-targeted pH-responsive cerium nanoparticles for anabolic therapy in osteoporosis. Bioact. Mater. 2021, 6, 4697–4706.

[15]

Rizzo, M. A.; Springer, G. H.; Granada, B.; Piston, D. W. An improved cyan fluorescent protein variant useful for FRET. Nat. Biotechnol. 2004, 22, 445–449.

[16]

Biskup, C.; Zimmer, T.; Benndorf, K. FRET between cardiac Na+ channel subunits measured with a confocal microscope and a streak camera. Nat. Biotechnol. 2004, 22, 220–224.

[17]

Jebelli, A.; Oroojalian, F.; Fathi, F.; Mokhtarzadeh, A.; De La Guardia, M. Recent advances in surface plasmon resonance biosensors for microRNAs detection. Biosens. Bioelectron. 2020, 169, 112599.

[18]

Choi, J. S.; Kim, S.; Yoo, D.; Shin, T. H.; Kim, H.; Gomes, M. D.; Kim, S. H.; Pines, A.; Cheon, J. Distance-dependent magnetic resonance tuning as a versatile MRI sensing platform for biological targets. Nat. Mater. 2017, 16, 537–542.

[19]

Wang, Z. L.; Xue, X. D.; Lu, H. W.; He, Y. X.; Lu, Z. W.; Chen, Z. J.; Yuan, Y.; Tang, N.; Dreyer, C. A.; Quigley, L. et al. Two-way magnetic resonance tuning and enhanced subtraction imaging for non-invasive and quantitative biological imaging. Nat. Nanotechnol. 2020, 15, 482–490.

[20]

Viswanath, P.; Batsios, G.; Mukherjee, J.; Gillespie, A. M.; Larson, P. E. Z.; Luchman, H. A.; Phillips, J. J.; Costello, J. F.; Pieper, R. O.; Ronen, S. M. Non-invasive assessment of telomere maintenance mechanisms in brain tumors. Nat. Commun. 2021, 12, 92.

[21]

Subramani, E.; Radoul, M.; Najac, C.; Batsios, G.; Molloy, A. R.; Hong, D.; Gillespie, A. M.; Santos, R. D.; Viswanath, P.; Costello, J. F. et al. Glutamate is a noninvasive metabolic biomarker of IDH1-mutant glioma response to temozolomide treatment. Cancer Res. 2020, 80, 5098–5108.

[22]

Le Page, L. M.; Guglielmetti, C.; Taglang, C.; Chaumeil, M. M. Imaging brain metabolism using hyperpolarized 13C magnetic resonance spectroscopy. Trends Neurosci. 2020, 43, 343–354.

[23]

Li, C. G.; Zhao, J. J.; Cheng, K.; Ge, Y. W.; Wu, Q.; Ye, Y. S.; Xu, G. H.; Zhang, Z. T.; Zheng, W. W.; Zhang, X. et al. Magnetic resonance spectroscopy as a tool for assessing macromolecular structure and function in living cells. Annu. Rev. Anal. Chem. 2017, 10, 157–182.

[24]

Luo, Z. C.; Hu, D. H.; Gao, D. Y.; Yi, Z. G.; Zheng, H. R.; Sheng, Z. H.; Liu, X. G. High-specificity in vivo tumor imaging using bioorthogonal NIR-IIb nanoparticles. Adv. Mater. 2021, 33, 210295.

[25]

Verry, C.; Dufort, S.; Lemasson, B.; Grand, S.; Pietras, J.; Troprès, I.; Crémillieux, Y.; Lux, F.; Mériaux, S.; Larrat, B. et al. Targeting brain metastases with ultrasmall theranostic nanoparticles, a first-in-human trial from an MRI perspective. Sci. Adv. 2020, 6, eaay5279.

[26]

Qiao, R. R.; Zhu, R.; Gao, M. Y. Imaging tumor metastases with molecular probes. Curr. Pharm. Des. 2015, 21, 6260–6264.

[27]

Zheng, S.; Zhang, Z. Y.; Qu, Y. W.; Zhang, X. J.; Guo, H. B.; Shi, X. J.; Cai, M. S.; Cao, C. G.; Hu, Z. H.; Liu, H. F. et al. Radiopharmaceuticals and fluorescein sodium mediated triple-modality molecular imaging allows precise image-guided tumor surgery. Adv. Sci. (Weinh. ) 2019, 6, 1900159.

[28]

Zhao, Y.; Peng, J.; Li, J. J.; Huang, L.; Yang, J. Y.; Huang, K.; Li, H. W.; Jiang, N.; Zheng, S. K.; Zhang, X. N. et al. Tumor-targeted and clearable human protein-based MRI nanoprobes. Nano Lett. 2017, 17, 4096–4100.

[29]

Estrella, V.; Chen, T. A.; Lloyd, M.; Wojtkowiak, J.; Cornnell, H. H.; Ibrahim-Hashim, A.; Bailey, K.; Balagurunathan, Y.; Rothberg, J. M.; Sloane, B. F. et al. Acidity generated by the tumor microenvironment drives local invasion. Cancer Res. 2013, 73, 1524–1535.

[30]

Anemone, A.; Consolino, L.; Conti, L.; Irrera, P.; Hsu, M. Y.; Villano, D.; Dastrù, W.; Porporato, P. E.; Cavallo, F.; Longo, D. L. Tumour acidosis evaluated in vivo by MRI-CEST pH imaging reveals breast cancer metastatic potential. Br. J. Cancer 2021, 124, 207–216.

[31]

Chen, Y. L.; Cai, Y. J.; Yu, X. S.; Xiao, H.; He, H. Z.; Xiao, Z. C.; Wang, Y.; Shuai, X. T. A photo and tumor microenvironment activated nano-enzyme with enhanced ROS generation and hypoxia relief for efficient cancer therapy. J. Mater. Chem. B 2021, 9, 8253–8262.

[32]

Helmlinger, G.; Yuan, F.; Dellian, M.; Jain, R. K. Interstitial pH and pO2 gradients in solid tumors in vivo: High-resolution measurements reveal a lack of correlation. Nat. Med. 1997, 3, 177–182.

[33]

Zhong, Y.; Huang, S.; Zheng, C. J.; Huang, J. S.; Li, B.; Han, S. S.; Xiao, H.; Wang, Y.; Shuai, X. T. A light and hypoxia-activated nanodrug for cascade photodynamic-chemo cancer therapy. Biomater. Sci. 2021, 9, 5218–5226.

[34]

Gatenby, R. A.; Gillies, R. J. Why do cancers have high aerobic glycolysis. Nat. Rev. Cancer 2004, 4, 891–899.

[35]

Medzhitov, R. Origin and physiological roles of inflammation. Nature 2008, 454, 428–435.

[36]

Certo, M.; Tsai, C. H.; Pucino, V.; Ho, P. C.; Mauro, C. Lactate modulation of immune responses in inflammatory versus tumour microenvironments. Nat. Rev. Immunol. 2021, 21, 151–161.

[37]

Xu, X. Q.; An, H. J.; Zhang, D. L.; Tao, H.; Dou, Y.; Li, X. H.; Huang, J.; Zhang, J. X. A self-illuminating nanoparticle for inflammation imaging and cancer therapy. Sci. Adv. 2019, 5, eaat2953.

[38]

Mi, P.; Kokuryo, D.; Cabral, H.; Wu, H. L.; Terada, Y.; Saga, T.; Aoki, I.; Nishiyama, N.; Kataoka, K. A pH-activatable nanoparticle with signal-amplification capabilities for non-invasive imaging of tumour malignancy. Nat. Nanotechnol. 2016, 11, 724–730.

[39]

Bohn, T.; Rapp, S.; Luther, N.; Klein, M.; Bruehl, T. J.; Kojima, N.; Lopez, P. A.; Hahlbrock, J.; Muth, S.; Endo, S. et al. Tumor immunoevasion via acidosis-dependent induction of regulatory tumor-associated macrophages. Nat. Immunol. 2018, 19, 1319–1329.

[40]

Maddock, R. J.; Buonocore, M. H.; Copeland, L. E.; Richards, A. L. Elevated brain lactate responses to neural activation in panic disorder: A dynamic 1H-MRS study. Mol. Psychiatry 2009, 14, 537–545.

[41]

Martel, A. L.; Fraser, D.; Delay, G. S.; Morgan, P. S.; Moody, A. R. Separating arterial and venous components from 3D dynamic contrast-enhanced MRI studies using factor analysis. Magn. Reson. Med. 2003, 49, 928–933.

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Publication history
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Acknowledgements

Publication history

Received: 25 December 2022
Revised: 18 March 2023
Accepted: 20 March 2023
Published: 15 April 2023
Issue date: July 2023

Copyright

© Tsinghua University Press 2023

Acknowledgements

Acknowledgements

The authors would like to acknowledge Shanghai General Hospital of Shanghai Jiaotong University. This work was supported by the National Natural Science Foundation of China (Nos. 81971664 and 82272057) and the Shanghai Pujiang Program (No. 2019PJD044).

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