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Enhanced Tumor Diagnostic and Therapeutic Effect of Mesoporous Silica Nanoparticle-Mediated Pre-targeted Strategy

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Abstract

Purpose

Improving the targeting efficiency of imaging agents or anticancer drugs has become essential in the current primary mission to enhance the diagnostic or therapeutic effects. To improve the tumor diagnosis and therapy effect, a promising drug-delivery and targeting strategy was established based on the bioorthogonal chemistry.

Method

The delivery system was composed of the pre-targeting carrier Biotin-MSNs-DBCO nanoparticles and the azido cargoes. The fluorescence probe 1-(3-azidopropyl) fluorescein (FITC-N3) and ruthenium N-heterocyclic carbene complex N3-S-S-NHC-Ru were synthesized and served as the tumor imaging and therapy probes, respectively. The cell imaging and viability was investigated by the Biotin-MSNs-DBCO pre-targeted for 4 h in colonic carcinoma (HeLa) cells.

Results

For the tumor cell imaging, Biotin-MSNs-DBCO could react with FITC-N3 rapidly and completely in 20 min with 93% yields. The fluorescence intensity of tumor cells was obviously increased by the Biotin-MSNs-DBCO pre-targeted. The cytotoxicity of the ruthenium complex N3-S-S-NHC-Ru was significantly improved appropriately three times with the IC50 (half inhibitory concentration) value of 6.68 ± 1.29 μM and enhancement of the mitochondrial dysfunction.

Conclusions

The pre-targeting nanoparticle Biotin-MSNs-DBCO could selectively capture the azido compounds in tumor cells, which provided a site-specific target for the cargoes and then resulted in an enhancement of diagnostic or therapeutic effects.

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Abbreviations

BJH:

Barrett–Joyner–Halenda

DAPI:

4′,6-diamidino-2-phenylindole

DBCO:

Aza-dibenzocyclooctynes

EPR:

Enhanced permeability and retention

ESI-MS:

Electrospray ionization mass

FITC-N3 :

1-(3-azidopropyl) fluorescein

FT-IR:

Flourier transform infrared spectra

GSH:

Glutathione

HPLC:

High performance liquid chromatography

MMP:

Mitochondrial membrane potential

MSNs:

Mesoporous silica nanoparticles

MTT:

3-(4,5-dimethylthiazol-2-yl) -2,5-diphenyltetrazolium bromide

N3-OH:

2-Azidoethanol

N3-S-S-NHC-Ru:

2-azidoethyl (2-((2-hydroxyethyl)disulfanyl)ethyl) N-heterocyclic carbene ruthenium complex

NHC-Ru:

N-heterocyclic carbene ruthenium complex

NMR:

Nuclear magnetic resonance

PBS:

Phosphate-buffered saline

SPAAC:

Strain-promoted alkyne azide cycloaddition

TEM:

Transmission electron microscopy

References

  1. Wang X, Guo Z. Targeting and delivery of platinum-based anticancer drugs. Chem Soc Rev. 2013;42(1):202–24.

    Article  CAS  PubMed  Google Scholar 

  2. He L, Huang Y, Zhu H, Pang G, Zheng W, Wong Y, et al. Cancer-targeted monodisperse mesoporous silica nanoparticles as carrier of ruthenium polypyridyl complexes to enhance theranostic effects. Adv Funct Mater. 2014;24(19):2754–63.

    Article  CAS  Google Scholar 

  3. Deng Z, Gao P, Yu L, Ma B, You Y, Chan L, et al. Ruthenium complexes with phenylterpyridine derivatives target cell membrane and trigger death receptors-mediated apoptosis in cancer cells. Biomaterials. 2017;129:111–26.

    Article  CAS  PubMed  Google Scholar 

  4. Cisnetti F, Gautier A. Metal/N-heterocyclic carbene complexes: opportunities for the development of anticancer metallodrugs. Angew Chem Int Ed. 2013;52(46):11976–8.

    Article  CAS  Google Scholar 

  5. Arambula JF, McCall R, Sidoran KJ, Magda D, Mitchell NA, Bielawski CW, et al. Targeting antioxidant pathways with ferrocenylated N-heterocyclic carbene supported Gold(I) complexes in A549 lung cancer cells. Chem Sci. 2016;7(2):1245–56.

    Article  CAS  PubMed  Google Scholar 

  6. Bertrand B, Fernandez-Cestau J, Angulo J, Cominetti MMD, Waller ZAE, Searcey M, et al. Cytotoxicity of pyrazine-based cyclometalated (C^Npz^C)Au(III) cabene complexes: impact of the nature of the ancillary ligand on the biological properties. Inorg Chem. 2017;56(10):5728–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Lv GC, Guo LB, Qiu L, Yang H, Wang T, Liu H, et al. Lipophilicity-dependent ruthenium N-heterocyclic carbene complexes as potential anticancer agents. Dalton Trans. 2015;44(16):7324–31.

    Article  CAS  PubMed  Google Scholar 

  8. He L, Chen T, You Y, Hu H, Zheng W, Wong WK, et al. A cancer-targeted nanosystem for delivery of Gold(III) complexes: enhanced selectivity and apoptosis-inducing efficacy of a Gold(III) porphyrin complex. Angew Chem Int Ed. 2014;53(46):12532–6.

    CAS  Google Scholar 

  9. Schutt C, Ibsen S, Zahavy E, Aryal S, Kuo S, Esener S, et al. Drug delivery nanoparticles with locally tunable toxicity made entirely from a light-activatable prodrug of doxorubicin. Pharm Res. 2017;34:3540–57.

    Article  Google Scholar 

  10. Chen L, Fu C, Deng YJ, Wu W, Fu AL. A pH-sensitive nanocarrier for tumor targeting. Pharm Res. 2016;33:2989–98.

    Article  CAS  PubMed  Google Scholar 

  11. Polo E, Collado M, Pelaz B, Del Pino P. Advances toward more efficient targeted delivery of nanoparticles. ACS Nano. 2017;11(3):2397–402.

    Article  CAS  PubMed  Google Scholar 

  12. Argyo C, Weiss V, Bräuchle C, Bein T. Multifunctional mesoporous silica nanoparticles as a universal platform for drug delivery. Chem Mater. 2014;26(1):435–51.

    Article  CAS  Google Scholar 

  13. Li Z, Clemens DL, Lee B, Dillon BJ, Horwitz MA, Zink JI. Mesoporous silica nanoparticles with pH-sensitive nanovalves for delivery of moxifloxacin provide improved treatment of lethal pneumonic tularemia. ACS Nano. 2015;9(11):10778–89.

    Article  CAS  PubMed  Google Scholar 

  14. Tang Y, Hu H, Zhang MG, Song J, Nie L, Wang S, et al. An aptamer-targeting photoresponsive drug delivery system using “off–on” graphene oxide wrapped mesoporous silica nanoparticles. Nano. 2015;7(14):6304–10.

    CAS  Google Scholar 

  15. Gada KS, Patil V, Panwar R, Hatefi A, Khaw BA. Bispecific antibody complex pre-targeted delivery of polymer-drug conjugates for cancer therapy. Drug Deliv Transl Res. 2012;2(1):65–76.

    Article  CAS  PubMed  Google Scholar 

  16. Goldenberg DM, Chang CH, Rossi EA, McBride WJ, Sharkey RM. Pretargeted molecular imaging and radioimmunotherapy. Theranostics. 2012;2(5):523–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Frampas E, Rousseau C, Bodet-Milin C, Barbet J, Catal JF, Kraeber-Bodéré F. Improvement of radioimmunotherapy using pretargeting. Front Oncol. 2013;3(3):159–67.

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Patra M, Zarschler K, Pietzsch HJ, Stephan H, Gasser G. New insight into the pretargeting approach to image and treat tumors. Chem Soc Rew. 2016;45(23):6415–31.

    Article  CAS  Google Scholar 

  19. Hou S, Choi J, Garcia MA, Xing Y, Chen K, Chen Y, et al. Pretargeted positron emission tomography imaging that employs supramolecular nanoparticles with in vivo bioorthogonal chemistry. ACS Nano. 2016;10(1):1417–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Murrey HE, Judkins JC, Am Ende CW, Ballard TE, Fang Y, Riccardi K, et al. Systematic evaluation of bioorthogonal reactions in live cells with clickable halotag ligands: implications for intracellular imaging. J Am Chem Soc. 2015;137(35):11461–75.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Lee SB, Kim HL, Jeong H, Lim ST, Sohn M, Kim DW. Mesoporous silica nanoparticle pretargeting for PET imaging based on a rapid bioorthogonal reaction in a living body. Angew Chem Int Ed. 2013;52(40):10549–52.

    Article  CAS  Google Scholar 

  22. Sun Q, Sun D, Song L, Chen Z, Zhang W, Qian J. Highly selective fluorescent turn-on probe for proten thiols in biotin receptor-positive cancer cells. Anal Chem. 2016;88(6):3400–5.

    Article  CAS  PubMed  Google Scholar 

  23. Yang W, Cheng Y, Xu T, Wang X, Wen L. Targeting cancer cells with biotin-dendrimer conjugates. Eur J Med Chem. 2009;44(2):862–8.

    Article  CAS  PubMed  Google Scholar 

  24. Chow S, Zhao S, Lo PC, Ng DKP. A cell-selective glutathione-responsive tris(phthalocyanine) as a smart photosensitizer for targeted photodynamic therapy. Dalton Trans. 2017;46(34):11223–9.

    Article  CAS  PubMed  Google Scholar 

  25. Lv GC, Qiu L, Liu G, Wang W, Li K, Zhao X, et al. pH sensitive chitosan-mesoporous silica nanoparticles for targeted delivery of a ruthenium complex with enhanced anticancer effects. Dalton Trans. 2016;45(45):18147–55.

    Article  CAS  PubMed  Google Scholar 

  26. Yang HY, Jang M, Li Y, Lee JH, Lee DS. Multifunctional and redox-responsive self-assembled magnetic nanovectors for protein delivery and dual-modal imaging. ACS Appl Mater Interfaces. 2017;9(22):19184–92.

    Article  CAS  PubMed  Google Scholar 

  27. Guo L, Lv GC, Qiu L, Yang H, Zhang L, Yu H, et al. Insights into anticancer activity and mechanism of action of a ruthenium(II) complex in human esophageal squamous carcinoma EC109 cells. Eur J Pharmacol. 2016;786:60–71.

    Article  CAS  PubMed  Google Scholar 

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ACKNOWLEDGMENTS AND DISCLOSURES

This work was financially supported by National Natural Science Foundation of China (21501074 and 21371082), Natural Science Foundation of Jiangsu Province (BK20151118), the 333 Project of Jiangsu Province (BRA2016518) and the Key Youth Medical Talent Project of Jiangsu Province (QNRC20162016626 and QNRC20162016629).

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Correspondence to Ling Qiu or Jianguo Lin.

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Lv, G., Li, K., Qiu, L. et al. Enhanced Tumor Diagnostic and Therapeutic Effect of Mesoporous Silica Nanoparticle-Mediated Pre-targeted Strategy. Pharm Res 35, 63 (2018). https://doi.org/10.1007/s11095-017-2338-5

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