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SCIENCE CHINA Materials, Volume 62, Issue 8: 1199-1209(2019) https://doi.org/10.1007/s40843-019-9423-5

A pH-responsive zinc (II) metalated porphyrin for enhanced photodynamic/photothermal combined cancer therapy

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  • ReceivedJan 9, 2019
  • AcceptedMar 26, 2019
  • PublishedApr 12, 2019

Abstract

The acidic tumor microenvironment is triggered by glycolysis in hypoxic condition, which can motivate the pH-responsive system to build certain triggers for efficiently tumor-targeted phototherapy. Additionally, the metalated porphyrin structures are widely studied in biomedical applications due to the favorable properties of high singlet oxygen quantum yield as well as strong fluorescence imaging ability. Herein, a pH-responsive zinc (II) metalated porphyrin (P-4) was designed and synthesized for amplifying cancer photodynamic/photothermal therapy with excellent fluorescence quantum yield (67.4%), superb singlet oxygen quantum yield (84.3%) and desired photothermal conversion efficiency (30.0%). In vitro, the self-assembled P-4 nanoparticles can specifically target to lysosome subcellular site and realize protonated process of dibutaneaminophenyl (DBAP) groups with high photo toxicity. Under single 660 nm laser illumination, the tumor can be ablated completely with no side effects in vivo. This work demonstrates that the pH-responsive P-4 nanoparticles provide a new avenue for highly efficient cancer combination therapy.


Funded by

National Natural Science Foundation of China(61525402,61775095,21704043)

Jiangsu Provincial Key Research and Development Plan(BE2017741)

Six talent peak innovation team in Jiangsu Province(TD-SWYY-009)

and the Natural Science Foundation of Jiangsu Province(BK20170990,17KJB150020)


Acknowledgment

This work was supported by the National Natural Science Foundation of China (61525402, 61775095 and 21704043), Jiangsu Provincial Key Research and Development Plan (BE2017741), Six Talent Peak Innovation Team in Jiangsu Province (TD-SWYY-009), and the Natural Science Foundation of Jiangsu Province (BK20170990 and 17KJB150020).


Interest statement

The authors declare that they have no conflict of interest.


Contributions statement

Dong X designed the project. Dong X, Si W and Yang Z guided the project. Liang P and Tang H performed the experiments. Gu R, Xue L, Chen D and Wang W performed some supplemental experiments. Dong X, Si W and Liang P analyzed the results and wrote the manuscript. All authors participated in general discussion of the paper.


Author information

Pingping Liang is studying for a PhD degree at the Institute of Advanced Materials (IAM), Nanjing Tech University. Her research interest focuses on the cancer phototherapy.


Weili Si received her PhD degree in 2015, from Tohoku University, Japan. Then she joined the Institute of Advanced Materials, Nanjing Tech University as an associate professor. Her current research interests focus on the development of novel photosensitizers and the application in medicinal chemistry.


Xiaochen Dong obtained his PhD degree from Zhejiang University in China in 2007. Then he joined the School of Materials Science and Engineering in Nanyang Technological University as a postdoc. In 2012, he joined the Institute of Advanced Materials, Nanjing Tech University, as a Full Professor. He has published more than 200 papers, including those in Adv. Mater., ACS Nano, JACS, etc. His current research involves biophotonics and bioelectronics.


Supplement

Supplementary information

The synthesis of N,N-dibutyl-4-ethynylaniline and supporting results are available in the online version of the paper.


References

[1] Kuimova MK, Botchway SW, Parker AW, et al. Imaging intracellular viscosity of a single cell during photoinduced cell death. Nat Chem, 2009, 1: 69-73 CrossRef PubMed ADS Google Scholar

[2] Ethirajan M, Chen Y, Joshi P, et al. The role of porphyrin chemistry in tumor imaging and photodynamic therapy. Chem Soc Rev, 2011, 40: 340-362 CrossRef PubMed Google Scholar

[3] Kennedy LC, Bickford LR, Lewinski NA, et al. A new era for cancer treatment: gold-nanoparticle-mediated thermal therapies. Small, 2011, 7: 169-183 CrossRef PubMed Google Scholar

[4] Qian C, Yu J, Chen Y, et al. Light-activated hypoxia-responsive nanocarriers for enhanced anticancer therapy. Adv Mater, 2016, 28: 3313-3320 CrossRef PubMed Google Scholar

[5] Chen H, Tian J, He W, et al. H2O2-activatable and O2-evolving nanoparticles for highly efficient and selective photodynamic therapy against hypoxic tumor cells. J Am Chem Soc, 2015, 137: 1539-1547 CrossRef PubMed Google Scholar

[6] Tian J, Ding L, Xu HJ, et al. Cell-specific and pH-activatable rubyrin-loaded nanoparticles for highly selective near-infrared photodynamic therapy against cancer. J Am Chem Soc, 2013, 135: 18850-18858 CrossRef PubMed Google Scholar

[7] McDonnell SO, Hall MJ, Allen LT, et al. Supramolecular photonic therapeutic agents. J Am Chem Soc, 2005, 127: 16360-16361 CrossRef PubMed Google Scholar

[8] Wang Z, Li S, Zhang M, et al. Laser-triggered small interfering RNA releasing gold nanoshells against heat shock protein for sensitized photothermal therapy. Adv Sci, 2017, 4: 1600327 CrossRef PubMed Google Scholar

[9] Yang Y, Zhu W, Dong Z, et al. 1D coordination polymer nanofibers for low-temperature photothermal therapy. Adv Mater, 2017, 29: 1703588 CrossRef PubMed Google Scholar

[10] Zhou J, Schmid T, Frank R, et al. PI3K/Akt is required for heat shock proteins to protect hypoxia-inducible factor 1α from pvhl-independent degradation. J Biol Chem, 2004, 279: 13506-13513 CrossRef PubMed Google Scholar

[11] Lin J, Wang S, Huang P, et al. Photosensitizer-loaded gold vesicles with strong plasmonic coupling effect for imaging-guided photothermal/photodynamic therapy. ACS Nano, 2013, 7: 5320-5329 CrossRef PubMed Google Scholar

[12] Jang B, Park JY, Tung CH, et al. Gold nanorod−photosensitizer complex for near-infrared fluorescence imaging and photodynamic/photothermal therapy in vivo. ACS Nano, 2011, 5: 1086-1094 CrossRef PubMed Google Scholar

[13] Kolishetti N, Dhar S, Valencia PM, et al. Engineering of self-assembled nanoparticle platform for precisely controlled combination drug therapy. Proc Natl Acad Sci USA, 2010, 107: 17939-17944 CrossRef PubMed ADS Google Scholar

[14] Tian B, Wang C, Zhang S, et al. Photothermally enhanced photodynamic therapy delivered by nano-graphene oxide. ACS Nano, 2011, 5: 7000-7009 CrossRef PubMed Google Scholar

[15] Kim YK, Na HK, Kim S, et al. One-pot synthesis of multifunctional Au@graphene oxide nanocolloid core@shell nanoparticles for raman bioimaging, photothermal, and photodynamic therapy. Small, 2015, 11: 2527-2535 CrossRef PubMed Google Scholar

[16] Yong Y, Zhou L, Gu Z, et al. WS2 nanosheet as a new photosensitizer carrier for combined photodynamic and photothermal therapy of cancer cells. Nanoscale, 2014, 6: 10394-10403 CrossRef PubMed ADS Google Scholar

[17] Kim S, Tachikawa T, Fujitsuka M, et al. Far-red fluorescence probe for monitoring singlet oxygen during photodynamic therapy. J Am Chem Soc, 2014, 136: 11707-11715 CrossRef PubMed Google Scholar

[18] Dougherty TJ, Gomer CJ, Henderson BW, et al. Photodynamic therapy. J Natl Cancer Institute, 1998, 90: 889-905 CrossRef Google Scholar

[19] Yu M, Guo F, Wang J, et al. Photosensitizer-loaded pH-responsive hollow gold nanospheres for single light-induced photothermal/photodynamic therapy. ACS Appl Mater Interfaces, 2015, 7: 17592-17597 CrossRef Google Scholar

[20] Tian J, Ding L, Ju H, et al. A multifunctional nanomicelle for real-time targeted imaging and precise near-infrared cancer therapy. Angew Chem Int Ed, 2014, 53: 9544-9549 CrossRef PubMed Google Scholar

[21] Gatenby RA, Gillies RJ. Why do cancers have high aerobic glycolysis?. Nat Rev Cancer, 2004, 4: 891-899 CrossRef PubMed Google Scholar

[22] Ozlem S, Akkaya EU. Thinking outside the silicon box: Molecular and logic as an additional layer of selectivity in singlet oxygen generation for photodynamic therapy. J Am Chem Soc, 2008, 131: 48-49 CrossRef PubMed Google Scholar

[23] Weerakkody D, Moshnikova A, Thakur MS, et al. Family of pH (low) insertion peptides for tumor targeting. Proc Natl Acad Sci USA, 2013, 110: 5834-5839 CrossRef PubMed ADS Google Scholar

[24] Jiang XJ, Lo PC, Yeung SL, et al. A pH-responsive fluorescence probe and photosensitiser based on a tetraamino silicon(IV) phthalocyanine. Chem Commun, 2010, 46: 3188-3190 CrossRef PubMed Google Scholar

[25] Ke MR, Ng DKP, Lo PC. A pH-responsive fluorescent probe and photosensitiser based on a self-quenched phthalocyanine dimer. Chem Commun, 2012, 48: 9065-9067 CrossRef PubMed Google Scholar

[26] Lan M, Zhang J, Zhu X, et al. Highly stable organic fluorescent nanorods for living-cell imaging. Nano Res, 2015, 8: 2380-2389 CrossRef Google Scholar

[27] Wang F, Cui X, Lou Z, et al. Switching of the triplet excited state of rhodamine-C60 dyads. Chem Commun, 2014, 50: 15627-15630 CrossRef PubMed Google Scholar

[28] Venkatesan R, Periasamy N, Srivastava T. Singlet molecular oxygen quantum yield measurements of some porphyrins and metalloporphyrins. Proc Indian Acad Sci-Chem Sci, 1992, 104: 713–722. Google Scholar

[29] Niedre M, Patterson MS, Wilson BC. Direct near-infrared luminescence detection of singlet oxygen generated by photodynamic therapy in cells in vitro and tissues in vivo. PhotoChem PhotoBiol, 2002, 75: 382-391 CrossRef Google Scholar

[30] Cheng Y, Cheng H, Jiang C, et al. Perfluorocarbon nanoparticles enhance reactive oxygen levels and tumour growth inhibition in photodynamic therapy. Nat Commun, 2015, 6: 8785 CrossRef PubMed ADS Google Scholar

[31] Zheng R, Wang S, Tian Y, et al. Polydopamine-coated magnetic composite particles with an enhanced photothermal effect. ACS Appl Mater Interfaces, 2015, 7: 15876-15884 CrossRef Google Scholar

[32] Tian Q, Jiang F, Zou R, et al. Hydrophilic Cu9S5 nanocrystals: a photothermal agent with a 25.7% heat conversion efficiency for photothermal ablation of cancer cells in vivo. ACS Nano, 2011, 5: 9761-9771 CrossRef PubMed Google Scholar

[33] Liang P, Wang Y, Wang P, et al. Triphenylamine flanked furan-diketopyrrolopyrrole for multi-imaging guided photothermal/photodynamic cancer therapy. Nanoscale, 2017, 9: 18890-18896 CrossRef PubMed Google Scholar

  • Figure 1

    (a) Proposed protonation mechanism of P-4 triggered by H+. (b–d) Color, absorbance and emission changes of P-4 solution (in DCM) with TFA addition.

  • Scheme 1

    Simplified representation of multi-imaging guided pH-responsive cancer PTT/PDT in vitro and in vivo with P-4 NPs.

  • Figure 2

    (a) Photographs of P-4 and P-4 NPs. (b) TEM image of P-4 NPs (pH 7.4), inset: DLS size distribution. (c, d) Absorbance of P-4 and P-4 NPs at different concentrations. (e) Fluorescence spectra of SOSG mixed with P-4 NPs (pH 7.4). (f, g) Photothermal curves of P-4 NPs at different concentrations and pH. (h) Heating and cooling curves of P-4 NPs (80 µg mL−1) for four cycles (660 nm, 0.8 W cm−2). (i) Photothermal curve of P-4 NPs (0.5 mL, 80 µg mL−1) during laser on and off (660 nm, 0.8 W cm−2, control: PBS).

  • Figure 3

    (a, b) MTT and flow cytometry assays (660 nm, 8 min, 0.8 W cm−2). (c, d) Fluorescence images (200×) of calcein-AM/PI co-staining HeLa cells incubated without and with P-4 NPs (660 nm, 10 min, 0.8 W cm−2, 16 µg mL−1).

  • Figure 4

    (a, b) Confocal fluorescence images of HeLa cells incubated with P-4 NPs (10 µg mL−1) and DCFH-DA after laser illumination. (c) Sub-cellular localization of P-4 NPs at pH 7.4 in HeLa cells. Scale bar: 10 µm; P-4 NPs and trackers were excited at 488 nm.

  • Figure 5

    (a) Fluorescence images of tumor and selected organs in tumor-bearing mice after intravenous injection of P-4 NPs. (b) Photothermal images of tumor-bearing mice in the absence and presence of P-4 NPs intravenous injection (80 µg mL−1, 100 µL). (c) Visual photographs of mice from three groups after 18 days treatment.

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