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A transistor-like pH-sensitive nanodetergent for selective cancer therapy

Nature Nanotechnology volume 17, pages 541–551 (2022)Cite this article

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A Publisher Correction to this article was published on 12 May 2022

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Abstract

Plasma membrane rupture is a promising strategy for drug-resistant cancer treatment, but its application is limited by the low tumour selectivity of membranolytic molecules. Here we report the design of ‘proton transistor’ nanodetergents that can convert the subtle pH perturbation signals of tumour tissues into sharp transition signals of membranolytic activity for selective cancer therapy. Our top-performing ‘proton transistor’ nanodetergent, P(C6-Bn20), can achieve a >32-fold change in cytotoxicity with a 0.1 pH input signal. At physiological pH, P(C6-Bn20) self-assembles into neutral nanoparticles with inactive membranolytic blocks shielded by poly(ethylene glycol) shells, exhibiting low toxicity. At tumour acidity, a sharp transition in its protonation state induces a morphological transformation and an activation of the membranolytic blocks, and the cation–π interaction facilitates the insertion of benzyl groups-containing hydrophobic domains into the cell membranes, resulting in potent membranolytic activity. P(C6-Bn20) is well tolerated in mice and shows high anti-tumour efficacy in various mouse tumour models.

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Fig. 1: The construction of pTNTs.
Fig. 2: P(C6-Bn20) showed the best selectivity with the contribution of aromatic interaction.
Fig. 3: The pH-dependent properties and membranolytic behaviour of P(C6-Bn20).
Fig. 4: PS contributes to the membranolytic activity of P(C6-Bn20).
Fig. 5: P(C6-Bn20) inhibits Panc02 tumour growth in tumour-bearing mice.
Fig. 6: P(C6-Bn20) effectively inhibits tumour growth in a lung metastasis model and a PDX model but exhibits minimal toxicity against normal tissues.

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Data availability

All relevant data of this study are available within the paper and its Supplementary Information files. Full gels of the SDS–PAGE image in Fig. 3i are provided as Source data with this paper. The raw and analysed datasets generated during the study are available for research purposes from the corresponding authors on reasonable request.

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Acknowledgements

We thank G. Yao (Nanfang Hospital) for providing the patient sample. We thank J. Li (Sun Yat-sen Memorial Hospital, Sun Yat-sen University) for providing the cisplatin-resistant human tongue cancer cell line CAL27/DDP. This work was supported by National Key R&D Program of China grant no. 2017YFA0205600 (J.W.); the National Natural Science Foundation of China grants no. 51633008 (J.W.), no. 52073102 (M.X.), no. 32171319 (Y.B.), no. 31971297 (Y.B.), no. U1801252 (M.X.) and no. 32000949 (M.L.); the Program for Guangdong Introducing Innovative and Entrepreneurial Teams grant no. 2017ZT07S054 (J.W.); Guangdong Provincial Pearl River Talents Program grants no. 2019QN01Y090 (M.X.) and no. 2017GC010713 (J.W.); the Key Research and Development Program of Guangzhou grant no. 202007020002 (M.X.); the Natural Science Foundation of Guangdong Province grants no. 2019A1515110617 (M.L.) and no. 2021A1515012492 (M.L.); the China Postdoctoral Science Foundation grant no. 2019M652909 (M.L.); and Guangdong Science and Technology Department grants no. 2020B1212060018 (Y.B.) and no. 2020B1212030004 (Y.B.).

Author information

Author notes

  1. These authors contributed equally: Mingdong Liu, Liangqi Huang, Weinan Zhang.

Authors and Affiliations

  1. School of Biomedical Sciences and Engineering, South China University of Technology, Guangzhou International Campus, Guangzhou, P. R. China

    Mingdong Liu, Liangqi Huang, Weinan Zhang, Xiaochuan Wang, Yuanyuan Geng, Yuhao Zhang, Menghua Xiong & Jun Wang

  2. National Engineering Research Centre for Tissue Restoration and Reconstruction, South China University of Technology, Guangzhou, P. R. China

    Mingdong Liu, Liangqi Huang, Weinan Zhang, Xiaochuan Wang, Yuanyuan Geng, Wenbin Zhang, Yun-Jiao Zhang, Menghua Xiong & Jun Wang

  3. Key Laboratory of Biomedical Materials and Engineering of the Ministry of Education, South China University of Technology, Guangzhou, P. R. China

    Yuhao Zhang

  4. Department of Polymer Science and Engineering, University of Science and Technology of China, Hefei, P. R. China

    Li Wang & Shiyan Xiao

  5. Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, P. R. China

    Yan Bao

  6. Key Laboratory of Biomedical Engineering of Guangdong Province, and Innovation Centre for Tissue Restoration and Reconstruction, South China University of Technology, Guangzhou, P. R. China

    Jun Wang

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Contributions

M.L., L.H. and Weinan Zhang designed and performed the majority of the experiments, analysed the data and wrote the manuscript. X.W. and Y.Z. assisted with polymer synthesis and characterization. Y.G. performed the GUV study. L.W. helped with the cryo-TEM observation. S.X. performed and analysed the simulation studies, and wrote the manuscript. Wenbin Zhang helped with the PDX model. Y.-J.Z. provided the PDX model. Y.B., M.X. and J.W. supervised all of the experiments, analysed the data and revised the final manuscript.

Corresponding authors

Correspondence to Shiyan Xiao, Yan Bao, Menghua Xiong or Jun Wang.

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Competing interests

M.L., L.H., X.W., Y.B., M.X. and J.W. have submitted a patent application (PCT/CN2021/102758) related to this study. The other authors declare no competing interests.

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Nature Nanotechnology thanks Cameron Alexander, Yiyan Yang and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Extended data

Extended Data Fig. 1 The proton transistor-like properties of P(C6-Rx) copolymers.

a, PD as a function of pH for P(C6-Rx) copolymers when R was methyl (Me), ethyl (E), butyl (Bu), hexyl (H), iso-octyl (IO), tetradecyl (T). b, Merged images of Panc02GFP/mCherry cells incubated with P(C6-Rx) copolymers (160 μg ml-1) at different pH conditions for 2 h by a HCAS. The red fluorescence represents the fluorescent protein mCherry, and the green fluorescence represents MyrPalm-GFP. The scale bar is 40 μm. The cytotoxicity of P(C6-Bnx) (c) and P(C6-R20) (d) copolymers (160 μg ml-1) against Panc02 cells at different pH conditions after 2 h incubation. In c, d, n = 3 biologically independent samples, and the data are presented as the mean ± s.d. The representative images in b were shown from two independent experiments.

Extended Data Fig. 2 The cytotoxicity of P(C6-Rx) at pH 7.4 or 6.8.

The concentration dependent cytotoxicity of pTNTs against Panc02 cells after 24 h incubation at pH 7.4 (a) and after 4 h incubation at pH 6.8 (b). c, The concentration-dependent cytotoxicity of P(C6-Bn20) against normal cell lines at pH 7.4 after 24 h of incubation. d, The concentration-dependent cytotoxicity of P(C6-Bn20) against a variety of cancer cells at pH 6.8 after 4 h incubation. In c, d, n = 3 biologically independent samples, and the data are presented as the mean ± s.d.

Extended Data Fig. 3 The chemical structures, pH dependent PD and cytotoxicity of P(C6-Ph20) and P(C6-NPh20).

Illustration of chemical structure of P(C6-Ph20) (a) and P(C6-NPh20) (b). c, The PD as a function of pH for P(C6-Ph20) and P(C6-NPh20). The concentration dependent cytotoxicity of P(C6-Ph20) and P(C6-NPh20) against Panc02 cells after 24 h incubation at pH 7.4 (d) and after 4 h incubation at pH 6.8 (e). In d, e, n = 3 biologically independent samples, and the data are presented as the mean ± s.d.

Extended Data Fig. 4 Atomic molecular dynamics simulation studies.

The recorded force of pulling a P(C6-Bn20)l (a), P(C6-Bn20)h (b), P(C6-H20)l (c) and P(C6-H20)h (d) molecule away from an aggregated particle of 8 molecules as a function of the distance between the selected molecule and the mass centre of the other seven molecules. Time evolution of the interactions between P(C6-Bn20)l (e), P(C6-Bn20)h (f), P(C6-H20)l (g) and P(C6-H20)h (h) molecules with bilayer membranes (a mixed PC/PS bilayer with a fixed ratio of 3:1). The recorded force of pulling a molecule of P(C6-Bn20)h (i) and P(C6-H20)h (j) towards the bilayer membrane as a function of the height between the molecule and the bilayer centre. In a-d, i, j, n ≥ 10 independent experiments, and the data are shown as the mean ± s.d.

Extended Data Fig. 5 The NMR spectra of P(C6-Bn20) and P(C6-NPh20) at different pH conditions.

a, 1H NMR spectra of P(C6-Bn20) at pH 7.4, 7.0, 6.8 and 6.5. The diffusion ordered NMR spectra of P(C6-Bn20) at pH 7.4 (b) and 6.8 (c) in D2O. d, 1H NMR spectra of P(C6-NPh20) at pH 7.4, 7.0, 6.8 and 6.5. The diffusion ordered NMR spectra of P(C6-NPh20) at pH 7.4 (e) and 6.8 (f) in D2O.

Extended Data Fig. 6 The cytotoxicity of P(C6-Bn20) at pH 6.8 when incubated at 4 °C, with inhibitors, or with FBS.

a, The concentration-dependent cytotoxicity of P(C6-Bn20) against Panc02 cells when incubated at 37 °C or 4 °C at pH 7.4 or 6.8. b, The concentration-dependent cytotoxicity of P(C6-Bn20) against Panc02 cells at pH 6.8 after the pretreatment with methyl-β-cyclodextrin (M-β-C, a caveolae-dependent endocytosis inhibitor, 50 μM), wortmannin (Wor, a macropinocytosis inhibitor, 50 nM), deoxyglucose (Deo, an energy-dependent endocytosis inhibitor, 50 mM), or chlorpromazine (Chl, a clathrin-dependent endocytosis inhibitor, 10 μg ml-1) for 0.5 h. c, The concentration-dependent cytotoxicity of P(C6-Bn20) against Panc02 cells at pH 6.8 after the pretreatment with VX-765 (a caspase 1/4 inhibitor, 40 µM), Z-VAD (a pan-caspase inhibitor, 40 µM), ferrostatin (Fer, a ferroptosis inhibitor, 1 µM) or Nec-1 (a necrosis inhibitor, 100 µM) for 0.5 h. d, The diameter of P(C6-Bn20) (1.0 mg ml-1) as a function of time when incubated in PBS with 10% FBS at 37 °C under gentle stirring. e, The concentration-dependent cytotoxicity of P(C6-Bn20) against Panc02 cells at pH 6.8 when preincubated with or without 10% FBS for 24 h at pH 7.4. In a-e, n = 3 biologically independent samples, and the data are presented as the mean ± s.d.

Extended Data Fig. 7 The anti-tumour efficacy of P(C6-Bn20) against CT26 colon tumour model and B16-F10 melanoma model.

a, Treatment schedule for the murine CT26 colon tumour model. BALB/c mice were inoculated with CT26 cells on day 0. The tumour-bearing mice were then treated with PBS or P(C6-Bn20) (50 mg kg-1) daily from day 15 to 20. b, The tumour growth inhibition study of CT26 tumours. Images (c) and weight (d) of excised CT26 tumours after treatment. e, The weight of mice during the treatments. f, Treatment schedule for the murine B16-F10 melanoma model. C57BL/6 mice were inoculated with B16-F10 cells on day 0. The tumour-bearing mice were then treated with PBS or P(C6-Bn20) (50 mg kg-1) daily from day 6 to 10. g, The tumour growth inhibition study of B16-F10 tumours. Images (h) and weight (i) of excised B16-F10 tumours after treatment. j, The weight of mice during the treatments. In b, d, e, g, i, j, data are shown as the mean ± s.e.m. (n = 7 independent mice in b, d, e; n = 6 independent mice in g, i, j). Statistical significance was determined by unpaired two-tailed Student’s t-test.

Extended Data Fig. 8 The pharmacokinetic behaviours, distribution, and in-vivo toxicity of P(C6-Bn20).

a, The pharmacokinetic behaviours of cy5 labelled P(C6-Bn20) following intravenous (i.v.) injection at a dose of 50 mg kg-1 into healthy ICR mice. b, The biodistribution of cy5 labelled P(C6-Bn20) after i.v. injection into Panc02 tumour-bearing C57BL/6 mice. c, H&E staining of normal tissues, including the heart, liver, spleen, lung, and kidney 24 h after one i.v. injection of PBS or P(C6-Bn20) (50 mg kg-1). The scale bar is 200 μm. d, The schedule for the evaluation of toxicity of P(C6-Bn20). PBS or P(C6-Bn20) (50 mg kg-1) was intravenously administrated every other day for 4 injections. The mice were sacrificed and serum samples were collected at 7, 14 and 28 days after the last injection for the detection of the concentrations of AST (e), ALT (f), Urea (g) and UA (h). In a, data are shown as the mean ± s.d. (n = 5 independent mice). In b, e-h, data are shown as the mean ± s.e.m. (n = 3 independent mice). Statistical significance was determined by unpaired two-tailed Student’s t-test. In c, the representative images from three independent mice were shown.

Supplementary information

Supplementary Information

Additional materials and methods and Supplementary Table 1, Schemes 1 and 2, and Fig. 1.

Reporting Summary

Supplementary Video 1

The distribution of Bn groups in the aggregation of P(C6-Bn20)l.

Supplementary Video 2

The distribution of Bn groups in the aggregation of P(C6-Bn20)h.

Supplementary Video 3

The distribution of H groups in the aggregation of P(C6-H20)l.

Supplementary Video 4

The distribution of H groups in the aggregation of P(C6-H20)h.

Supplementary Video 5

Video of pulling a P(C6-Bn20)l molecule away from an aggregated particle of 8 molecules.

Supplementary Video 6

Video of pulling a P(C6-Bn20)h molecule away from an aggregated particle of 8 molecules.

Supplementary Video 7

Video of pulling a P(C6-H20)l molecule away from an aggregated particle of 8 molecules.

Supplementary Video 8

Video of pulling a P(C6-H20)h molecule away from an aggregated particle of 8 molecules.

Supplementary Video 9

Video of pulling P(C6-Bn20)h through the membrane until complete polymer insertion.

Supplementary Video 10

Video of pulling P(C6-H20)h through the membrane until complete polymer insertion.

Supplementary Video 11

Video of the interactions between the P(C6-Bn20)-cy5 and Panc02GFP/mCherry cells at pH 7.4.

Supplementary Video 12

Video of the interactions between the P(C6-Bn20)-cy5 and Panc02GFP/mCherry cells at pH 6.8.

Supplementary Video 13

Video of Panc02 cells incubated with P(C6-Bn20)-cy5, Annexin V-FITC and PI at pH 6.8.

Source data

Source Data Fig. 1

Unprocessed gels for Fig. 3i.

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Liu, M., Huang, L., Zhang, W. et al. A transistor-like pH-sensitive nanodetergent for selective cancer therapy. Nat. Nanotechnol. 17, 541–551 (2022). https://doi.org/10.1038/s41565-022-01085-5

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