Abstract
Escherichia coli (E. coli) DH5α has been recognized as a non-pathogenic bacterial strain with tumor colonization ability. However, whether such a bacteria-driven drug-delivery system can improve the targeting of tumor therapy or not remains essentially untouched. Herein, a series of zinc phthalocyanine (ZnPc) photosensitizers with different numbers of charges were prepared and their electrostatic adhesion properties on E. coli were investigated via measuring their fluorescence intensities by flow cytometer. Among these ZnPc photosensitizers investigated, the ZnPc conjugate with four positive charges (named ZnPc-IR710) exhibited the highest loading capacity and the best fluorescence imaging performance of E. coli. With the help of E. coli, E. coli@ZnPc-IR710 presented a significantly enhanced cytotoxicity on human breast cancer MCF-7 cells compared with ZnPc-IR710 (survival rate of tumor cells was 39% vs. 57% at a concentration of 50 nmol L−1). Moreover, in vivo study showed that E. coli@ZnPc-IR710 remarkably inhibited the tumor growth and resulted in a complete tumor growth suppress in subcutaneous mouse 4T1 breast tumor model. These results demonstrated the great promise of bacterial-guided photodynamic therapy (PDT) in the treatment of solid tumors, and provide a unique strategy to enhance the antitumor efficacy of PDT by utilizing bacterial vectors in tumors.
摘要
大肠杆菌(简称E. coli) DH5α被认为是具有肿瘤定植能力的非致病菌, 然而这种细菌驱动的药物传递系统能否提高肿瘤治疗的靶向性却鲜有报道. 本文中, 我们通过制备一系列带有不同电荷数的酞菁锌(ZnPc)光敏剂, 研究了它们在大肠杆菌上的静电黏附特性, 并借助流式细胞仪检测了其荧光强度. 在所研究的ZnPc光敏剂中, 带有4个正电荷的酞菁光敏剂ZnPc-IR710对E. coli具有最高的载药量和最佳的荧光成像性能. 实验结果表明, 与没有E. coli的ZnPc-IR710比较, E. coli@ZnPc-IR710对人乳腺癌MCF-7细胞的细胞毒性显著增强(同样条件下, 该肿瘤细胞的存活率分别为39% (50 nmol L−1 E. coli@ZnPc-IR710)和57% (ZnPc-IR710). 此外, 在体药理实验研究表明, E. coli@ZnPc-IR710对小鼠4T1皮下乳腺肿瘤的生长具有明显抑制作用, 可完全抑制肿瘤生长. 这些实验结果显示了利用细菌作为药物驱动传递系统在光动力疗法治疗实体肿瘤中的巨大潜力, 同时也为增强光动力疗法的靶向抗肿瘤作用提供了独特策略.
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References
Jia Q, Chen M, Liu Q, et al. Ethylene glycol-mediated synthetic route for production of luminescent silicon nanorod as photodynamic therapy agent. Sci China Mater, 2017, 60: 881–891
Liang P, Tang H, Gu R, et al. A pH-responsive zinc(II) metalated porphyrin for enhanced photodynamic/photothermal combined cancer therapy. Sci China Mater, 2019, 62: 1199–1209
Han W, Zhang S, Deng R, et al. Self-assembled nanostructured photosensitizer with aggregation-induced emission for enhanced photodynamic anticancer therapy. Sci China Mater, 2020, 63: 136–146
Flentie K, Kocher B, Gammon ST, et al. A bioluminescent transposon reporter-trap identifies tumor-specific microenvironment-induced promoters in Salmonella for conditional bacterial-based tumor therapy. Cancer Discov, 2012, 2: 624–637
Stritzker J, Weibel S, Hill PJ, et al. Tumor-specific colonization, tissue distribution, and gene induction by probiotic Escherichia coli nissle 1917 in live mice. Int J Med Microbiol, 2007, 297: 151–162
Sasaki T, Fujimori M, Hamaji Y, et al. Genetically engineered bifidobacterium longum for tumor-targeting enzyme-prodrug therapy of autochthonous mammary tumors in rats. Cancer Sci, 2006, 97: 649–657
Bettegowda C, Dang LH, Abrams R, et al. Overcoming the hypoxic barrier to radiation therapy with anaerobic bacteria. Proc Natl Acad Sci USA, 2003, 100: 15083–15088
Neri D, Supuran CT. Interfering with pH regulation in tumours as a therapeutic strategy. Nat Rev Drug Discov, 2011, 10: 767–777
Khong HT, Restifo NP. Natural selection of tumor variants in the generation of “tumor escape” phenotypes. Nat Immunol, 2002, 3: 999–1005
Webb BA, Chimenti M, Jacobson MP, et al. Dysregulated pH: A perfect storm for cancer progression. Nat Rev Cancer, 2011, 11: 671–677
Yazawa K, Fujimori M, Nakamura T, et al. Bifidobacterium longum as a delivery system for gene therapy of chemically induced rat mammary tumors. Breast Cancer Res Treat, 2001, 66: 165–170
Zheng DW, Chen Y, Li ZH, et al. Optically-controlled bacterial metabolite for cancer therapy. Nat Commun, 2018, 9: 1680
Fan JX, Li ZH, Liu XH, et al. Bacteria-mediated tumor therapy utilizing photothermally-controlled TNF-α expression via oral administration. Nano Lett, 2018, 18: 2373–2380
Jia LJ, Xu HM, Ma DY, et al. Enhanced therapeutic effect by combination of tumor-targeting salmonella and endostatin in murine melanoma model. Cancer Biol Ther, 2005, 4: 840–845
Low KB, Ittensohn M, Le T, et al. Lipid a mutant salmonella with suppressed virulence and TNFα induction retain tumor-targeting in vivo. Nat Biotechnol, 1999, 17: 37–41
Zhang HY, Man JH, Liang B, et al. Tumor-targeted delivery of biologically active trail protein. Cancer Gene Ther, 2010, 17: 334–343
Cheng CM, Lu YL, Chuang KH, et al. Tumor-targeting prodrug-activating bacteria for cancer therapy. Cancer Gene Ther, 2008, 15: 393–401
Chen J, Chen N, Huang J, et al. Derivatizable phthalocyanine with single carboxyl group: Synthesis and purification. Inorg Chem Commun, 2006, 9: 313–315
Liu JY, Jiang XJ, Fong WP, et al. Highly photocytotoxic 1,4-dipegylated zinc(II) phthalocyanines. Effects of the chain length on the in vitro photodynamic activities. Org Biomol Chem, 2008, 6: 4560
Chen Z, Zhou S, Chen J, et al. An effective zinc phthalocyanine derivative for photodynamic antimicrobial chemotherapy. J Lumin, 2014, 152: 103–107
Zhang Y, Zheng K, Chen Z, et al. Rapid killing of bacteria by a new type of photosensitizer. Appl Microbiol Biotechnol, 2017, 101: 4691–4700
Zhang Y, Huang P, Wang D, et al. Near-infrared-triggered antibacterial and antifungal photodynamic therapy based on lanthanide-doped upconversion nanoparticles. Nanoscale, 2018, 10: 15485–15495
Forbes NS. Engineering the perfect (bacterial) cancer therapy. Nat Rev Cancer, 2010, 10: 785–794
Boumahdi S, de Sauvage FJ. The great escape: tumour cell plasticity in resistance to targeted therapy. Nat Rev Drug Discov, 2020, 19: 39–56
Xie S, Zhao L, Song X, et al. Doxorubicin-conjugated Escherichia coli nissle 1917 swimmers to achieve tumor targeting and responsive drug release. J Control Release, 2017, 268: 390–399
Li Y, Bai G, Zeng S, et al. Theranostic carbon dots with innovative NIR-II emission for in vivo renal-excreted optical imaging and photothermal therapy. ACS Appl Mater Interfaces, 2019, 11: 4737–4744
Jiang M, Liu H, Zeng S, et al. A general in situ growth strategy of designing theranostic NaLnF4@Cu2−xS nanoplatform for in vivo NIR-II optical imaging beyond 1500 nm and photothermal therapy. Adv Therap, 2019, 2: 1800153
Yi P, Chen G, Zhang H, et al. Magnetic resonance imaging of Fe3O4@SiO2-labeled human mesenchymal stem cells in mice at 11.7 T. Biomaterials, 2013, 34: 3010–3019
Tang S, Hu J, Meng Q, et al. Daidzein induced apoptosis via down-regulation of Bcl-2/Bax and triggering of the mitochondrial pathway in BGC-823 cells. Cell Biochem Biophys, 2013, 65: 197–202
Acknowledgements
This work was supported by the National Natural Science Foundation of China (81572944, 21471033, 21877113 and 81971983), the CAS/SAFEA International Partnership Program for Creative Research Teams, the High-Level Entrepreneurship and Innovation Talents Projects in Fujian Province (2018-8-1), and the FJIRSM&IUE Joint Research Fund (RHZX-2018-004).
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Author contributions Dai T and Chen Z conceived and designed the project. Ye F, Hu P and Chen J designed and synthesized zinc phthalocyanine conjugates 1–5. Dai T and Wang H performed the experiments. Dai T, Zhang L and Pan X analyzed the data. Chen J, Huang Y, Pan X and Huang M provided the technical support. Chen Z and Dai T finished the writing.
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Tao Dai received his BSc degree in biotechnology from Anhui Normal University in 2014. Currently he is a Master student in Prof. Zhuo Chen’s group at Fujian Institute of Research on the Structure of Matter (FJIRSM), Chinese Academy of Sciences. His current research focuses on the targeted drug delivery in tumor therapy.
Zhuo Chen received her PhD from FJIRSM, Chinese Academy of Sciences, following her MD degree from Fujian Medical University and her BSc degree from Chinese Pharmaceutical University. From 2001 to 2008, she worked on molecular pharmacology & therapeutics in Loyola University Chicago as a Research Associate. Her research focuses on tumor detection and targeted photodynamic therapy, including design and synthesis of new anticancer drug entities and evaluation of their pharmacological effects through experiments in cells and animals.
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Dai, T., Ye, F., Hu, P. et al. A strategy for enhanced tumor targeting of photodynamic therapy based on Escherichia coli-driven drug delivery system. Sci. China Mater. 64, 232–240 (2021). https://doi.org/10.1007/s40843-020-1363-2
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DOI: https://doi.org/10.1007/s40843-020-1363-2