Skip to main content
SpringerLink
Log in

Engineering a recombinant chlorotoxin as cell-targeted cytotoxic nanoparticles

重组氯毒素构建细胞靶向的活性纳米颗粒

  • Letters
  • Published:
Science China Materials Aims and scope Submit manuscript

摘要

功能性蛋白质在纳米尺度的可控寡聚化提供了通过重组DNA技术来设计和生产改良材料和药物的可能性. 氯毒素(CTX), 作为一种重组的蝎毒素, 由于其优先结合癌细胞的能力而引起人们的兴趣. 本研究将氯毒素设计并自组装为12 nm的常规纳米颗粒, 这些纳米颗粒可穿透具有和天然毒素相同受体特异性的培养细胞. 这些生物相容且可生物降解的材料, 表现出与同时作为载体和治疗剂的重组毒素相应的温和但仍然显著的细胞毒活性, 有希望成为用于细胞靶向治疗胶质瘤的药物载体. 此外, 对CTX侧区域的修改可有效影响纳米颗粒的性能, 说明基于CTX的构建体可通过常规基因工程来调节其多重功能性.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

References

  1. Serna N, Sánchez-García L, Unzueta U, et al. Protein-based therapeutic killing for cancer therapies. Trends Biotech, 2018, 36: 318–335

    Article  Google Scholar 

  2. DeBin JA, Maggio JE, Strichartz GR. Purification and characterization of chlorotoxin, a chloride channel ligand from the venom of the scorpion. Am J Physiol-Cell Physiol, 1993, 264: C361–C369

    Article  Google Scholar 

  3. DeBin JA, Strichartz GR. Chloride channel inhibition by the venom of the scorpion Leiurus quinquestriatus. Toxicon, 1991, 29: 1403–1408

    Article  Google Scholar 

  4. Veiseh M, Gabikian P, Bahrami SB, et al. Tumor paint: a chlorotoxin: Cy5.5 bioconjugate for intraoperative visualization of cancer foci. Cancer Res, 2007, 67: 6882–6888

    Article  Google Scholar 

  5. Deshane J, Garner CC, Sontheimer H. Chlorotoxin inhibits glioma cell invasion via matrix metalloproteinase-2. J Biol Chem, 2003, 278: 4135–4144

    Article  Google Scholar 

  6. Xu T, Fan Z, Li W, et al. Identification of two novel chlorotoxin derivatives CA4 and CTX-23 with chemotherapeutic and antiangiogenic potential. Sci Rep, 2016, 6: 19799

    Article  Google Scholar 

  7. Ojeda PG, Henriques ST, Pan Y, et al. Lysine to arginine mutagenesis of chlorotoxin enhances its cellular uptake. Biopolymers, 2017, 108: e23025

    Article  Google Scholar 

  8. Mamelak AN, Jacoby DB. Targeted delivery of antitumoral therapy to glioma and other malignancies with synthetic chlorotoxin (TM-601). Expert Opin Drug Deliver, 2007, 4: 175–186

    Article  Google Scholar 

  9. Kasai T, Nakamura K, Vaidyanath A, et al. Chlorotoxin fused to IgG-Fc inhibits glioblastoma cell motility via receptor-mediated endocytosis. J Drug Deliver, 2012, 2012: 1–10

    Article  Google Scholar 

  10. Vazquez E, Mangues R, Villaverde A. Functional recruitment for drug delivery through protein-based nanotechnologies. Nanomedicine, 2016, 11: 1333–1336

    Article  Google Scholar 

  11. Rueda F, Céspedes MV, Conchillo-Solé O, et al. Bottom-up instructive quality control in the biofabrication of smart protein materials. Adv Mater, 2015, 27: 7816–7822

    Article  Google Scholar 

  12. Serna N, Céspedes MV, Sánchez-García L, et al. Peptide-based nanostructured materials with intrinsic proapoptotic activities in CXCR4+ solid tumors. Adv Funct Mater, 2017, 27: 1700919

    Article  Google Scholar 

  13. Sánchez-García L, Serna N, Álamo P, et al. Self-assembling toxin-based nanoparticles as self-delivered antitumoral drugs. J Control Release, 2018, 274: 81–92

    Article  Google Scholar 

  14. Díaz R, Pallarès V, Cano-Garrido O, et al. Selective CXCR4+ cancer cell targeting and potent antineoplastic effect by a nanostructured version of recombinant ricin. Small, 2018, 14: 1800665

    Article  Google Scholar 

  15. Céspedes MV, Unzueta U, Aviñó A, et al. Selective depletion of metastatic stem cells as therapy for human colorectal cancer. EMBO Mol Med, 2018, 10: e8772

    Article  Google Scholar 

  16. Unzueta U, Ferrer-Miralles N, Cedano J, et al. Non-amyloidogenic peptide tags for the regulatable self-assembling of protein-only nanoparticles. Biomaterials, 2012, 33: 8714–8722

    Article  Google Scholar 

  17. Sánchez JM, Sánchez-García L, Pesarrodona M, et al. Conformational conversion during controlled oligomerization into nonamylogenic protein nanoparticles. Biomacromolecules, 2018, 19: 3788–3797

    Article  Google Scholar 

  18. Céspedes MV, Unzueta U, Tatkiewicz W, et al. In vivo architectonic stability of fully de novo designed protein-only nanoparticles. ACS Nano, 2014, 8: 4166–4176

    Article  Google Scholar 

  19. Unzueta U, Céspedes MV, Ferrer-Miralles N, et al. Intracellular CXCR4+ cell targeting with T22-empowered protein-only nanoparticles. Int J Nanomedicine, 2012, 7: 4533–4544

    Google Scholar 

  20. Serna N, Céspedes MV, Saccardo P, et al. Rational engineering of single-chain polypeptides into protein-only, BBB-targeted nanoparticles. NanoMed-Nanotechnol Biol Med, 2016, 12: 1241–1251

    Article  Google Scholar 

  21. Locatelli E, Naddaka M, Uboldi C, et al. Targeted delivery of silver nanoparticles and alisertib: in vitro and in vivo synergistic effect against glioblastoma. Nanomedicine, 2014, 9: 839–849

    Article  Google Scholar 

  22. Graf N, Mokhtari TE, Papayannopoulos IA, et al. Platinum(IV)-chlorotoxin (CTX) conjugates for targeting cancer cells. J Inorg Biochem, 2012, 110: 58–63

    Article  Google Scholar 

  23. Asphahani F, Wang K, Thein M, et al. Single-cell bioelectrical impedance platform for monitoring cellular response to drug treatment. Phys Biol, 2011, 8: 015006

    Article  Google Scholar 

  24. Locatelli E, Broggi F, Ponti J, et al. Lipophilic silver nanoparticles and their polymeric entrapment into targeted-PEG-based micelles for the treatment of glioblastoma. Adv Healthcare Mater, 2012, 1: 342–347

    Article  Google Scholar 

  25. Poty S, Désogère P, Goze C, et al. New AMD3100 derivatives for CXCR4 chemokine receptor targeted molecular imaging studies: synthesis, anti-HIV-1 evaluation and binding affinities. Dalton Trans, 2015, 44: 5004–5016

    Article  Google Scholar 

  26. Richard JP, Melikov K, Vives E, et al. Cell-penetrating peptides. J Biol Chem, 2003, 278: 585–590

    Article  Google Scholar 

  27. Dardevet L, Rani D, Aziz TAE, et al. Chlorotoxin: a helpful natural scorpion peptide to diagnose glioma and fight tumor invasion. Toxins, 2015, 7: 1079–1101

    Article  Google Scholar 

  28. Allen M, Bjerke M, Edlund H, et al. Origin of the U87MG glioma cell line: Good news and bad news. Sci Transl Med, 2016, 8: 354re3

    Article  Google Scholar 

  29. Shen J, Wolfram J, Ferrari M, et al. Taking the vehicle out of drug delivery. Mater Today, 2017, 20: 95–97

    Article  Google Scholar 

Download references

Acknowledgements

This study has been funded by the Agencia Estatal de Investigación (AEI) and Fondo Europeo de Desarrollo Regional (FEDER) (BIO2016-76063-R, AEI/FEDER, UE), AGAUR (2017SGR-229) and CIBER-BBN (project VENOM4CANCER) granted to Villaverde A, ISCIII (PI15/00272 co-founding FEDER) to Vázquez E. Protein production and DLS have been partially performed by the ICTS “NANBIOSIS”, more specifically by the Protein Production Platform of CIBER-BBN/IBB (https://doi.org/www.nanbiosis.es/unit/u1-protein-productionplatform-ppp/) and the Biomaterial Processing and Nanostructuring Unit (https://doi.org/www.nanbiosis.es/portfolio/u6-biomaterial-processing-andnanostructuring-unit/). Cytometry and cell culture experiments were performed at the Cytometry and Cell Culture Unit of the UAB (SCAC). Díaz R received an overseas predoctoral fellowship from Conacyt (Gobierno de México, 2016). Sánchez-Garcia L was supported by predoctoral fellowship from AGAUR (2018FI_B2_00051), Serna N was supported by a predoctoral fellowship from the Government of Navarra, and Unzueta U is supported by PERIS program from the health department of la Generalitat de Cataluña. Villaverde A received an ICREA ACADEMIA award.

Author information

Author notes

  1. Olivia Cano-Garrido

    Present address: Present address: Biomedical Research Institute Sant Pau (IIB-Sant Pau) and Josep Carreras Research Institute, Hospital de la Santa Creu i Sant Pau, 08025, Barcelona, Spain

Authors and Affiliations

  1. Institut de Biotecnologia i de Biomedicina, Universitat Autònoma de Barcelona, Bellaterra, 08193, Barcelona, Spain

    Raquel Díaz, Laura Sánchez-García, Naroa Serna, Olivia Cano-Garrido, Julieta M. Sánchez, Esther Vazquez & Antonio Villaverde

  2. Departament de Genètica i de Microbiologia, Universitat Autònoma de Barcelona, Bellaterra, 08193, Barcelona, Spain

    Raquel Díaz, Laura Sánchez-García, Naroa Serna, Olivia Cano-Garrido, Julieta M. Sánchez, Ugutz Unzueta, Esther Vazquez & Antonio Villaverde

  3. CIBER de Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN), Bellaterra, 08193, Barcelona, Spain

    Raquel Díaz, Laura Sánchez-García, Naroa Serna, Olivia Cano-Garrido, Esther Vazquez & Antonio Villaverde

  4. Servei de Microscòpia, Universitat Autònoma de Barcelona, Bellaterra, 08193, Barcelona, Spain

    Alejandro Sánchez-Chardi

  5. Universidad Nacional de Córdoba, Facultad de Ciencias Exactas, Físicas y Naturales, Córdoba, Argentina

    Julieta M. Sánchez

  6. ICTA and Departamento de Química, Cátedra de Química Biológica, Córdoba, Argentina

    Julieta M. Sánchez

  7. CONICET, Instituto de Investigaciones Biológicas y Tecnológicas (IIBYT), Córdoba, Argentina

    Julieta M. Sánchez

  8. Av. Velez Sarsfield 1611, X5016GCA, Córdoba, Argentina

    Julieta M. Sánchez

  9. Present address: Biomedical Research Institute Sant Pau (IIB-Sant Pau) and Josep Carreras Research Institute, Hospital de la Santa Creu i Sant Pau, 08025, Barcelona, Spain

    Ugutz Unzueta

Authors
  1. Raquel Díaz
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Laura Sánchez-García
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Naroa Serna
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Alejandro Sánchez-Chardi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Olivia Cano-Garrido
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Julieta M. Sánchez
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Ugutz Unzueta
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Esther Vazquez
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Antonio Villaverde
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Ugutz Unzueta or Antonio Villaverde.

Additional information

Raquel Díaz studied chemical engineering at the University of Sonora, (Mexico, 2008) and achieved a one-year academic exchange at the University of British Columbia (Canada, 2007-2008). Later she fulfilled her Master’s study in materials science at the University of Sonora (Mexico, 2012) and is currently studying her PhD in biotechnology at the Autonomous University of Barcelona (Spain, 2019), particularly in the cancer research investigation line.

Ugutz Unzueta developed his PhD in Biotechnology at the Nanobiotechnology group led by Prof. Villaverde at the Autonomous University of Barcelona and he is currently a post-doctoral researcher at Oncogenesis and Antitumoral drugs group at Sant Pau Biomedical Research Institute in Barcelona. His research line is mainly focused on the design, production and characterization of self-assembling protein nanoparticles and nanoconjugates for targeted cancer nanomedicines.

Antonio Villaverde graduated in biological sciences in 1982 and got his PhD in 1985. Since 1987, he is Professor of Microbiology at the Universitat Autònoma de Barcelona in Spain, where he got a Full Professorship in 2002. He leads the Nanobiotechnology group in this university and in the CIBER-BBN, and he is devoted to the design of protein-based materials for biomedical applications. He founded the journal Microbial Cell Factories in 2002 being its Editor-in-Chief for 15 years.

Electronic supplementary material

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Díaz, R., Sánchez-García, L., Serna, N. et al. Engineering a recombinant chlorotoxin as cell-targeted cytotoxic nanoparticles. Sci. China Mater. 62, 892–898 (2019). https://doi.org/10.1007/s40843-018-9391-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40843-018-9391-y

Search

Navigation