Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Tailoring renal-clearable zwitterionic cyclodextrin for colorectal cancer-selective drug delivery

Nature Nanotechnology volume 18, pages 945–956 (2023)Cite this article

Subjects

Abstract

Although cyclodextrin-based renal-clearable nanocarriers have a high potential for clinical translation in targeted cancer therapy, their designs remain to be optimized for tumour retention. Here we report on the design of a tailored structure for renal-clearable zwitterionic cyclodextrin for colorectal cancer-selective drug delivery. Twenty cyclodextrin derivatives with different charged moieties and spacers are synthesized and screened for colloidal stability. The resulting five candidates are evaluated for biodistribution and an optimized structure is identified. The optimized cyclodextrin shows a high tumour accumulation and is used for delivery of doxorubicin and ulixertinib. Higher tumour accumulation and tumour penetration facilitates tumour elimination. The improved antitumour efficacy is demonstrated in heterotopic and orthotopic colorectal cancer models.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Renal-clearable CD derivatives for enhanced tumour retention and reduced off-target accumulation.
Fig. 2: Tumour targetability, pharmacokinetics and urinary excretion of PBA-(ZW)-CD/ACy7.
Fig. 3: Preparation and characterization of PBA-(ZW)-CD/drug inclusion complexes.
Fig. 4: Biodistribution of PBA-(ZW)-CD/drug inclusion complexes.
Fig. 5: PBA-(ZW)-CD/drug-assisted combination therapy in CRC models.

Similar content being viewed by others

Data availability

All data generated or analysed during this study are included in this published article and its Supplementary Information files. Source data is available for Figs. 1c,e, 2d,f,g, 3e,f, 4a,b,d,e and 5a–c,e,f, and Supplementary Figs. 8d, 9c, 11a,b, 13a,c, 14b,c, 15a,d,f, 16a,b, 17a,b, 18a,b,d, 19a–c, 20a–c, 21a,b, 22 and 25a–c in the associated source data files.

References

  1. Blanco, E. et al. Principles of nanoparticle design for overcoming biological barriers to drug delivery. Nat. Biotechnol. 33, 941–951 (2015).

    Article  CAS  Google Scholar 

  2. Yu, M. X. & Zheng, J. Clearance pathways and tumor targeting of imaging nanoparticles. ACS Nano 9, 6655–6674 (2015).

    CAS  Google Scholar 

  3. Nurunnabi, M. et al. In vivo biodistribution and toxicology of carboxylated graphene quantum dots. ACS Nano 7, 6858–6867 (2013).

    CAS  Google Scholar 

  4. Li, B. & Lane, L. A. Probing the biological obstacles of nanomedicine with gold nanoparticles. Wiley Interdiscip. Rev. Nanomed. Nanobiotechnol. 11, e1542 (2019).

    Google Scholar 

  5. Zhang, Y. N. et al. Nanoparticle–liver interactions: cellular uptake and hepatobiliary elimination. J. Control. Release 240, 332–348 (2016).

    Article  CAS  Google Scholar 

  6. Longmire, M. et al. Clearance properties of nano-sized particles and molecules as imaging agents: considerations and caveats. Nanomedicine 3, 703–717 (2008).

    Article  CAS  Google Scholar 

  7. Cheng, Y. H. et al. Meta-analysis of nanoparticle delivery to tumors using a physiologically based pharmacokinetic modeling and simulation approach. ACS Nano 14, 3075–3095 (2020).

    CAS  Google Scholar 

  8. Lammers, T. Macro-nanomedicine: targeting the big picture. J. Control. Release 294, 372–375 (2019).

    Article  CAS  Google Scholar 

  9. Choi, H. S. et al. Renal clearance of quantum dots. Nat. Biotechnol. 25, 1165–1170 (2007).

    Article  CAS  Google Scholar 

  10. Liu, J. B. et al. Renal clearable inorganic nanoparticles: a new frontier of bionanotechnology. Mater. Today 16, 477–486 (2013).

    Article  CAS  Google Scholar 

  11. Zhou, C. et al. Luminescent gold nanoparticles with efficient renal clearance. Angew. Chem. Int. Ed. 50, 3168–3172 (2011).

    Article  CAS  Google Scholar 

  12. Zhou, C. et al. Near-infrared emitting radioactive gold nanoparticles with molecular pharmacokinetics. Angew. Chem. Int. Ed. 51, 10118–10122 (2012).

    Article  CAS  Google Scholar 

  13. Liu, J. B. et al. Passive tumor targeting of renal-clearable luminescent gold nanoparticles: long tumor retention and fast normal tissue clearance. J. Am. Chem. Soc. 135, 4978–4981 (2013).

    Article  CAS  Google Scholar 

  14. Burns, A. A. et al. Fluorescent silica nanoparticles with efficient urinary excretion for nanomedicine. Nano Lett. 9, 442–448 (2009).

    CAS  Google Scholar 

  15. Ruggiero, A. et al. Paradoxical glomerular filtration of carbon nanotubes. Proc. Natl Acad. Sci. USA 107, 12369–12374 (2010).

    Article  CAS  Google Scholar 

  16. Peng, C. Q. et al. Correlating anticancer drug delivery efficiency with vascular permeability of renal clearable versus non-renal clearable nanocarriers. Angew. Chem. Int. Ed. 58, 12076–12080 (2019).

    Article  CAS  Google Scholar 

  17. Peng, C. Q. et al. Renal clearable nanocarriers: overcoming the physiological barriers for precise drug delivery and clearance. J. Control. Release 322, 64–80 (2020).

    Article  CAS  Google Scholar 

  18. Peng, C. et al. Tuning the in vivo transport of anticancer drugs using renal-clearable gold nanoparticles. Angew. Chem. Int. Ed. 58, 8479–8483 (2019).

    Article  CAS  Google Scholar 

  19. Liu, J. et al. PEGylation and zwitterionization: pros and cons in the renal clearance and tumor targeting of near-IR-emitting gold nanoparticles. Angew. Chem. Int. Ed. 52, 12572–12576 (2013).

    Article  CAS  Google Scholar 

  20. Kang, H. et al. Renal clearable theranostic nanoplatforms for gastrointestinal stromal tumors. Adv. Mater. 32, e1905899 (2020).

    Article  Google Scholar 

  21. Kang, H. et al. Renal clearable organic nanocarriers for bioimaging and drug delivery. Adv. Mater. 28, 8162–8168 (2016).

    Article  CAS  Google Scholar 

  22. Wang, H. et al. Renal-clearable porphyrinic metal–organic framework nanodots for enhanced photodynamic therapy. ACS Nano 13, 9206–9217 (2019).

    CAS  Google Scholar 

  23. Choi, H. S. et al. Design considerations for tumour-targeted nanoparticles. Nat. Nanotechnol. 5, 42–47 (2010).

    Article  CAS  Google Scholar 

  24. Huang, H. et al. Inorganic nanoparticles in clinical trials and translations. Nano Today 35, 100972 (2020).

    CAS  Google Scholar 

  25. Missaoui, W. N. et al. Toxicological status of nanoparticles: what we know and what we don’t know. Chem. Biol. Interact. 295, 1–12 (2018).

    Article  CAS  Google Scholar 

  26. Kang, H. et al. Size-dependent EPR effect of polymeric nanoparticles on tumor targeting. Adv. Healthc. Mater. 9, 1901223 (2020).

    Article  CAS  Google Scholar 

  27. Choi, H. S. et al. Targeted zwitterionic near-infrared fluorophores for improved optical imaging. Nat. Biotechnol. 31, 148–153 (2013).

    Article  CAS  Google Scholar 

  28. Verbeek, F. P. R. et al. Near-infrared fluorescence imaging of both colorectal cancer and ureters using a low-dose integrin targeted probe. Ann. Surg. Oncol. 21, S528–S537 (2014).

    Article  Google Scholar 

  29. Sofias, A. M. et al. Tumor targeting by αvβ3-integrin-specific lipid nanoparticles occurs via phagocyte hitchhiking. ACS Nano 14, 7832–7846 (2020).

    CAS  Google Scholar 

  30. McNeeley, K. M. et al. Decreased circulation time offsets increased efficacy of PEGylated nanocarriers targeting folate receptors of glioma. Nanotechnology 18, 385101 (2007).

    Article  Google Scholar 

  31. Shuhendler, A. J. et al. A novel solid lipid nanoparticle formulation for active targeting to tumor αvβ3 integrin receptors reveals cyclic RGD as a double-edged sword. Adv. Healthc. Mater. 1, 600–608 (2012).

    Article  CAS  Google Scholar 

  32. Cheng, W. W. & Allen, T. M. Targeted delivery of anti-CD19 liposomal doxorubicin in B-cell lymphoma: a comparison of whole monoclonal antibody, Fab′ fragments and single chain Fv. J. Control. Release 126, 50–58 (2008).

    Article  CAS  Google Scholar 

  33. Zhang, Y. et al. Strategies and challenges to improve the performance of tumor-associated active targeting. J. Mater. Chem. B 8, 3959–3971 (2020).

    Article  CAS  Google Scholar 

  34. Zhao, Z. et al. Targeting strategies for tissue-specific drug delivery. Cell 181, 151–167 (2020).

    Article  CAS  Google Scholar 

  35. Bray, F. et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin. 70, 313–313 (2020).

    Article  Google Scholar 

  36. McCleary, N. J. et al. Personalizing adjuvant therapy for stage II/III colorectal cancer. Am. Soc. Clin. Oncol. Educ. Book. 37, 232–245 (2017).

    Article  Google Scholar 

  37. Jalaeikhoo, H. et al. Effectiveness of adjuvant chemotherapy in patients with stage II colorectal cancer: a multicenter retrospective study. J. Res. Med. Sci. 24, 39 (2019).

    Article  CAS  Google Scholar 

  38. Taieb, J. & Gallois, C. Adjuvant chemotherapy for stage III colon cancer. Cancers 12, 2679 (2020).

    Article  CAS  Google Scholar 

  39. Braun, M. S. & Seymour, M. T. Balancing the efficacy and toxicity of chemotherapy in colorectal cancer. Ther. Adv. Med. Oncol. 3, 43–52 (2011).

    Article  CAS  Google Scholar 

  40. Xie, Y. H. et al. Comprehensive review of targeted therapy for colorectal cancer. Signal Transduct. Target. Ther. 5, 22 (2020).

    Article  CAS  Google Scholar 

  41. Ooi, H. W. et al. Multivalency enables dynamic supramolecular host-guest hydrogel formation. Biomacromolecules 21, 2208–2217 (2020).

    Article  CAS  Google Scholar 

  42. Lee, D. W. et al. Supramolecular assembly based on host–guest interaction between beta-cyclodextrin and adamantane for specifically targeted cancer imaging. J. Ind. Eng. Chem. 57, 37–44 (2018).

    Article  CAS  Google Scholar 

  43. Galema, H. A. et al. Fluorescence-guided surgery in colorectal cancer; a review on clinical results and future perspectives. Eur. J. Surg. Oncol. 48, 810–821 (2022).

    Article  Google Scholar 

  44. Tringale, K. R. et al. Image-guided surgery in cancer: a strategy to reduce incidence of positive surgical margins. Wiley Interdiscip. Rev. Syst. Biol. 10, e1412 (2018).

    Google Scholar 

  45. Keller, D. S. et al. Indocyanine green fluorescence imaging in colorectal surgery: overview, applications, and future directions. Lancet Gastroenterol. Hepatol. 2, 757 (2017).

    Article  Google Scholar 

  46. Shukla, A. et al. Blocking of ERK1 and ERK2 sensitizes human mesothelioma cells to doxorubicin. Mol. Cancer 9, 314 (2010).

    Article  CAS  Google Scholar 

  47. Salaroglio, I. C. et al. ERK is a pivotal player of chemo-immune-resistance in cancer. Int. J. Mol. Sci. 20, 2505 (2019).

    Article  CAS  Google Scholar 

  48. Christowitz, C. et al. Mechanisms of doxorubicin-induced drug resistance and drug resistant tumour growth in a murine breast tumour model. BMC Cancer 19, 757 (2019).

    Article  Google Scholar 

  49. Ortiz, R. et al. Nanomedicine to overcome multidrug resistance mechanisms in colon and pancreatic cancer: recent progress. Cancers 13, 2058 (2021).

    Article  CAS  Google Scholar 

  50. Kim, D. H. et al. Effects of kefir on doxorubicin-induced multidrug resistance in human colorectal cancer cells. J. Funct. Food 78, 104371 (2021).

    Article  CAS  Google Scholar 

  51. Yuan, C. et al. Inclusion complex of astaxanthin with hydroxypropyl-beta-cyclodextrin: UV, FTIR, H-1 NMR and molecular modeling studies. Carbohydr. Polym. 89, 492–496 (2012).

    Article  CAS  Google Scholar 

  52. Hamdi, H. et al. Spectroscopic studies of inclusion complex of beta-cyclodextrin and benzidine diammonium dipicrate. Spectrochim. Acta A 75, 32–36 (2010).

    Article  CAS  Google Scholar 

  53. Lv, S. et al. High drug loading and sub-quantitative loading efficiency of polymeric micelles driven by donor–receptor coordination interactions. J. Am. Chem. Soc. 140, 1235–1238 (2018).

    Article  CAS  Google Scholar 

  54. Hiensch, A. E. et al. Doxorubicin-induced skeletal muscle atrophy: elucidating the underlying molecular pathways. Acta Physiol. 229, e13400 (2020).

    Article  Google Scholar 

  55. Ou, H. C. et al. Low-level laser prevents doxorubicin-induced skeletal muscle atrophy by modulating AMPK/SIRT1/PCG-1alpha-mediated mitochondrial function, apoptosis and up-regulation of pro-inflammatory responses. Cell Biosci. 11, 200 (2021).

    Article  CAS  Google Scholar 

  56. Henriksen, P. A. Anthracycline cardiotoxicity: an update on mechanisms, monitoring and prevention. Heart 104, 971–977 (2018).

    Article  CAS  Google Scholar 

  57. Tian, Z. et al. High cumulative doxorubicin dose for advanced soft tissue sarcoma. BMC Cancer 20, 1139 (2020).

    Article  CAS  Google Scholar 

  58. Luo, R. et al. Distinct biodistribution of doxorubicin and the altered dispositions mediated by different liposomal formulations. Int. J. Pharm. 519, 1–10 (2017).

    Article  CAS  Google Scholar 

  59. Patel, K. J. et al. Distribution of the anticancer drugs doxorubicin, mitoxantrone and topotecan in tumors and normal tissues. Cancer Chemother. Pharmacol. 72, 127–138 (2013).

    Article  CAS  Google Scholar 

  60. Speth, P. A. et al. Clinical pharmacokinetics of doxorubicin. Clin. Pharmacokinet. 15, 15–31 (1988).

    Article  CAS  Google Scholar 

  61. Terasaki, T. et al. Pharmacokinetic study on the mechanism of tissue distribution of doxorubicin: interorgan and interspecies variation of tissue-to-plasma partition coefficients in rats, rabbits, and guinea pigs. J. Pharm. Sci. 73, 1359–1363 (1984).

    Article  CAS  Google Scholar 

  62. Tredan, O. et al. Drug resistance and the solid tumor microenvironment. J. Natl Cancer Inst. 99, 1441–1454 (2007).

    Article  CAS  Google Scholar 

  63. Torok, S. et al. Limited tumor tissue drug penetration contributes to primary resistance against angiogenesis inhibitors. Theranostics 7, 400–412 (2017).

    Article  CAS  Google Scholar 

  64. Ziemys, A. et al. Progression-dependent transport heterogeneity of breast cancer liver metastases as a factor in therapeutic resistance. J. Control. Release 291, 99–105 (2018).

    Article  CAS  Google Scholar 

  65. Cabral, H. et al. Accumulation of sub-100 nm polymeric micelles in poorly permeable tumours depends on size. Nat. Nanotechnol. 6, 815–823 (2011).

    Article  CAS  Google Scholar 

  66. Zhou, Q. et al. Enzyme-activatable polymer–drug conjugate augments tumour penetration and treatment efficacy. Nat. Nanotechnol. 14, 799–809 (2019).

    Article  CAS  Google Scholar 

  67. Jain, R. K. & Stylianopoulos, T. Delivering nanomedicine to solid tumors. Nat. Rev. Clin. Oncol. 7, 653–664 (2010).

    Article  CAS  Google Scholar 

  68. Waite, C. L. & Roth, C. M. Nanoscale drug delivery systems for enhanced drug penetration into solid tumors: current progress and opportunities. Crit. Rev. Biomed. Eng. 40, 21–41 (2012).

    Article  Google Scholar 

  69. Sun, D. X. et al. What went wrong with anticancer nanomedicine design and how to make it right. ACS Nano 14, 12281–12290 (2020).

    CAS  Google Scholar 

  70. Feng, H. Y. et al. Targeted micellar phthalocyanine for lymph node metastasis homing and photothermal therapy in an orthotopic colorectal tumor model. Nanomicro Lett. 13, 145 (2021).

    CAS  Google Scholar 

  71. Hackl, C. et al. Metronomic oral topotecan prolongs survival and reduces liver metastasis in improved preclinical orthotopic and adjuvant therapy colon cancer models. Gut 62, 259–271 (2013).

    Article  Google Scholar 

  72. Song, W. et al. Synergistic and low adverse effect cancer immunotherapy by immunogenic chemotherapy and locally expressed PD-L1 trap. Nat. Commun. 9, 2237 (2018).

    Article  Google Scholar 

  73. Zhu, C. et al. Suppress orthotopic colon cancer and its metastasis through exact targeting and highly selective drug release by a smart nanomicelle. Biomaterials 161, 144–153 (2018).

    Article  CAS  Google Scholar 

  74. Blackman, L. D. et al. An introduction to zwitterionic polymer behavior and applications in solution and at surfaces. Chem. Soc. Rev. 48, 757–770 (2019).

    Article  CAS  Google Scholar 

  75. Okamatsu, A. et al. Design and evaluation of folate-appended alpha-, beta-, and gamma-cyclodextrins having a caproic acid as a tumor selective antitumor drug carrier in vitro and in vivo. Biomacromolecules 14, 4420–4428 (2013).

    Article  CAS  Google Scholar 

  76. Okamatsu, A. et al. Folate-appended beta-cyclodextrin as a promising tumor targeting carrier for antitumor drugs in vitro and in vivo. Bioconjugate Chem. 24, 724–733 (2013).

    Article  CAS  Google Scholar 

  77. Hyun, H. et al. 700-nm zwitterionic near-infrared fluorophores for dual-channel image-guided surgery. Mol. Imaging Biol. 18, 52–61 (2016).

    Article  CAS  Google Scholar 

  78. Shao, Q. & Jiang, S. Influence of charged groups on the properties of zwitterionic moieties: a molecular simulation study. J. Phys. Chem. B 118, 7630–7637 (2014).

    Article  CAS  Google Scholar 

  79. Dwivedi, R. et al. Design of therapeutically improved analogue of the antimicrobial peptide, indolicidin, using a glycosylation strategy. Amino Acids 51, 1443–1460 (2019).

    Article  CAS  Google Scholar 

  80. Xu, X. D. et al. In situ recognition of cell-surface glycans and targeted imaging of cancer cells. Sci. Rep. 3, 2679 (2013).

    Article  CAS  Google Scholar 

  81. Kasashima, H. et al. Mouse model of colorectal cancer: orthotopic co-implantation of tumor and stroma cells in cecum and rectum. STAR Protoc. 2, 100297 (2021).

    Article  CAS  Google Scholar 

  82. Gontijo, S. M. L. et al. Erlotinib/hydroxypropyl-beta-cyclodextrin inclusion complex: characterization and in vitro and in vivo evaluation. J. Incl. Phenom. Macrocycl. Chem. 83, 267–279 (2015).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by the National Research Foundation of Korea (NRF) grants funded by the Ministry of Science and ICT (grant nos. NRF-2021R1C1C1009320 (J.-Y.L.); NRF-2018R1A5A2024425, NRF-2018M3A7B4071203 and NRF-2020R1A2C2099983 (D.-D.K.); and NRF-2018H1A2A1062046, (M.-J.B.)).

Author information

Authors and Affiliations

  1. College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Republic of Korea

    Min-Jun Baek, Duy-Thuc Nguyen, Dahan Kim & Dae-Duk Kim

  2. College of Pharmacy, Chungnam National University, Daejeon, Republic of Korea

    So-Yeol Yoo, Sang Min Lee & Jae-Young Lee

Authors
  1. Min-Jun Baek
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Duy-Thuc Nguyen
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Dahan Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. So-Yeol Yoo
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Sang Min Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jae-Young Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Dae-Duk Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

M.-J.B., J.-Y.L. and D.-D.K. conceived and designed the experiments. M.-J.B., D.-T.N., D.K., S.-Y.Y. and S.M.L. performed the experiments. M.-J.B., J.-Y.L. and D.-D.K. interpreted the data and developed the discussion. M.-J.B., J.-Y.L. and D.-D.K. composed the paper. J.-Y.L. and D.-D.K. supervised the entire project.

Corresponding authors

Correspondence to Jae-Young Lee or Dae-Duk Kim.

Ethics declarations

Competing interests

The authors declare no competing interests.

Peer review

Peer review information

Nature Nanotechnology thanks Jean-Luc Coll and Roger Gomis for their contribution to the peer review of this work.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Supplementary Information

Magnified version of Fig. 1a, Supplementary Figs. 1–25 and References.

Reporting Summary

Supplementary Data 1

Statistical source data for supplementary figures.

Source data

Source Data Fig. 1

Statistical source data.

Source Data Fig. 2

Statistical source data.

Source Data Fig. 3

Statistical source data.

Source Data Fig. 4

Statistical source data.

Source Data Fig. 5

Statistical source data

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Baek, MJ., Nguyen, DT., Kim, D. et al. Tailoring renal-clearable zwitterionic cyclodextrin for colorectal cancer-selective drug delivery. Nat. Nanotechnol. 18, 945–956 (2023). https://doi.org/10.1038/s41565-023-01381-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41565-023-01381-8

Search

Advanced search

Quick links

Nature Briefing: Translational Research

Sign up for the Nature Briefing: Translational Research newsletter — top stories in biotechnology, drug discovery and pharma.

Get what matters in translational research, free to your inbox weekly. Sign up for Nature Briefing: Translational Research