Skip to main content

Advertisement

Log in

Rapid Microwave-Assisted Synthesis of pH-Sensitive Carbon-Based Nanoparticles for the Controlled Release of Doxorubicin to Cancer Cells

  • Research Article
  • Published:
AAPS PharmSciTech Aims and scope Submit manuscript

Abstract

Carbon-based nanoparticles (CNPs) are a new type of interesting nanomaterials applied in various pharmaceutical fields due to their outstanding biocompatible properties. Novel pH-sensitive CNPs were rapidly synthesized within 1 min by microwave-assisted technique for doxorubicin (DOX) delivery into five cancer cell lines, including breast cancer (BT-474 and MDA-MB-231 cell lines), colon cancer (HCT and HT29 cell lines), and cervical cancer (HeLa cell lines). CNPs and DOX-loaded CNPs (CNPs-DOX) had nano-size of 11.66 ± 2.32 nm and 43.24 ± 13.25 nm, respectively. DOX could be self-assembled with CNPs in phosphate buffer solution at pH 7.4 through electrostatic interaction, exhibiting high loading efficiency at 85.82%. The release of DOX from CNPs-DOX at pH 5.0, often observed in the tumor, was nearly two times greater than the release at physiological condition pH 7.4. Furthermore, the anticancer activity of CNPs-DOX was significantly enhanced compared to free DOX in five cancer cell lines. CNPs-DOX could induce cell death through apoptosis induction in MDA-MB-231 cells. The findings revealed that CNPs-DOX exhibited a promising pH-sensitive nano-system as a drug delivery carrier for cancer treatment.

Graphical Abstract

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

Access this article

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

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9
Fig. 10

Similar content being viewed by others

References

  1. Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global cancer statistics 2020: globocan estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71:209–49. https://doi.org/10.3322/caac.21660.

    Article  PubMed  Google Scholar 

  2. Duan Q, Ma Y, Che M, Zhang B, Zhang Y, Li Y, et al. Fluorescent carbon dots as carriers for intracellular doxorubicin delivery and track. J Drug Deliv Sci. 2019;49:527–33. https://doi.org/10.1016/j.jddst.2018.12.015.

    Article  CAS  Google Scholar 

  3. Kong T, Hao L, Wei Y, Cai X, Zhu B. Doxorubicin conjugated carbon dots as a drug delivery system for human breast cancer therapy. Cell Prolif. 2018;51:e12488. https://doi.org/10.1111/cpr.12488.

  4. Longhi A, Ferrari S, Bacci G, Specchia S. Long-term follow-up of patients with doxorubicin-induced cardiac toxicity after chemotherapy for osteosarcoma. Anticancer Drugs. 2007;18:737–44. https://doi.org/10.1097/cad.0b013e32803d36fe.

    Article  CAS  PubMed  Google Scholar 

  5. Dessale M, Mengistu G, Mengist HM. Nanotechnology: a promising approach for cancer diagnosis, therapeutics and theragnosis. Int J Nanomed. 2022;17:3735–49. https://doi.org/10.2147/IJN.S378074.

    Article  Google Scholar 

  6. Gmeiner WH, Ghosh S. Nanotechnology for cancer treatment. Nanotechnol Rev. 2015;3:111-122. https://doi.org/10.1515/ntrev-2013-0013.

  7. Jeevanandam J, Barhoum A, Chan YS, Dufresne A, Danquah MK. Review on nanoparticles and nanostructured materials: history, sources, toxicity and regulations. Beilstein J Nanotechnol. 2018;9:1050–74. https://doi.org/10.3762/bjnano.9.98.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Wang Y, Hu A. Carbon quantum dots: synthesis, properties and applications. J Mater Chem C. 2014;2:6921–39. https://doi.org/10.1039/c4tc00988f.

    Article  CAS  Google Scholar 

  9. Gavas S, Quazi S, Karpinski TM. Nanoparticles for cancer therapy: current progress and challenges. Nanoscale Res Lett. 2021;16:173–93. https://doi.org/10.1186/s11671-021-03628-6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Goodwin TJ, Huang L. Findings questioning the involvement of sigma-1 receptor in the uptake of anisamide-decorated particles. J Control Release. 2016;224:229–38. https://doi.org/10.1016/j.jconrel.2016.11.022.

    Article  CAS  Google Scholar 

  11. Lobo G, Paiva KLR, Silva ALG, Simoes MM, Radicchi MA, Bao SN. Nanocarriers used in drug delivery to enhance immune system in cancer therapy. Pharmaceutics. 2021;13:1167–85. https://doi.org/10.3390/pharmaceutics13081167.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Zhou Q, Zhang L, Wu H. Nanomaterials for cancer therapies. Nanotechnol. Rev. 2017;6:473-496. https://doi.org/10.1515/ntrev-2016-0102.

  13. Chu S, Shi X, Tian Y, Gao F. pH-Responsive polymer nanomaterials for tumor therapy. Front Oncol 2022;12:855019. https://doi.org/10.3389/fonc.2022.855019.

  14. Shen Y, Tang H, Radosz M, Van Kirk E, Murdoch WJ. pH-Responsive nanoparticles for cancer drug delivery. In: Jain KK, editor. Drug Delivery Systems. Totowa, NJ: Humana Press; 2008. p. 183-216.

  15. Farooq MA, Aquib M, Farooq A, Haleem Khan D, Joelle Maviah MB, Sied Filli M, et al. Recent progress in nanotechnology-based novel drug delivery systems in designing of cisplatin for cancer therapy: an overview. Artif Cells Nanomed Biotechnol. 2019;47:1674–92. https://doi.org/10.1080/21691401.2019.1604535.

    Article  CAS  PubMed  Google Scholar 

  16. Mitchell MJ, Billingsley MM, Haley RM, Wechsler ME, Peppas NA, Langer R. Engineering precision nanoparticles for drug delivery. Nat Rev Drug Discov. 2021;20:101–24. https://doi.org/10.1038/s41573-020-0090-8.

    Article  CAS  PubMed  Google Scholar 

  17. Ramburrun P, Khan RA, Choonara YE. Design, preparation, and functionalization of nanobiomaterials for enhanced efficacy in current and future biomedical applications. Nanotechnol Rev. 2022;11:1802–26. https://doi.org/10.1515/ntrev-2022-0106.

    Article  CAS  Google Scholar 

  18. Sahatsapan N, Pamornpathomkul B, Rojanarata T, Ngawhirunpat T, Poonkhum R, Opanasopit P, et al. Feasibility of mucoadhesive chitosan maleimide-coated liposomes for improved buccal delivery of a protein drug. J Drug Deliv Sci. 2022;69:103173. https://doi.org/10.1016/j.jddst.2022.103173.

  19. Dumkliang E, Pamornpathomkul B, Patrojanasophon P, Ngawhirunpat T, Rojanarata T, Yoksan S, et al. Feasibility of chitosan-based nanoparticles approach for intranasal immunisation of live attenuated Japanese encephalitis vaccine. Int J Biol Macromol. 2021;183:1096–105. https://doi.org/10.1016/j.ijbiomac.2021.05.050.

    Article  CAS  PubMed  Google Scholar 

  20. Amaral SI, Costa-Almeida R, Gonçalves IC, Magalhães FD, Pinto AM. Carbon nanomaterials for phototherapy of cancer and microbial infections. Carbon. 2022;190:194–244. https://doi.org/10.1016/j.carbon.2021.12.084.

    Article  CAS  Google Scholar 

  21. Maiti D, Tong X, Mou X, Yang K. Carbon-based nanomaterials for biomedical applications: a recent study. Front Pharmacol. 2018;9:1401–16. https://doi.org/10.3389/fphar.2018.01401.

    Article  CAS  PubMed  Google Scholar 

  22. Wang Y, Zhu Y, Yu S, Jiang C. Fluorescent carbon dots: rational synthesis, tunable optical properties and analytical applications. RSC Adv. 2017;7:40973–89. https://doi.org/10.1039/c7ra07573a.

    Article  CAS  Google Scholar 

  23. Li Y, Liu C, Chen M, An Y, Zheng Y, Tian H, et al. Solvent-free preparation of tannic acid carbon dots for selective detection of Ni2+ in the environment. Int J Mol Sci. 2022;23:6681–93. https://doi.org/10.3390/ijms23126681.

  24. Sun Y, Zheng S, Liu L, Kong Y, Zhang A, Xu K, et al. The cost-effective preparation of green fluorescent carbon dots for bioimaging and enhanced intracellular drug delivery. Nanoscale Res Lett. 2020;15:55–63. https://doi.org/10.1186/s11671-020-3288-0.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Xu X, Ray R, Gu Y, Ploehn HJ, Gearheart L, Raker K, et al. Electrophoretic analysis and purification of fluorescent single-walled carbon nanotube fragments. J Am Chem Soc. 2004;126:12736–7. https://doi.org/10.1021/ja040082h.

    Article  CAS  PubMed  Google Scholar 

  26. Mansuriya BD, Altintas Z. Carbon dots: classification, properties, synthesis, characterization, and applications in health care-an updated review (2018–2021). Nanomaterials. 2021;11:2525–79. https://doi.org/10.3390/nano11102525.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Ross S, Wu RS, Wei SC, Ross GM, Chang HT. The analytical and biomedical applications of carbon dots and their future theranostic potential: a review. J Food Drug Anal. 2020;28:677–695. https://doi.org/10.38212/2224-6614.1154.

  28. Yu T, Wang H, Guo C, Zhai Y, Yang J, Yuan J. A rapid microwave synthesis of green-emissive carbon dots with solid-state fluorescence and pH-sensitive properties. R Soc Open Sci. 2018;5:180245. https://doi.org/10.1098/rsos.180245.

  29. Wang YC, Morrison G, Gillihan R, Guo J, Ward RM, Fu X, et al. Different mechanisms for resistance to trastuzumab versus lapatinib in HER2-positive breast cancers–role of estrogen receptor and HER2 reactivation. Breast Cancer Res. 2011;13:121–39. https://doi.org/10.1186/bcr3067.

    Article  CAS  Google Scholar 

  30. Sakowicz-Burkiewicz M, Kitowska A, Grden M, Maciejewska I, Szutowicz A, Pawelczyk T. Differential effect of adenosine receptors on growth of human colon cancer HCT 116 and HT-29 cell lines. Arch Biochem Biophys. 2013;533:47–54. https://doi.org/10.1016/j.abb.2013.02.007.

    Article  CAS  PubMed  Google Scholar 

  31. Zhang SL, Wang YS, Zhou T, Yu XW, Wei ZT, Li YL. Isolation and characterization of cancer stem cells from cervical cancer HeLa cells. Cytotechnology. 2012;64:477–84. https://doi.org/10.1007/s10616-012-9436-3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Thanayutsiri T, Patrojanasophon P, Opanasopit P, Ngawhirunpat T, Plianwong S, Rojanarata T. Rapid synthesis of chitosan-capped gold nanoparticles for analytical application and facile recovery of gold from laboratory waste. Carbohydr Polym. 2020;250:116983. https://doi.org/10.1016/j.carbpol.2020.116983.

  33. Singpanna K, Chareonying T, Patrojanasophon P, Rojanarata T, Sukma M, Opanasopit P. Fabrication of a floating device of domperidone tablets using 3d-printing technologies. Key Eng Mater. 2020;859:289–94. https://doi.org/10.4028/www.scientific.net/KEM.859.289.

    Article  Google Scholar 

  34. Tang X-D, Yu H-M, Nguyen W, Amador E, Cui S-P, Ma K, et al. New observations on concentration-regulated carbon dots. Adv Photonics Res. 2023;4:1–7. https://doi.org/10.1002/adpr.202200314.

    Article  CAS  Google Scholar 

  35. Danaei M, Dehghankhold M, Ataei S, Hasanzadeh Davarani F, Javanmard R, Dokhani A, et al. Impact of particle size and polydispersity index on the clinical applications of lipidic nanocarrier systems. Pharmaceutics. 2018;10:1–17. https://doi.org/10.3390/pharmaceutics10020057.

    Article  CAS  Google Scholar 

  36. Bhaisare ML, Talib A, Khan MS, Pandey S, Wu H-F. Synthesis of fluorescent carbon dots via microwave carbonization of citric acid in presence of tetraoctylammonium ion, and their application to cellular bioimaging. Mikrochim Acta. 2015;182:2173–81. https://doi.org/10.1007/s00604-015-1541-5.

    Article  CAS  Google Scholar 

  37. Mintz KJ, Bartoli M, Rovere M, Zhou Y, Hettiarachchi SD, Paudyal S, et al. A deep investigation into the structure of carbon dots. Carbon. 2021;173:433–47. https://doi.org/10.1016/j.carbon.2020.11.017.

    Article  CAS  Google Scholar 

  38. Pal A, Sk MP, Chattopadhyay A. Recent advances in crystalline carbon dots for superior application potential. Adv Mater. 2020;1:525–53. https://doi.org/10.1039/d0ma00108b.

    Article  CAS  Google Scholar 

  39. Shabir Q, Pokale A, Loni A, Johnson DR, Canham LT, Fenollosa R, et al. Medically biodegradable hydrogenated amorphous silicon microspheres. Silicon. 2011;3:173–176. https://doi.org/10.1007/s12633-011-9097-4.

  40. Siddique AB, Pramanick AK, Chatterjee S, Ray M. Amorphous carbon dots and their remarkable ability to detect 2,4,6-trinitrophenol. Sci Rep. 2018;8:9770–9. https://doi.org/10.1038/s41598-018-28021-9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Alarfaj NA, El-Tohamy MF, Oraby HF. CA 19–9 pancreatic tumor marker fluorescence immunosensing detection via immobilized carbon quantum dots conjugated gold nanocomposite. Int J Mol Sci. 2018;19:1162–77. https://doi.org/10.3390/ijms19041162.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Tucureanu V, Matei A, Avram AM. FTIR Spectroscopy for carbon family study. Crit Rev Anal Chem. 2016;46:502–20. https://doi.org/10.1080/10408347.2016.1157013.

    Article  CAS  PubMed  Google Scholar 

  43. Nath A, Mishra A, Pande PP. A review natural polymeric coagulants in wastewater treatment. Mater Today Proc. 2021;46:6113–6117. https://doi.org/10.1016/j.matpr.2020.03.551.

  44. Dharmayanti C, Gillam TA, Klingler-Hoffmann M, Albrecht H, Blencowe A. Strategies for the development of ph-responsive synthetic polypeptides and polymer-peptide hybrids: recent advancements. Polymers. 2021;13:624–39. https://doi.org/10.3390/polym13040624.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Sun T, Zheng M, Xie Z, Jing X. Supramolecular hybrids of carbon dots with doxorubicin: synthesis, stability and cellular trafficking. Mater Chem Front. 2017;1:354–60. https://doi.org/10.1039/c6qm00042h.

    Article  CAS  Google Scholar 

  46. Hailing Y, Xiufang L, Lili W, Baoqiang L, Kaichen H, Yongquan H, et al. Doxorubicin-loaded fluorescent carbon dots with PEI passivation as a drug delivery system for cancer therapy. Nanoscale. 2020;12:17222–37. https://doi.org/10.1039/d0nr01236j.

    Article  CAS  PubMed  Google Scholar 

  47. Ehtesabi H, Massah F. Improvement of hydrophilicity and cell attachment of polycaprolactone scaffolds using green synthesized carbon dots. Mater Today Sustain. 2021;13:100075. https://doi.org/10.1016/j.mtsust.2021.100075.

  48. Kathiravan A, Gowri A, Srinivasan V, Smith TA, Ashokkumar M, Asha JM. A simple and ubiquitous device for picric acid detection in latent fingerprints using carbon dots. Analyst. 2020;145:4532–9. https://doi.org/10.1039/d0an00750a.

    Article  CAS  PubMed  Google Scholar 

  49. Gonzlez-Ruiz V, I A, Antonia M, Ribelles P, Teresa M, Carlos J. An overview of analytical techniques employed to evidence drug-dna interactions. Applications to the design of genosensors. biomedical engineering, trends, research and technologies. 2011. p. 65–90.

  50. Dong X, Wei C, Chen H, Qin J, Liang J, Kong D, et al. Real-time imaging tracking of a dual fluorescent drug delivery system based on zinc phthalocyanine-incorporated hydrogel. ACS Biomater Sci Eng. 2016;2:2001–10. https://doi.org/10.1021/acsbiomaterials.6b00403.

    Article  CAS  PubMed  Google Scholar 

  51. Myat YY, Ngawhirunpat T, Rojanarata T, Opanasopit P, Bradley M, Patrojanasophon P, et al. Synthesis of polyethylene glycol diacrylate/acrylic acid nanoparticles as nanocarriers for the controlled delivery of doxorubicin to colorectal cancer cells. Pharmaceutics. 2022;14:479–91. https://doi.org/10.3390/pharmaceutics14030479.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Mussi SV, Torchilin VP. Recent trends in the use of lipidic nanoparticles as pharmaceutical carriers for cancer therapy and diagnostics. J Mater Chem B. 2013;1:5201–9. https://doi.org/10.1039/c3tb20990c.

    Article  CAS  PubMed  Google Scholar 

  53. Ghaffar A, Yameen B, Latif M, Malik MI. Chapter 14 - pH-sensitive drug delivery systems. In: Shah MR, Imran M, Ullah S, editors. Metal Nanoparticles for Drug Delivery and Diagnostic Applications. Elsevier; 2020. p. 259–78.

  54. Karimi S, Namazi H. A photoluminescent folic acid-derived carbon dot functionalized magnetic dendrimer as a pH-responsive carrier for targeted doxorubicin delivery. New J Chem. 2021;45:6397–405. https://doi.org/10.1039/D0NJ06261H.

    Article  CAS  Google Scholar 

  55. Aghdam KJ, Sabeti B, Chekin F, Mashreghi M. Conjugation of doxorubicin and carbon based-nanostructures for drug delivery against HT-29 colon cancer cells. 02 March 2023, PREPRINT (Version 1) available at Research Square. 2023. https://doi.org/10.21203/rs.3.rs-2632275/v1.

  56. Shinde VR, Khatun S, Thanekar AM, Hak A, Rengan AK. Lipid-coated red fluorescent carbon dots for imaging and synergistic phototherapy in breast cancer. Photodiagnosis Photodyn Ther. 2023;41:103314. https://doi.org/10.1016/j.pdpdt.2023.103314.

Download references

Acknowledgements

We would like to thank Paul Mines for English proofreading.

Funding

This research was funded by the National Research Council of Thailand (NRCT): N42A650551 and the Office of the Permanent Secretary, Ministry of Higher Education, Science, Research and Innovation (OPS MHESI), Thailand Science Research and Innovation (TSRI) (Grant No. RGNS 65-195), as well as the Ph.D. Student Scholarship provided by the Faculty of Pharmacy, Silpakorn University.

Author information

Authors and Affiliations

Authors

Contributions

Koranat Dechsri: investigation, methodology, writing—original draft; Cheewita Suwanchawalit: writing—review and editing, methodology; Padungkwan Chitropas: writing—review and editing; Tanasait Ngawhirunpat: writing—review and editing; Theerasak Rojanarata: methodology; Praneet Opanasopit: conceptualization, resources, funding acquisition; Supusson Pengnam: supervision, conceptualization, funding acquisition.

Corresponding author

Correspondence to Supusson Pengnam.

Ethics declarations

Conflict of Interest

The authors declare no competing interests.

Additional information

Publisher's Note

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

Highlights

• Novel pH-sensitive carbon-based nanoparticles were rapidly synthesized by using microwave irradiation and were non-toxic to cancer cell lines.

• The release of DOX was pH-dependent, which released significantly in an acidic tumor environment (pH 5.0), while the release was lower at physiological condition pH 7.4 at 24 h.

• The CNPs-DOX significantly enhanced the cytotoxicity of DOX in many cancer cell lines and induced apoptosis in MDA-MB-231 cells.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 18.1 KB)

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

Dechsri, K., Suwanchawalit, C., Chitropas, P. et al. Rapid Microwave-Assisted Synthesis of pH-Sensitive Carbon-Based Nanoparticles for the Controlled Release of Doxorubicin to Cancer Cells. AAPS PharmSciTech 24, 135 (2023). https://doi.org/10.1208/s12249-023-02593-w

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1208/s12249-023-02593-w

Keywords

Navigation