Skip to main content

Advertisement

SpringerLink
Log in

Glycol chitosan amphiphile nanotheranostic system for ultrasound-mediated localized release and biodistribution of doxorubicin

  • Research paper
  • Published:
Journal of Nanoparticle Research Aims and scope Submit manuscript

Abstract

Ultrasound-mediated delivery has garnered attention as a noninvasive modality for localized drug delivery in cancer. Doxorubicin, a chemotherapeutic drug, shows low penetration, nonspecific distribution, and uncontrolled release. We have synthesized a hydrophobic doxorubicin (hDox)-loaded palmitoyl-modified glycol chitosan amphiphile (PmGCA) polymer-based nanotheranostic drug delivery system (hDox-NDS) for ultrasound (US)-mediated release. PmGCA encapsulates 210 μg/mL hDox in 90 ± 15 nm cationic micelles. The reappearance of the Dox fluorescence peak after 2 MHz US exposure confirms the encapsulated drug release.

hDox-NDS display a considerable drug release (~30 to 50%) over 72 h, following the Weibull model. Fluorescence microscopy shows a higher uptake of hDox-NDS (~10%) in rhabdomyosarcoma (RD) cells compared to DoxHCl. Ultrasound exposure significantly (p < 0.001) enhances the anticancer effect of hDox-NDS on RD cells, as shown by its lower IC50 value of 1.7 ± 0.05 μM compared to that of DoxHCl (2.62 ± 1.2 μM). In vivo optical imaging shows significantly lower fluorescence in the heart (~84%) and liver (~59%) compared to DoxHCl, thereby reducing side effects. This nanotheranostic hDox-NDS has been considered an effective drug delivery system, offering enhanced therapeutic effects in cancer treatment.

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

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

Similar content being viewed by others

References

  1. Ladju RB, Ulhaq ZS, Soraya GV (2022) Nanotheranostics: a powerful next-generation solution to tackle hepatocellular carcinoma. World J Gastroenterol 28:176

    Article  CAS  Google Scholar 

  2. Afadzi M, Myhre OF, Yemane PT et al (2020) Effect of acoustic radiation force on the distribution of nanoparticles in solid tumors. IEEE Trans Ultrason Ferroelectr Freq Control 68:432–445

    Article  Google Scholar 

  3. Kim D, Lee JH, Moon H et al (2021) Development and evaluation of an ultrasound-triggered microbubble combined transarterial chemoembolization (TACE) formulation on rabbit VX2 liver cancer model. Theranostics 11:79

    Article  CAS  Google Scholar 

  4. Young RC, Ozols RF, Myers CE (1981) The anthracycline antineoplastic drugs. N Engl J Med 305:139–153

    Article  CAS  Google Scholar 

  5. Melim C, Magalhães M, Santos AC et al (2022) Nanoparticles as phytochemical carriers for cancer treatment: news of the last decade. Expert Opin Drug Deliv 19:179–197

    Article  CAS  Google Scholar 

  6. Gabizon A, Shmeeda H, Barenholz Y (2003) Pharmacokinetics of pegylated liposomal doxorubicin. Clin Pharmacokinet 42:419–436

    Article  CAS  Google Scholar 

  7. Hekmatirad S, Moloudizargari M, Moghadamnia AA et al (2021) Inhibition of exosome release sensitizes U937 cells to PEGylated liposomal doxorubicin. Front Immunol 12:2008

    Article  Google Scholar 

  8. Hilger RA, Richly H, Grubert M et al (2005) Pharmacokinetics (PK) of a liposomal encapsulated fraction containing doxorubicin and of doxorubicin released from the liposomal capsule after intravenous infusion of Caelyx/Doxil. Int J Clin Pharmacol Ther 43:588–589

    Article  CAS  Google Scholar 

  9. Liu L, Kshirsagar PG, Gautam SK et al (2022) Nanocarriers for pancreatic cancer imaging, treatments, and immunotherapies. Theranostics 12:1030

    Article  Google Scholar 

  10. Entzian K, Aigner A (2021) Drug delivery by ultrasound-responsive nanocarriers for cancer treatment. Pharmaceutics 13:1135

    Article  CAS  Google Scholar 

  11. Mohan P, Rapoport N (2010) Doxorubicin as a molecular nanotheranostic agent: effect of doxorubicin encapsulation in micelles or nanoemulsions on the ultrasound-mediated intracellular delivery and nuclear trafficking. Mol Pharm 7:1959–1973

    Article  CAS  Google Scholar 

  12. Mi P (2020) Stimuli-responsive nanocarriers for drug delivery, tumor imaging, therapy and theranostics. Theranostics 10:4557

    Article  CAS  Google Scholar 

  13. Behera SK, Mohanty ME, Mohapatra M (2021) A fluorescence study of the interaction of anticancer drug molecule doxorubicin hydrochloride in pluronic P123 and F127 micelles. J Fluoresc 31:17–27

    Article  CAS  Google Scholar 

  14. Afshari AR, Sanati M, Mollazadeh H et al (2022) Nanoparticle-based drug delivery systems in cancer: a focus on inflammatory pathways. Semin Cancer Biol. https://doi.org/10.1016/j.semcancer.2022.01.008

  15. Xia H, Yang D, He W et al (2021) Ultrasound-mediated microbubbles cavitation enhanced chemotherapy of advanced prostate cancer by increasing the permeability of blood-prostate barrier. Transl Oncol 14:101177

    Article  CAS  Google Scholar 

  16. Zia N, Iqbal Z, Raza A et al (2022) Glycol-chitosan-based Technetium-99m-loaded multifunctional nanomicelles: synthesis, evaluation, and in vivo biodistribution. Nanomaterials 12:2198. https://doi.org/10.3390/nano12132198

    Article  CAS  Google Scholar 

  17. Uchegbu IF, Sadiq L, Arastoo M et al (2001) Quaternary ammonium palmitoyl glycol chitosan—a new polysoap for drug delivery. Int J Pharm 224:185–199

    Article  CAS  Google Scholar 

  18. Lalatsa A, Schätzlein AG, Garrett NL et al (2015) Chitosan amphiphile coating of peptide nanofibres reduces liver uptake and delivers the peptide to the brain on intravenous administration. J Controlled Release 197:87–96. https://doi.org/10.1016/j.jconrel.2014.10.028

    Article  CAS  Google Scholar 

  19. Min HS, You DG, Son S et al (2015) Echogenic glycol chitosan nanoparticles for ultrasound-triggered cancer Theranostics. Theranostics 5:1402–1418. https://doi.org/10.7150/thno.13099

    Article  Google Scholar 

  20. Zhou X, Guo L, Shi D et al (2019) Biocompatible chitosan nanobubbles for ultrasound-mediated targeted delivery of doxorubicin. Nanoscale Res Lett 14:24. https://doi.org/10.1186/s11671-019-2853-x

    Article  CAS  Google Scholar 

  21. Meng D, Guo L, Shi D et al (2019) Charge-conversion and ultrasound-responsive O-carboxymethyl chitosan nanodroplets for controlled drug delivery. Nanomed 14:2549–2565

    Article  CAS  Google Scholar 

  22. Kanwal U, Bukhari NI, Rana NF et al (2019) Doxorubicin-loaded quaternary ammonium palmitoyl glycol chitosan polymeric nanoformulation: uptake by cells and organs. Int J Nanomedicine 14:1–15

  23. Wei T, Chen C, Liu J et al (2015) Anticancer drug nanomicelles formed by self-assembling amphiphilic dendrimer to combat cancer drug resistance. Proc Natl Acad Sci 112:2978–2983

    Article  CAS  Google Scholar 

  24. Khan MA, Ansari MM, Arif ST et al (2021) Eplerenone nanocrystals engineered by controlled crystallization for enhanced oral bioavailability. Drug Deliv 28:2510–2524

    Article  CAS  Google Scholar 

  25. Ovais M, Nadhman A, Khalil AT et al (2017) Biosynthesized colloidal silver and gold nanoparticles as emerging leishmanicidal agents: an insight. Nanomed 12:2807–2819

    Article  CAS  Google Scholar 

  26. Li K, Li P, Jia Z et al (2018) Enhanced fluorescent intensity of magnetic-fluorescent bifunctional PLGA microspheres based on Janus electrospraying for bioapplication. Sci Rep 8:1–11

    Google Scholar 

  27. Rehman M, Raza A, Khan JA, Zia MA (2021) Laser responsive cisplatin-gold nano-assembly synergizes the effect of cisplatin with compliance. J Pharm Sci 110:1749–1760

    Article  CAS  Google Scholar 

  28. Mannaris C, Teo BM, Seth A et al (2018) Gas-stabilizing gold nanocones for acoustically mediated drug delivery. Adv Healthc Mater 7:1800184

    Article  Google Scholar 

  29. Sarwar U, Naeem M, Nurjis F, et al (2022) Ultrasound-mediated in vivo biodistribution of coumarin-labeled sorafenib-loaded liposome-based nanotheranostic system. Nanomed 17:1909–1927

  30. Salgarella AR, Zahoranová A, Šrámková P et al (2018) Investigation of drug release modulation from poly (2-oxazoline) micelles through ultrasound. Sci Rep 8:1–13

    Article  CAS  Google Scholar 

  31. Nelson TR, Fowlkes JB, Abramowicz JS, Church CC (2009) Ultrasound biosafety considerations for the practicing sonographer and sonologist. J Ultrasound Med 28:139–150. https://doi.org/10.7863/jum.2009.28.2.139

    Article  Google Scholar 

  32. Schneider CA, Rasband WS, Eliceiri KW (2012) NIH Image to ImageJ: 25 years of image analysis. Nat Methods 9:671–675

    Article  CAS  Google Scholar 

  33. Lefort CT, Kim M (2010) Human T lymphocyte isolation, culture and analysis of migration in vitro. JoVE J Vis Exp e2017

  34. Jawaid P, Rehman MU, Hassan MA et al (2016) Effect of platinum nanoparticles on cell death induced by ultrasound in human lymphoma U937 cells. Ultrason Sonochem 31:206–215. https://doi.org/10.1016/j.ultsonch.2015.12.013

    Article  CAS  Google Scholar 

  35. Esmaeilzadeh-Gharedaghi E, Faramarzi MA, Amini MA et al (2012) Effects of processing parameters on particle size of ultrasound prepared chitosan nanoparticles: an artificial neural networks study. Pharm Dev Technol 17:638–647

    Article  CAS  Google Scholar 

  36. Uchegbu IF, Breznikar J, Zaffalon A et al (2021) Polymeric micelles for the enhanced deposition of hydrophobic drugs into ocular tissues, without plasma exposure. Pharmaceutics 13:744

    Article  CAS  Google Scholar 

  37. Gnapareddy B, Reddy Dugasani S, Ha T et al (2015) Chemical and physical characteristics of doxorubicin hydrochloride drug-doped salmon DNA thin films. Sci Rep 5:1–9

    Article  Google Scholar 

  38. Huang K-Y, He H-X, He S-B et al (2019) Gold nanocluster-based fluorescence turn-off probe for sensing of doxorubicin by photoinduced electron transfer. Sens Actuators B Chem 296:126656

    Article  CAS  Google Scholar 

  39. Chooi KW, Carlos MIS, Soundararajan R et al (2014) Physical characterisation and long-term stability studies on quaternary ammonium palmitoyl glycol chitosan (GCPQ)—a new drug delivery polymer. J Pharm Sci 103:2296–2306

    Article  CAS  Google Scholar 

  40. Lu Y, Zhang E, Yang J, Cao Z (2018) Strategies to improve micelle stability for drug delivery. Nano Res 11:4985–4998. https://doi.org/10.1007/s12274-018-2152-3

    Article  Google Scholar 

  41. Lu D, Wen X, Liang J et al (2009) A pH-sensitive nano drug delivery system derived from pullulan/doxorubicin conjugate. J Biomed Mater Res B Appl Biomater 89B:177–183. https://doi.org/10.1002/jbm.b.31203

    Article  CAS  Google Scholar 

  42. Choi J-S, Park J-W, Seu Y-B, Doh K-O (2021) Enhanced efficacy of folate-incorporated cholesteryl doxorubicin liposome in folate receptor abundant cancer cell. J Drug Deliv Sci Technol 62:102385

    Article  CAS  Google Scholar 

  43. Wu P, Jia Y, Qu F et al (2017) Ultrasound-responsive polymeric micelles for sonoporation-assisted site-specific therapeutic action. ACS Appl Mater Interfaces 9:25706–25716

    Article  CAS  Google Scholar 

  44. Lalatsa A, Schatzlein AG, Uchegbu IF (2014) Strategies to deliver peptide drugs to the brain. Mol Pharm 11:1081–1093

    Article  CAS  Google Scholar 

  45. Izci M, Maksoudian C, Manshian BB, Soenen SJ (2021) The use of alternative strategies for enhanced nanoparticle delivery to solid tumors. Chem Rev 121:1746–1803

    Article  CAS  Google Scholar 

  46. Herdiana Y, Wathoni N, Shamsuddin S, Muchtaridi M (2022) Drug release study of the chitosan-based nanoparticles. Heliyon 8:e08674. https://doi.org/10.1016/j.heliyon.2021.e08674

    Article  CAS  Google Scholar 

  47. Foroozandeh P, Aziz AA (2018) Insight into cellular uptake and intracellular trafficking of nanoparticles. Nanoscale Res Lett 13:1–12

    Article  CAS  Google Scholar 

  48. Snipstad S, Berg S, Mørch Ý et al (2017) Ultrasound improves the delivery and therapeutic effect of nanoparticle-stabilized microbubbles in breast cancer xenografts. Ultrasound Med Biol 43:2651–2669

    Article  Google Scholar 

  49. Xiong R, Xu RX, Huang C et al (2021) Stimuli-responsive nanobubbles for biomedical applications. Chem Soc Rev 50:5746–5776

    Article  CAS  Google Scholar 

  50. Champion JA, Walker A, Mitragotri S (2008) Role of particle size in phagocytosis of polymeric microspheres. Pharm Res 25:1815–1821

    Article  CAS  Google Scholar 

  51. Fang C, Kievit FM, Cho Y-C et al (2012) Effect of cationic side-chains on intracellular delivery and cytotoxicity of pH sensitive polymer–doxorubicin nanocarriers. Nanoscale 4:7012–7020

    Article  CAS  Google Scholar 

  52. Jiang LQ, Wang TY, Webster TJ et al (2017) Intracellular disposition of chitosan nanoparticles in macrophages: intracellular uptake, exocytosis, and intercellular transport. Int J Nanomedicine 12:6383

    Article  CAS  Google Scholar 

  53. Alqahtani MS, Syed R, Alshehri M (2020) Size-dependent phagocytic uptake and immunogenicity of gliadin nanoparticles. Polymers 12:2576

    Article  CAS  Google Scholar 

  54. Vonarbourg A, Passirani C, Saulnier P, Benoit J-P (2006) Parameters influencing the stealthiness of colloidal drug delivery systems. Biomaterials 27:4356–4373

    Article  CAS  Google Scholar 

  55. Nittayacharn P, Yuan H-X, Hernandez C et al (2019) Enhancing tumor drug distribution with ultrasound-triggered nanobubbles. J Pharm Sci 108:3091–3098

    Article  CAS  Google Scholar 

  56. Fant C, Lafond M, Rogez B et al (2019) In vitro potentiation of doxorubicin by unseeded controlled non-inertial ultrasound cavitation. Sci Rep 9:15581. https://doi.org/10.1038/s41598-019-51785-7

    Article  CAS  Google Scholar 

  57. Liang H-D, Lu QL, Xue S-A et al (2004) Optimisation of ultrasound-mediated gene transfer (sonoporation) in skeletal muscle cells. Ultrasound Med Biol 30:1523–1529. https://doi.org/10.1016/j.ultrasmedbio.2004.08.021

    Article  Google Scholar 

  58. Zhang Z, Wang Y, Ma Q et al (2021) Biomimetic carrier-free nanoparticle delivers digoxin and doxorubicin to exhibit synergetic antitumor activity in vitro and in vivo. Chem Eng J 406:126801

    Article  CAS  Google Scholar 

  59. Liu D, Mori A, Huang L (1992) Role of liposome size and RES blockade in controlling biodistribution and tumor uptake of GM1-containing liposomes. Biochim Biophys Acta BBA - Biomembr 1104:95–101. https://doi.org/10.1016/0005-2736(92)90136-A

    Article  CAS  Google Scholar 

Download references

Acknowledgements

Chemicals and equipment used in the research work are supported through the PAK-NORWAY Institutional Cooperation Program, PK3004, COMSTECH-TWAS (12-198 RG/PHA/AS_C-UNESCO FR: 3240270874), and Pakistan Science Foundation (PSF/Res/C-NILOP/Med (330). The authors are grateful to the Pakistan Institute of Applied Sciences (PIEAS) and the National Institute of Health (NIH) for technical support.

Author information

Authors and Affiliations

  1. NILOP Nanomedicine Research Laboratories (NNRL), National Institute of Laser and Optronics College, Pakistan Institute of Engineering and Applied Sciences, Islamabad, 46000, Pakistan

    Sidra Saeed

  2. Suleiman Bin Abdullah Aba Alkhail–Centre for Interdisciplinary Research in Basic Science (SA-CIRBS), Faculty of Sciences, International Islamic University, Islamabad, 44000, Pakistan

    Sidra Saeed & Masoom Yasinzai

  3. Department of Biotechnology, Quaid-i-Azam University, Islamabad, 46000, Pakistan

    Usama Sarwar

  4. National Center of Industrial Biotechnology, University Institute of Biochemistry and Biotechnology, Pir Mehr Ali Shah Arid Agriculture University, Rawalpindi, 46000, Pakistan

    Abida Raza

Authors
  1. Sidra Saeed
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Usama Sarwar
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Masoom Yasinzai
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Abida Raza
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Abida Raza.

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.

Supplementary information

ESM 1

(DOCX 153 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

Saeed, S., Sarwar, U., Yasinzai, M. et al. Glycol chitosan amphiphile nanotheranostic system for ultrasound-mediated localized release and biodistribution of doxorubicin. J Nanopart Res 25, 194 (2023). https://doi.org/10.1007/s11051-023-05835-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s11051-023-05835-x

Keywords

Search

Navigation