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:

Fabrication of anionic dextran-coated micelles for aptamer targeted delivery of camptothecin and survivin-shRNA to colon adenocarcinoma

Gene Therapy volume 29, pages 55–68 (2022)Cite this article

Subjects

Abstract

In this study, we synthesized PLA-PEI micelles which was co-loaded with an anticancer drug, camptothecin (CPT), and survivin-shRNA (sur-shRNA). The hydrophobic CPT was encapsulated in the core of the polymeric micelles while sur-shRNA was adsorbed on the shell of the cationic micelles. Then, the positively-charged sur-shRNA-loaded micelles were coated with poly carboxylic acid dextran (PCAD) to form PLA/PEI-CPT-SUR-DEX. To selectively target the system to colon cancer cells, AS1411 aptamer was covalently attached to the surface of the PCAD-coated nanoparticles (PLA/PEI-CPT-SUR-DEX-APT). PLA/PEI-CPT-SUR-DEX-APT enhanced cellular uptake through receptor-mediated endocytosis followed by increased CPT accumulation, downregulation of survivin, and thereby 38% cell apoptosis. In C26 tumor-bearing mice models, after administered intravenously, PLA/PEI-CPT-SUR-DEX-APT and PLA/PEI-CPT-SUR-DEX formulations resulted in a significant inhibition of the tumor growth with tumor inhibition rate of 93% and 87%, respectively. Therefore, PLA/PEI-CPT-SUR-DEX-APT could be a versatile co-delivery vehicle for promising therapy of colorectal cancer.

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: Schematic illustration of co-delivery system of CPT and survivin shRNA based on PCAD-coated PLA-PEI micelles tagged with AS1411 aptamer.
Fig. 2: Synthesis strategies of PLA-PEI and PCAD.
Fig. 3: Determination of PEI-PLA critical micelle concentration (CMC) using iodine in aqueous medium.
Fig. 4: Morphological investigation of the prepared nanoparticles using SEM.
Fig. 5: Stability investigation of the polyplexes in the presence of 30% FBS.
Fig. 6: In vitro release evaluation of CPT from the prepared NPs.
Fig. 7: In vitro cytotoxicity evaluation using MTT assay.
Fig. 8: Competetion assay of targeted NPs in terms of GFP exerssion after transfection and cytotoxicity after uptake of the NPs.
Fig. 9: Flow cytometry dot plots of treated C26 cells after Annexin V/ PI staining for evaluation of apoptotic effect.
Fig. 10: In vivo experiment on C26 ectopic tumor model in mice.
Fig. 11: Ex vivo investigation.

Similar content being viewed by others

References

  1. Xiao B, Si X, Han MK, Viennois E, Zhang M, Merlin D. Co-delivery of camptothecin and curcumin by cationic polymeric nanoparticles for synergistic colon cancer combination chemotherapy. J Mater Chem B. 2015;3:7724–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Teo PY, Cheng W, Hedrick JL, Yang YY. Co-delivery of drugs and plasmid DNA for cancer therapy. Adv Drug Deliv Rev. 2016;98:41–63.

    Article  CAS  PubMed  Google Scholar 

  3. Zhonghong L, Lianjie L, Changqing Z, Ying H, Yu J, Yan L. The influence of survivin shRNA on the cell cycle and the invasion of SW480 cells of colorectal carcinoma. J Exp Clin Cancer Res. 2008;27:20.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Wang K, Kievit FM, Zhang M. Nanoparticles for cancer gene therapy: Recent advances, challenges, and strategies. Pharmacol Res. 2016;114:56–66.

    Article  CAS  PubMed  Google Scholar 

  5. Bi Y, Lee RJ, Wang X, Sun Y, Wang M, Li L, et al. Liposomal codelivery of an SN38 prodrug and a survivin siRNA for tumor therapy. Int J Nanomedicine. 2018;13:5811–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Yan X, Yu Q, Guo L, Guo W, Guan S, Tang H, et al. Positively charged combinatory drug delivery systems against multidrug resistant breast cancer: beyond the drug combination. ACS Appl Mater Interfaces. 2017;9:6804–15.

    Article  CAS  PubMed  Google Scholar 

  7. Shim G, Kim M-G, Park JY, Oh Y-K. Application of cationic liposomes for delivery of nucleic acids. Asian J Pharm Sci. 2013;8:72–80.

    Article  CAS  Google Scholar 

  8. Son S, Kim WJ. Biodegradable nanoparticles modified by branched polyethylenimine for plasmid DNA delivery. Biomater. 2010;31:133–43.

    Article  CAS  Google Scholar 

  9. Zhu J, Tang A, Law LP, Feng M, Ho KM, Lee DK, et al. Amphiphilic core–shell nanoparticles with poly (ethylenimine) shells as potential gene delivery carriers. Bioconjug Chem. 2005;16:139–46.

    Article  CAS  PubMed  Google Scholar 

  10. Park YM, Shin BA, Oh IJ. Poly(L-lactic acid)/polyethylenimine nanoparticles as plasmid DNA carriers. Arch Pharm Res. 2008;31:96–102.

    Article  CAS  PubMed  Google Scholar 

  11. Mandal H, Katiyar SS, Swami R, Kushwah V, Katare PB, Meka AK, et al. ε-Poly-L-Lysine/plasmid DNA nanoplexes for efficient gene delivery in vivo. Int J Pharm. 2018;542:142–52.

  12. Shen W, Wang R, Fan Q, Gao X, Wang H, Shen Y, et al. Natural polyphenol inspired polycatechols for efficient siRNA delivery. CCS Chem. 2020;2:146–57.

    Article  CAS  Google Scholar 

  13. Nam JP, Kim S, Kim SW. Design of PEI-conjugated bio-reducible polymer for efficient gene delivery. Int J Pharm. 2018;545:295–305.

  14. Chang Y-C, Chu IM. Methoxy poly(ethylene glycol)-b-poly(valerolactone) diblock polymeric micelles for enhanced encapsulation and protection of camptothecin. Eur Polym J. 2008;44:3922–30.

    Article  CAS  Google Scholar 

  15. Torchilin VP. Targeted polymeric micelles for delivery of poorly soluble drugs. Cell Mol Life Sci. 2004;61:2549–59.

    Article  CAS  PubMed  Google Scholar 

  16. Kedar U, Phutane P, Shidhaye S, Kadam V. Advances in polymeric micelles for drug delivery and tumor targeting. Nanomedicine. 2010;6:714–29.

    Article  CAS  PubMed  Google Scholar 

  17. Kataoka K, Harada A, Nagasaki Y. Block copolymer micelles for drug delivery: design, characterization and biological significance. Adv Drug Delivery Rev. 2012;64:37–48.

    Article  Google Scholar 

  18. Date T, Nimbalkar V, Kamat J, Mittal A, Mahato RI, Chitkara D. Lipid-polymer hybrid nanocarriers for delivering cancer therapeutics. J Control Release. 2018;271:60–73.

    Article  CAS  PubMed  Google Scholar 

  19. Praetorius NP, Mandal TK. Engineered nanoparticles in cancer therapy. Recent Pat Drug Deliv Formul. 2007;1:37–51.

    Article  CAS  PubMed  Google Scholar 

  20. Kunii R, Onishi H, Ueki K-i, Koyama K-i, Machida Y. Particle characteristics and biodistribution of camptothecin-loaded PLA/(PEG-PPG-PEG) nanoparticles. Drug Deliv. 2008;15:3–10.

    Article  CAS  PubMed  Google Scholar 

  21. Danafar H. MPEG–PCL copolymeric nanoparticles in drug delivery systems. Cogent Med. 2016;3:1142411.

    Article  Google Scholar 

  22. Yu M, Huang S, Yu KJ, Clyne AM. Dextran and polymer polyethylene glycol (PEG) coating reduce both 5 and 30 nm iron oxide nanoparticle cytotoxicity in 2D and 3D cell culture. Int J Mol Sci. 2012;13:5554–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Bilensoy E. Cationic nanoparticles for cancer therapy. Expert Opin Drug Deliv. 2010;7:795–809.

    Article  CAS  PubMed  Google Scholar 

  24. Gu Q, Xing JZ, Huang M, He C, Chen J. SN-38 loaded polymeric micelles to enhance cancer therapy. Nanotechnology. 2012;23:205101.

    Article  PubMed  Google Scholar 

  25. Xu W, Siddiqui IA, Nihal M, Pilla S, Rosenthal K, Mukhtar H, et al. Aptamer-conjugated and doxorubicin-loaded unimolecular micelles for targeted therapy of prostate cancer. Biomaterials. 2013;34:5244–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Aravind A, Jeyamohan P, Nair R, Veeranarayanan S, Nagaoka Y, Yoshida Y, et al. AS1411 aptamer tagged PLGA-lecithin-PEG nanoparticles for tumor cell targeting and drug delivery. Biotechnol Bioeng. 2012;109:2920–31.

    Article  CAS  PubMed  Google Scholar 

  27. Taghavi S, Ramezani M, Alibolandi M, Abnous K, Taghdisi SM. Chitosan-modified PLGA nanoparticles tagged with 5TR1 aptamer for in vivo tumor-targeted drug delivery. Cancer Lett. 2017;400:1–8.

    Article  CAS  PubMed  Google Scholar 

  28. Alibolandi M, Abnous K, Hadizadeh F, Taghdisi SM, Alabdollah F, Mohammadi M, et al. Dextran-poly lactide-co-glycolide polymersomes decorated with folate-antennae for targeted delivery of docetaxel to breast adenocarcinima in vitro and in vivo. J Control Release. 2016;241:45–56.

    Article  CAS  PubMed  Google Scholar 

  29. Khalkhali M, Sadighian S, Rostamizadeh K, Khoeini F, Naghibi M, Bayat N, et al. Synthesis and characterization of dextran coated magnetite nanoparticles for diagnostics and therapy. BioImpacts. 2015;5:141.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Yu C, Hu Y, Duan J, Yuan W, Wang C, Xu H, et al. Novel aptamer-nanoparticle bioconjugates enhances delivery of anticancer drug to MUC1-positive cancer cells in vitro. PloS ONE. 2011;6:e24077.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Alibolandi M, Taghdisi SM, Ramezani P, Hosseini Shamili F, Farzad SA, Abnous K, et al. Smart AS1411-aptamer conjugated pegylated PAMAM dendrimer for the superior delivery of camptothecin to colon adenocarcinoma in vitro and in vivo. Int J Pharm. 2017;519:352–64.

    Article  CAS  PubMed  Google Scholar 

  32. Alibolandi M, Hoseini F, Mohammadi M, Ramezani P, Einafshar E, Taghdisi SM, et al. Curcumin-entrapped MUC-1 aptamer targeted dendrimer-gold hybrid nanostructure as a theranostic system for colon adenocarcinoma. Int J Pharm. 2018;549:67–75.

    Article  CAS  PubMed  Google Scholar 

  33. Shen S, Wu Y, Liu Y, Wu D. High drug-loading nanomedicines: progress, current status, and prospects. Int J Nanomedicine. 2017;12:4085.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Zhang Z, Wang X, Li B, Hou Y, Cai Z, Yang J, et al. Paclitaxel-loaded PLGA microspheres with a novel morphology to facilitate drug delivery and antitumor efficiency. RSC Adv. 2018;8:3274–85.

    Article  CAS  Google Scholar 

  35. Tang S, Yin Q, Zhang Z, Gu W, Chen L, Yu H, et al. Co-delivery of doxorubicin and RNA using pH-sensitive poly (β-amino ester) nanoparticles for reversal of multidrug resistance of breast cancer. Biomaterials. 2014;35:6047–59.

    Article  CAS  PubMed  Google Scholar 

  36. Alibolandi M, Mohammadi M, Taghdisi SM, Ramezani M, Abnous K. Fabrication of aptamer decorated dextran coated nano-graphene oxide for targeted drug delivery. Carbohydr Polym. 2017;155:218–29.

    Article  CAS  PubMed  Google Scholar 

  37. Alibolandi M, Ramezani M, Abnous K, Hadizadeh F. AS1411 aptamer-decorated biodegradable polyethylene glycol–poly (lactic-co-glycolic acid) nanopolymersomes for the targeted delivery of gemcitabine to non–small cell lung cancer in vitro. J Pharm sci. 2016;105:1741–50.

    Article  CAS  PubMed  Google Scholar 

  38. Quader S, Kataoka K. Nanomaterial-enabled cancer therapy. Mol Ther. 2017;25:1501–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Wang H, Huang Y. Combination therapy based on nano codelivery for overcoming cancer drug resistance. Med Drug Discov. 2020;6:100024.

  40. Alibolandi M, Ramezani M, Abnous K, Sadeghi F, Atyabi F, Asouri M, et al. In vitro and in vivo evaluation of therapy targeting epithelial-cell adhesion-molecule aptamers for non-small cell lung cancer. J Control Release. 2015;209:88–100.

    Article  CAS  PubMed  Google Scholar 

  41. Maeda H, Wu J, Sawa T, Matsumura Y, Hori K. Tumor vascular permeability and the EPR effect in macromolecular therapeutics: a review. J Control Release. 2000;65:271–84.

    Article  CAS  PubMed  Google Scholar 

  42. Alibolandi M, Rezvani R, Farzad SA, Taghdisi SM, Abnous K, Ramezani M. Tetrac-conjugated polymersomes for integrin-targeted delivery of camptothecin to colon adenocarcinoma in vitro and in vivo. Int J Pharm. 2017;532:581–94.

    Article  CAS  PubMed  Google Scholar 

  43. Sun W, Du Y, Liang X, Yu C, Fang J, Lu W, et al. Synergistic triple-combination therapy with hyaluronic acid-shelled PPy/CPT nanoparticles results in tumor regression and prevents tumor recurrence and metastasis in 4T1 breast cancer. Biomaterials. 2019;217:119264.

    Article  CAS  PubMed  Google Scholar 

  44. Bae YH, Park K. Targeted drug delivery to tumors: Myths, reality and possibility. J Control Release. 2011;153:198–205.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The authors are grateful for the Mashhad University of Medical Sciences (Grant no. 960957). This study was based on the Pharm D. thesis of SS.

Author information

Author notes

  1. These authors contributed equally: Setareh Sanati, Sahar Taghavi

Authors and Affiliations

  1. Pharmaceutical Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran

    Setareh Sanati, Sahar Taghavi, Khalil Abnous, Maryam Babaei, Mohammad Ramezani & Mona Alibolandi

  2. Department of Pharmaceutical Biotechnology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran

    Setareh Sanati, Mohammad Ramezani & Mona Alibolandi

  3. Targeted Drug Delivery Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran

    Seyed Mohammad Taghdisi

Authors
  1. Setareh Sanati
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sahar Taghavi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Khalil Abnous
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Seyed Mohammad Taghdisi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Maryam Babaei
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Mohammad Ramezani
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Mona Alibolandi
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

SS and ST: performance and formal analysis as well as writing—original draft. KA: formal analysis, review, and editing. SMT: formal analysis, review, and editing. MB: formal analysis. MR: conceptualization, supervision. MA: conceptualization, pereparation of final manuscript for submission, supervision. Finally, the paper was written through contributions of all authors. All authors have given approval to the final version of the paper.

Corresponding authors

Correspondence to Mohammad Ramezani or Mona Alibolandi.

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

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Sanati, S., Taghavi, S., Abnous, K. et al. Fabrication of anionic dextran-coated micelles for aptamer targeted delivery of camptothecin and survivin-shRNA to colon adenocarcinoma. Gene Ther 29, 55–68 (2022). https://doi.org/10.1038/s41434-021-00234-0

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41434-021-00234-0

This article is cited by

Search

Advanced search

Quick links