Skip to main content

Gene Expression Effects of the Delivery of SN-38 via Poly(D-L-lactide-co-caprolactone) Nanoparticles Comprising Dense and Collapsed Poloxamer Coronae



SN-38 is an antineoplastic drug with a three orders of magnitude higher activity than its prodrug, irinotecan, a common chemotherapeutic of choice in the treatment of colorectal cancer. A considerable number of genes are known to alter their expression under the influence of free SN-38, but no studies have looked at the gene expression effects of SN-38 delivered via poly(D-L-lactide-co-caprolactone) (PLCL) nanoparticles yet.


We evaluated changes to expression levels of genes encoding for ubiquitin D (UBD), fibroblast growth factor 3 (FGF3), histone (HIST), and regulator of cell cycle (RGCC) in SW-480 colon cancer cells in response to free SN-38 and two types of poloxamer-coated PLCL (PEO-PPO-PEO/PLCL) nanoparticles as carriers for SN-38, containing different conformations of the hydrophilic stealth corona: dense or collapsed.


Both the free drug and the two drug-loaded nanoformulations upregulated UBD and RGCC and downregulated FGF3 and HIST, which was consistent with the pharmacological activity of SN-38. Still, there was a clear difference in gene expression levels in SW-480 cells depending on whether they were challenged with free SN-38 or with nanoparticles loaded with SN-38. Most critically, the delivery of SN-38 with the nanoparticles prolonged its mode of action and, in the case of genes such as UBD, FGF3, and HIST, provided for a more intense effect on gene expression alteration than that achieved by the drug alone.


Nanoparticles comprising the collapsed PEO-PPO-PEO corona produced a more intense effect on gene expression alteration than the nanoparticles with the dense PEO-PPO-PEO corona.

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

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5


  1. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA: Cancer J Clin. 2018;68(6):394–424.

  2. Siegel RL, Miller KD, Sauer AG, Fedewa SA, Butterly LF, Anderson JC, Cercek A, Smith RA, Jemal A. Colorectal cancer statistics, 2020. Cancer J Clin. 2020;70:145–64.

    Article  Google Scholar 

  3. Perumal K, Ahmad S, Mohd-Zahid MH, Hanaffi WNW, Iskandar ZA, Boer JC, Ferji K, Uskoković V, Jaafar J, Mahmud R. Nanoparticles and gut microbiota in colorectal cancer. Front Nanotechnol 2021;3:681760.

  4. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2019. CA: Cancer J Clin. 2019;69(1):7–34.

  5. Key TJ, Bradbury KE, Perez-Cornago A, Sinha R, Tsilidis KK, Tsugane S. Diet, nutrition, and cancer risk: what do we know and what is the way forward? BMJ. 2020;368: m996.

    Google Scholar 

  6. Wang X, Zhang H, Chen X. Drug resistance and combating drug resistance in cancer. Cancer Drug Resist. 2019;2(2):141–60.

    PubMed  PubMed Central  Google Scholar 

  7. Romaniello D, Gelfo V, Pagano F, Ferlizza E, Sgarzi M, Mazzeschi M, Morselli A, Miano C, D’Uva G, Lauriola M. Senescence-associated reprogramming induced by interleukin-1 impairs response to EGFR neutralization. Cell Mol Biol Lett. 2022;27(1):20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Gao J, Hou D, Hu P, Mao G. Curcumol increases the sensitivity of colon cancer to 5-FU by regulating Wnt/β-catenin signaling. Transl Cancer Res. 2021;10(5):2437–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Ignjatović NL, Sakač M, Kuzminac I, Kojić V, Marković S, Vasiljević-Radović D, Wu VM, Uskoković V, Uskoković DP. Chitosan oligosaccharide lactate coated hydroxyapatite nanoparticles as a vehicle for the delivery of steroid drugs and the targeting of breast cancer cells. J Mater Chem B. 2018;6:6957–6968.

  10. Wu VM, Mickens J, Uskoković V. Bisphosphonate-functionalized calcium phosphate nanoparticles for the delivery of the bromodomain inhibitor JQ1 in the treatment of osteosarcoma. ACS Appl Mater Interfaces. 2017;9(31):25887–25904.

  11. Huang Y, Wang L, Liu Y, Li T, Xin B. Drug-loaded PLCL/PEO-SA bilayer nanofibrous membrane for controlled release. J Biomater Sci Polym Ed. 2021;32(18):2331–48.

    Article  CAS  PubMed  Google Scholar 

  12. Di Salle A, Viscusi G, Di Cristo F, Valentino A, Gorrasi G, Lamberti E, Vittoria V, Calarco A, Peluso G. Antimicrobial and antibiofilm activity of curcumin-loaded electrospun nanofibers for the prevention of the biofilm-associated ınfections. Molecules. 2021;26(16):4866.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Wu S, Bian C, Li X, Chen M, Yang J, Jin Y, Shen Y, Cheng L. Controlled release of triamcinolone from an episcleral micro film delivery system for open-globe eye injuries and proliferative vitreoretinopathy. J Control Release. 2021;10(333):76–90.

    Article  Google Scholar 

  14. Hevener K, Verstak TA, Lutat KE, Riggsbee DL, Mooney JW. Recent developments in topoisomerase-targeted cancer chemotherapy. Acta Pharmaceutica Sinica B. 2018;8(6):844–61.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Wallin Å, Svanvik J, Holmlund B, Ferreud L, Sun XF. Anticancer effect of SN-38 on colon cancer cell lines with different metastatic potential. Oncol Rep. 2008;19(6):1493–8.

    CAS  PubMed  Google Scholar 

  16. Ramesh M, Ahlawat P, Srinivas NR. Irinotecan and its active metabolite, SN-38: review of bioanalytical methods and recent update from clinical pharmacology perspectives. Biomed Chromatogr. 2010;24(1):104–23.

    Article  PubMed  Google Scholar 

  17. Burke TG, Munshi CB, Mi Z, Jiang Y. The important role of albumin in determining the relative human blood stabilities of the camptothecin anticancer drugs. J Pharm Sci. 1995;84:518–9.

    Article  CAS  PubMed  Google Scholar 

  18. Peters GJ. Chapter 1 - Drug resistance in colorectal cancer: general aspects, Editor(s): Chi Hin Cho, Tao Hu, In: Cancer sensitizing agents for chemotherapy, drug resistance in colorectal cancer: molecular mechanisms and therapeutic strategies, Academic Press. 2020;8:1–33.

  19. Li K, Wang S. Preparation, pharmacokinetic profile, and tissue distribution studies of a liposome-based formulation of SN-38 using an UPLC–MS/MS method. AAPS PharmSciTech. 2016;17(6):1450–6.

    Article  CAS  PubMed  Google Scholar 

  20. Poudel BK, Gupta B, Ramasamy T, Thapa RK, Youn YS, Choi H-G, et al. Development of polymeric irinotecan nanoparticles using a novel lactone preservation strategy. Int J Pharm. 2016;512(1):75–86.

    Article  CAS  PubMed  Google Scholar 

  21. Souza V, Dong YB, Zhou HS, Zacharias W, McMasters KM. SW-620 cells treated with topoisomerase I inhibitor SN-38: gene expression profiling. J Transl Med. 2005;3(1):1–7.

    Article  Google Scholar 

  22. Wallin A, Francis P, Nilbert M, Svanvik J, Sun XF. Gene expression profile of colon cancer cell lines treated with SN-38. Chemotherapy. 2010;56(1):17–25.

    Article  CAS  PubMed  Google Scholar 

  23. Koliqi R, Dimchevska S, Geskovski N, Petruševski G, Chacorovska M, Pejova B, Hristov DR, Ugarkovic S, Goracinova K. PEO-PPO-PEO/Poly(DL-lactide-co-caprolactone) nanoparticles as carriers for SN-38: design, optimization and nano-bio ınterface ınteractions. Curr Drug Deliv. 2016;13(3):339–52.

    Article  CAS  PubMed  Google Scholar 

  24. Fang YP, Chuang CH, Wu YJ, Lin HC, Lu YC. SN38-loaded< 100 nm targeted liposomes for improving poor solubility and minimizing burst release and toxicity: in vitro and in vivo study. Int J Nanomed. 2018;13:2789.

    Article  CAS  Google Scholar 

  25. Begines B, Ortiz T, Pérez-Aranda M, Martínez G, Merinero M, Argüelles-Arias F, Alcudia A. Polymeric nanoparticles for drug delivery: recent developments and future prospects. Nanomaterials. 2020;10(7):1403.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Wu D, Li Y, Zhu L, Zhang W, Xu S, Yang Y, Yan Q, Yang G. A biocompatible superparamagnetic chitosan-based nanoplatform enabling targeted SN-38 delivery for colorectal cancer therapy. Carbohydr Polym. 2021;15(274): 118641.

    Article  Google Scholar 

  27. Nakurte I, Jekabsons K, Rembergs R, Zandberga E, Abols A, Linē A, Muceniece R. Colorectal cancer cell line SW480 and SW620 Released extravascular vesicles: focus on hypoxia-induced surface proteome changes. Anticancer Res. 2018;38(11):6133–8.

    Article  CAS  PubMed  Google Scholar 

  28. Maamer-Azzabi A, Ndozangue-Touriguine O, Bréard J. Metastatic SW620 colon cancer cells are primed for death when detached and can be sensitized to anoikis by the BH3-mimetic ABT-737. Cell Death Dis. 2013;4: e801.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Badea TC, Niculescu FI, Soane L, Shin ML, Rus H. Molecular cloning and characterization of RGC-32, a novel gene induced by complement activation in oligodendrocytes. J Biol Chem. 1998;273(41):26977–81.

    Article  CAS  PubMed  Google Scholar 

  30. Erdem ZN, Schwarz S, Drev D, Heinzle C, Reti A, Heffeter P, Hudec X, Holzmann K, Grasl-Kraupp B, Berger W, Grusch M, Marian B. Irinotecan upregulates fibroblast growth factor receptor 3 expression in colorectal cancer cells, which mitigates ırinotecan-ınduced apoptosis. Transl Oncol. 2017;10(3):332–9.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Qin J, Wen B, Liang Y, Yu W, Li H. Histone modifications and their role in colorectal cancer. Pathol Oncol Res. 2019:1–11.

  32. Encarnação JC, Pires AS, Amaral RA, Gonçalves TJ, Laranjo M, Casalta-Lopes JE, Gonçalves AC, Sarmento-Ribeiro AB, Abrantes AM, Botelho MF. Butyrate, a dietary fiber derivative that improves irinotecan effect in colon cancer cells. J Nutr Biochem. 2018;56:183–92.

    Article  PubMed  Google Scholar 

  33. Khan MA, Wu VM, Ghosh S, Uskoković V. Gene delivery using calcium phosphate nanoparticles: optimization of the transfection process and the effects of citrate and poly(l-lysine) as additives. J Colloid Interface Sci. 2016;471:48–58.

  34. Liu XS, Zhang ZG, Zhang RL, Gregg SR, Meng H, Chopp M. Comparison of in vivo and in vitro gene expression profiles in subventricular zone neural progenitor cells from the adult mouse after middle cerebral artery occlusion. Neuroscience. 2007;146(3):1053–61.

    Article  CAS  PubMed  Google Scholar 

  35. Berthou L, Staels B, Saldicco I, Berthelot K, Casey J, Fruchart JC, Denèfle P, Branellec D. Opposite in vitro and in vivo regulation of hepatic apolipoprotein A-I gene expression by retinoic acid. Absence of effects on apolipoprotein A-II gene expression. Arterioscler Thromb. 1994;14(10):1657–64.

Download references

Author information

Authors and Affiliations


Corresponding author

Correspondence to Vuk Uskoković.

Ethics declarations

Conflict of Interest

The authors declare no competing interests.


The authors alone are responsible for the content and the writing of this paper.

Additional information

Publisher's Note

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

Rights and permissions

Springer Nature or its licensor 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

Koliqi, R., Grapci, A.D., Selmani, P.B. et al. Gene Expression Effects of the Delivery of SN-38 via Poly(D-L-lactide-co-caprolactone) Nanoparticles Comprising Dense and Collapsed Poloxamer Coronae. J Pharm Innov 18, 585–593 (2023).

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: