Pharmaceutical Research

, Volume 33, Issue 12, pp 2943–2953 | Cite as

Enhanced Anti-Tumor Efficacy of Lipid-Modified Platinum Derivatives in Combination with Survivin Silencing siRNA in Resistant Non-Small Cell Lung Cancer

  • George Mattheolabakis
  • Dandan Ling
  • Gulzar Ahmad
  • Mansoor AmijiEmail author
Research Paper



Cisplatin, is recognized as a first line therapeutic for the treatment of non-small cell lung cancer (NSCLC). Cisplatin resistance is identified as the most detrimental complication during treatment and has been associated with upregulation of several genes, such as the anti-apoptotic gene survivin. In this study, we have evaluated the cytotoxic activity of lipid (C6 and C8)-modified platinum compounds in combination with a survivin-silencing siRNA against cisplatin resistant tumors.


We synthesized and characterized several lipid-modified platinum compounds and evaluated their cytotoxic activity alone or in combination with survivin-silencing siRNA in vitro and in vivo against A549DDP cells and in vivo in tumor xenograft model.


The lipid-modified compounds exhibited significantly stronger cytotoxic activity in vitro compared to cisplatin, with CDDP-C6 and CDDP-C8 producing the most pronounced effect, in both A549 and A549DDP cells. Pre-treatment of the A549DDP cells with survivin-silencing siRNA enhanced the cytotoxic activity of these compounds. In vivo, the co-treatment of the survivin-silencing siRNA and CDDP-C8 produced the strongest tumor growth inhibition effect (64.5%, p < 0.05) on a cancer mouse model of chemoresistant lung cancer. In contrast, cisplatin treatment exhibited no significant tumor growth inhibition (4.5%, no p).


Co-treatment of lipid-modified compounds and survivin-silencing siRNA can constitute a reliable alternative to cisplatin treatment for cisplatin-resistant lung tumors that merit further evaluation.


chemoresistance lipid-modified platinates non-small cell lung cancer small interfering RNA survivin 



Alanine transaminase


Aspartate transaminase


Cis-diammine-dichloro-platinum (or cisplatin)




Cisplatin resistant




1-Ethyl-3-[3-(dimethylamino)propyl]carbodiimide hydrochloride


Hyaluronic acid


High pressure liquid chromatography


Inductively coupled plasma mass spectrometry


3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide


Nuclear magnetic resonance spetroscopy


Non-small cell lung cancer


Poly(ethylene glycol)




Quantitative polymerase chain reaction


Ribonucleic acid


RNA interference


Small interfering RNA





This study was supported by the National Cancer Institute’s (NCI) Alliance for Nanotechnology in Cancer Platform Partnership (CNPP) grant U01-CA151452 and by an NCI R21 grant CA-179652-01. We would like also to acknowledge Drs. Abhijit Kulkarni and Ganeshsingh Ganesh for their help on the LC-MS analysis of the platinum derivatives. ICP-MS platinum analysis in plasma and tissues was performed at the GLP Bioanalytical Laboratory, University of North Carolina (UNC) at Chapel Hill through a sub-contract agreement. We deeply appreciate the assistance of Professor William Zamboni, Dr. John Kagel, and others at the UNC with the analysis. The authors declare no conflicts of interest.

Supplementary material

11095_2016_2016_MOESM1_ESM.pptx (726 kb)
ESM 1 (PPTX 726 kb)


  1. 1.
    Jemal A, Siegel R, Xu JQ, Ward E. Cancer statistics, 2010. Ca-Cancer J Clin. 2010;60(5):277–300.CrossRefPubMedGoogle Scholar
  2. 2.
    Tiseo M, Ardizzoni A, Boni L. First-line chemotherapy treatment of advanced non-small-cell lung cancer: does cisplatin versus carboplatin make a difference? J Thorac Oncol. 2014;9(11):e82.CrossRefPubMedGoogle Scholar
  3. 3.
    Berghmans T, Paesmans M, Sculier JP. Cisplatin or carboplatin for the treatment of non-small cell lung cancer: do they have equivalent efficacy? Lung Cancer. 2001;34(1):15–7.CrossRefPubMedGoogle Scholar
  4. 4.
    Shen DW, Pouliot LM, Hall MD, Gottesman MM. Cisplatin resistance: a cellular self-defense mechanism resulting from multiple epigenetic and genetic changes. Pharmacol Rev. 2012;64(3):706–21.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Florea AM, Busselberg D. Cisplatin as an anti-tumor drug: cellular mechanisms of activity, drug resistance and induced side effects. Cancers (Basel). 2011;3(1):1351–71.CrossRefGoogle Scholar
  6. 6.
    Ganesh S, Iyer AK, Weiler J, Morrissey DV, Amiji MM. Combination of siRNA-directed gene silencing with cisplatin reverses drug resistance in human non-small cell lung cancer. Mol Ther Nucleic Acids. 2013;2:e110.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Wilson RC, Doudna JA. Molecular mechanisms of RNA interference. Annu Rev Biophys. 2013;42:217–39.CrossRefPubMedGoogle Scholar
  8. 8.
    Kim YD, Park TE, Singh B, Maharjan S, Choi YJ, Choung PH, et al. Nanoparticle-mediated delivery of siRNA for effective lung cancer therapy. Nanomedicine (Lond). 2015;10(7):1165–88.CrossRefGoogle Scholar
  9. 9.
    Shim G, Choi HW, Lee S, Choi J, Yu YH, Park DE, et al. Enhanced intrapulmonary delivery of anticancer siRNA for lung cancer therapy using cationic ethylphosphocholine-based nanolipoplexes. Mol Ther. 2013;21(4):816–24.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Schiffelers RM, Ansari A, Xu J, Zhou Q, Tang Q, Storm G, et al. Cancer siRNA therapy by tumor selective delivery with ligand-targeted sterically stabilized nanoparticle. Nucleic Acids Res. 2004;32(19):e149.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Xue W, Dahlman JE, Tammela T, Khan OF, Sood S, Dave A, et al. Small RNA combination therapy for lung cancer. Proc Natl Acad Sci U S A. 2014;111(34):E3553–61.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Qian Z, Zhao X, Jiang M, Jia W, Zhang C, Wang Y, et al. Downregulation of cyclophilin A by siRNA diminishes non-small cell lung cancer cell growth and metastasis via the regulation of matrix metallopeptidase 9. BMC Cancer. 2012;12:442.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Stoleriu MG, Steger V, Mustafi M, Michaelis M, Cinatl J, Schneider W, et al. A new strategy in the treatment of chemoresistant lung adenocarcinoma via specific siRNA transfection of SRF, E2F1, Survivin, HIF and STAT3. Eur J Cardiothorac Surg. 2014;46(5):877–86.CrossRefPubMedGoogle Scholar
  14. 14.
    Shi Y, Liu SA, Kerwood DJ, Goodisman J, Dabrowiak JC. Pt(IV) complexes as prodrugs for cisplatin. J Inorg Biochem. 2012;107(1):6–14.CrossRefPubMedGoogle Scholar
  15. 15.
    Chin CF, Wong DY, Jothibasu R, Ang WH. Anticancer platinum (IV) prodrugs with novel modes of activity. Curr Top Med Chem. 2011;11(21):2602–12.CrossRefPubMedGoogle Scholar
  16. 16.
    Nascimento AV, Singh A, Bousbaa H, Ferreira D, Sarmento B, Amiji MM. Combinatorial-designed epidermal growth factor receptor-targeted chitosan nanoparticles for encapsulation and delivery of lipid-modified platinum derivatives in wild-type and resistant Non-small-cell lung cancer cells. Mol Pharm. 2015;12(12):4466–77.CrossRefPubMedGoogle Scholar
  17. 17.
    Johnstone TC, Lippard SJ. The effect of ligand lipophilicity on the nanoparticle encapsulation of Pt(IV) prodrugs. Inorg Chem. 2013;52(17):9915–20.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Tran TH, Krishnan S, Amiji MM. MicroRNA-223 induced repolarization of peritoneal macrophages using CD44 targeting hyaluronic acid nanoparticles for anti-inflammatory effects. PLoS One. 2016;11(5):e0152024.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Ganesh S, Iyer AK, Gattacceca F, Morrissey DV, Amiji MM. In vivo biodistribution of siRNA and cisplatin administered using CD44-targeted hyaluronic acid nanoparticles. J Control Release. 2013;172(3):699–706.CrossRefPubMedGoogle Scholar
  20. 20.
    Kelland L. The resurgence of platinum-based cancer chemotherapy. Nat Rev Cancer. 2007;7(8):573–84.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  • George Mattheolabakis
    • 1
  • Dandan Ling
    • 1
  • Gulzar Ahmad
    • 1
  • Mansoor Amiji
    • 1
    • 2
    Email author
  1. 1.Department of Pharmaceutical Sciences, School of PharmacyNortheastern UniversityBostonUSA
  2. 2.Faculty of PharmacyKing Abdulaziz UniversityJeddahSaudi Arabia

Personalised recommendations