Pharmaceutical Research

, Volume 32, Issue 10, pp 3261–3268 | Cite as

A Study of Liposomal Formulations to Improve the Delivery of Aquated Cisplatin to a Multidrug Resistant Tumor

  • Yucheng Zhao
  • Jonathan P. May
  • I-Wen Chen
  • Elijus Undzys
  • Shyh-Dar Li
Research Paper



This study was aimed at exploring the use of liposomes to deliver aquated cisplatin (ACP), a metabolite of CDDP, with increased potency and toxicity. Three liposomal formulations were compared for delivery of ACP to a multidrug resistant tumor.


Three different liposomes (DMPC, DPPC and DSPC as the main lipid components) were loaded with ACP by the thin-film hydration method. In vitro drug release was assessed over 72 h at 37°C in PBS. The pharmacokinetics of free CDDP and the three ACP liposomes was determined using ICP-AES and their efficacy against EMT6-AR1 multidrug resistant murine breast tumor was compared.


The DSPC formulation, composed of a C18 acyl chain lipid, exhibited the slowest drug release (~2%) after 72 h at 37°C, compared to the other two formulations with decreased carbon chain lengths (C16 and C14; 7 and 25% release respectively). The pharmacokinetic profile was improved with all liposomal formulations relative to free CDDP, with clearance reduced by 500-fold for DSPC, 200-fold for DPPC and 130-fold for DMPC. The DSPC formulation displayed the highest drug accumulation in the tumor with 2-fold, 3-fold and 100-fold increases compared to DPPC, DMPC and free CDDP respectively. The DSPC formulation significantly inhibited the EMT6-AR1 tumor growth by ~90%, while the other formulations displayed no statistically significant improved activity compared to saline.


These results suggest that the DSPC liposomal formulation is a promising formulation for MDR tumor therapy over DMPC and DPPC formulations and free drug.


aquated cisplatin cisplatin long circulating liposome multidrug resistant tumor 



Aquated cisplatin


Area under the concentration curve








Copper transporter 1


Dynamic light scattering


Dulbecco’s Modified Eagle’s medium


1, 2-dimyristoyl-sn-glycero-3-phosphatidylcholine


1, 2-dipalmitoyl-sn-glycero-3-phosphatidylcholine






Enhanced permeability and retention effect


Fetal bovine serum


Inductively Coupled Plasma Atomic Emission Spectroscopy


Injected dose per gram of tissue


Long circulating liposomes


Multi-drug resistance


Multi-lamellar vesicles


Molecular weight cut-off




Phosphate buffered saline


Polydispersity index




Reticuloendothelial system


Half life


Steady state volume of distribution



We would like to acknowledge the Canadian Institutes for Health Research (CIHR) for assistance with funding for this project, through a combination of CIHR proof-of-principle and CIHR operating grants. SDL also received a CIHR New Investigator Award and a Young Investigator Award from the Prostate Cancer Foundation. The Ontario Institute for Cancer Research (Funded by the Government of Ontario), University Health Network and the Analest facility at the University of Toronto are also acknowledged for providing the facilities and equipment necessary to conduct this research.

Supplementary material

11095_2015_1702_MOESM1_ESM.docx (110 kb)
ESM 1 (DOCX 109 kb)


  1. 1.
    Rabik CA, Dolan ME. Molecular mechanisms of resistance and toxicity associated with platinating agents. Cancer Treat Rev. 2007;33(1):9–23.PubMedCentralCrossRefPubMedGoogle Scholar
  2. 2.
    Armstrong DK, Bundy B, Wenzel L, Huang HQ, Baergen R, Lele S, et al. Intraperitoneal cisplatin and paclitaxel in ovarian cancer. N Engl J Med. 2006;354(1):34–43.CrossRefPubMedGoogle Scholar
  3. 3.
    Daley-Yates PT, McBrien DC. Cisplatin metabolites in plasma, a study of their pharmacokinetics and importance in the nephrotoxic and antitumour activity of cisplatin. Biochem Pharmacol. 1984;33(19):3063–70.CrossRefPubMedGoogle Scholar
  4. 4.
    Siddik ZH. Cisplatin: mode of cytotoxic action and molecular basis of resistance. Oncogene. 2003;22(47):7265–79.CrossRefPubMedGoogle Scholar
  5. 5.
    Alberts DS, Noel JK. Cisplatin-associated neurotoxicity: can it be prevented? Anticancer Drugs. 1995;6(3):369–83.CrossRefPubMedGoogle Scholar
  6. 6.
    Zheng H, Fink D, Howell SB. Pharmacological basis for a novel therapeutic strategy based on the use of aquated cisplatin. Clin Cancer Res. 1997;3(7):1157–65.PubMedGoogle Scholar
  7. 7.
    Howell SB, Safaei R, Larson CA, Sailor MJ. Copper transporters and the cellular pharmacology of the platinum-containing cancer drugs. Mol Pharmacol. 2010;77(6):887–94.PubMedCentralCrossRefPubMedGoogle Scholar
  8. 8.
    Fang J, Nakamura H, Maeda H. The EPR effect: unique features of tumor blood vessels for drug delivery, factors involved, and limitations and augmentation of the effect. Adv Drug Deliv Rev. 2011;63(3):136–51.CrossRefPubMedGoogle Scholar
  9. 9.
    Harrington KJ, Lewanski CR, Northcote AD, Whittaker J, Wellbank H, Vile RG, et al. Phase I-II study of pegylated liposomal cisplatin (SPI-077) in patients with inoperable head and neck cancer. Ann Oncol. 2001;12(4):493–6.CrossRefPubMedGoogle Scholar
  10. 10.
    White SC, Lorigan P, Margison GP, Margison JM, Martin F, Thatcher N, et al. Phase II study of SPI-77 (sterically stabilised liposomal cisplatin) in advanced non-small-cell lung cancer. Br J Cancer. 2006;95(7):822–8.PubMedCentralCrossRefPubMedGoogle Scholar
  11. 11.
    Meerum Terwogt JM, Groenewegen G, Pluim D, Maliepaard M, Tibben MM, Huisman A, et al. Phase I and pharmacokinetic study of SPI-77, a liposomal encapsulated dosage form of cisplatin. Cancer Chemother Pharmacol. 2002;49(3):201–10.CrossRefPubMedGoogle Scholar
  12. 12.
    Liu D, He C, Wang AZ, Lin W. Application of liposomal technologies for delivery of platinum analogs in oncology. Int J Nanomedicine. 2013;8:3309–19.PubMedCentralPubMedGoogle Scholar
  13. 13.
    Charrois GJ, Allen TM. Drug release rate influences the pharmacokinetics, biodistribution, therapeutic activity, and toxicity of pegylated liposomal doxorubicin formulations in murine breast cancer. Biochim Biophys Acta. 2004;1663(1–2):167–77.CrossRefPubMedGoogle Scholar
  14. 14.
    Anderson M, Omri A. The effect of different lipid components on the in vitro stability and release kinetics of liposome formulations. Drug Deliv. 2004;11(1):33–9.CrossRefPubMedGoogle Scholar
  15. 15.
    Maeda H. The enhanced permeability and retention (EPR) effect in tumor vasculature: the key role of tumor-selective macromolecular drug targeting. Adv Enzym Regul. 2001;41:189–207.CrossRefGoogle Scholar
  16. 16.
    Senior JH. Fate and behavior of liposomes in vivo: a review of controlling factors. Crit Rev Ther Drug Carrier Syst. 1987;3(2):123–93.PubMedGoogle Scholar
  17. 17.
    Pownall HJ, Massey JB, Kusserow SK, Gotto Jr AM. Kinetics of lipid–protein interactions: interaction of apolipoprotein A-I from human plasma high density lipoproteins with phosphatidylcholines. Biochemistry. 1978;17(7):1183–8.CrossRefPubMedGoogle Scholar
  18. 18.
    Semple SC, Chonn A, Cullis PR. Influence of cholesterol on the association of plasma proteins with liposomes. Biochemistry. 1996;35(8):2521–5.CrossRefPubMedGoogle Scholar
  19. 19.
    Chono S, Tanino T, Seki T, Morimoto K. Uptake characteristics of liposomes by rat alveolar macrophages: influence of particle size and surface mannose modification. J Pharm Pharmacol. 2007;59(1):75–80.CrossRefPubMedGoogle Scholar
  20. 20.
    Ahsan F, Rivas IP, Khan MA, Torres Suarez AI. Targeting to macrophages: role of physicochemical properties of particulate carriers–liposomes and microspheres–on the phagocytosis by macrophages. J Control Release. 2002;79(1–3):29–40.CrossRefPubMedGoogle Scholar
  21. 21.
    Wijagkanalan W, Kawakami S, Higuchi Y, Yamashita F, Hashida M. Intratracheally instilled mannosylated cationic liposome/NFkappaB decoy complexes for effective prevention of LPS-induced lung inflammation. J Control Release. 2011;149(1):42–50.CrossRefPubMedGoogle Scholar
  22. 22.
    Alinaghi A, Rouini MR, Johari Daha F, Moghimi HR. The influence of lipid composition and surface charge on biodistribution of intact liposomes releasing from hydrogel-embedded vesicles. Int J Pharm. 2014;459(1–2):30–9.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Yucheng Zhao
    • 1
    • 2
    • 3
  • Jonathan P. May
    • 1
    • 2
  • I-Wen Chen
    • 2
    • 3
  • Elijus Undzys
    • 2
  • Shyh-Dar Li
    • 1
    • 2
    • 3
  1. 1.Faculty of Pharmaceutical SciencesUniversity of British ColumbiaVancouverCanada
  2. 2.Drug Discovery ProgramOntario Institute for Cancer ResearchTorontoCanada
  3. 3.Leslie Dan Faculty of PharmacyUniversity of TorontoTorontoCanada

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