Skip to main content

Advertisement

SpringerLink
Log in

A New Polymer–Lipid Hybrid Nanoparticle System Increases Cytotoxicity of Doxorubicin Against Multidrug-Resistant Human Breast Cancer Cells

  • Research Paper
  • Published:
Pharmaceutical Research Aims and scope Submit manuscript

Purpose

This work is intended to develop and evaluate a new polymer–lipid hybrid nanoparticle system that can efficiently load and release water-soluble anticancer drug doxorubicin hydrochloride (Dox) and enhance Dox toxicity against multidrug-resistant (MDR) cancer cells.

Methods

Cationic Dox was complexed with a new soybean-oil-based anionic polymer and dispersed together with a lipid in water to form Dox-loaded solid lipid nanoparticles (Dox–SLNs). Drug loading and release properties were measured spectrophotometrically. The in vitro cytotoxicity of Dox–SLN and the excipients in an MDR human breast cancer cell line (MDA435/LCC6/MDR1) and its wild-type line were evaluated by trypan blue exclusion and clonogenic assays. Cellular uptake and retention of Dox were determined with a microplate fluorometer.

Results

Dox–SLNs were prepared with a drug encapsulation efficiency of 60–80% and a particle size range of 80–350 nm. About 50% of the loaded drug was released in the first few hours and an additional 10–20% in 2 weeks. Treatment of the MDR cells with Dox–SLN resulted in over 8-fold increase in cell kill when compared to Dox solution treatment at equivalent doses. The blank SLN and the excipients exhibited little cytotoxicity. The biological activity of the released Dox remained unchanged from fresh, free Dox. Cellular Dox uptake and retention by the MDR cells were both significantly enhanced (p < 0.05) when Dox was delivered in Dox–SLN form.

Conclusions

The new polymer–lipid hybrid nanoparticle system is effective for delivery of Dox and enhances its efficacy against MDR breast cancer cells.

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
Fig. 10
Fig. 11

Similar content being viewed by others

References

  1. P. E. Lonning (2003) ArticleTitleStudy of suboptimum treatment response: lessons from breast cancer Lancet Oncol. 4 177–185 Occurrence Handle12623363 Occurrence Handle10.1016/S1470-2045(03)01022-2

    Article  PubMed  Google Scholar 

  2. InstitutionalAuthorNameEarly Breast Cancer Trialists' Collaborative Group (1998) ArticleTitlePolychemotherapy for early breast cancer: an overview of the randomized trials Lancet 352 930–942 Occurrence Handle10.1016/S0140-6736(98)03301-7

    Article  Google Scholar 

  3. M. M. Gottesman (2002) ArticleTitleMechanisms of cancer drug resistance Annu. Rev. Med. 53 615–627 Occurrence Handle11818492 Occurrence Handle1:CAS:528:DC%2BD38Xitl2mtLo%3D Occurrence Handle10.1146/annurev.med.53.082901.103929

    Article  PubMed  CAS  Google Scholar 

  4. F. Leonessa R. Clarke (2003) ArticleTitleATP binding cassette transporters and drug resistance in breast cancer Endocr.-Relat. Cancer 10 43–73 Occurrence Handle12653670 Occurrence Handle1:CAS:528:DC%2BD3sXksVahtLk%3D Occurrence Handle10.1677/erc.0.0100043

    Article  PubMed  CAS  Google Scholar 

  5. I. Mohamed R. T. Skeel (2003) Carcinoma of breast R. T.. T. Skeel (Eds) Handbook of Cancer Chemotherapy Lippincott Williams & Wilkins Philadelphia 269–293

    Google Scholar 

  6. H. C. Chung S. Y. Rha J. H. Kim J. K. Roh J. S. Min K. S. Lee B. S. Kim K. B. Lee (1967) ArticleTitleP-glycoprotein: the intermediate end point of drug response to induction chemotherapy in locally advanced breast cancer Breast Cancer Res. Tr. 42 65–72 Occurrence Handle10.1023/A:1005739525196

    Article  Google Scholar 

  7. Z. Liu X. Y. Wu R. Bendayan (1999) ArticleTitleIn vitro investigation of ionic polysaccharide microspheres for simultaneous delivery of chemosensitizer and antineoplastic agent to multidrug-resistant cells J. Pharm. Sci. 88 412–418 Occurrence Handle10187751 Occurrence Handle1:CAS:528:DyaK1MXhslersLk%3D Occurrence Handle10.1021/js9803353

    Article  PubMed  CAS  Google Scholar 

  8. R. Y. Cheung A. M. Rauth X. Y. Wu (2005) ArticleTitleIn vivo efficacy and toxicity of intratumorally delivered mitomycin C and its combination with doxorubicin using microsphere formulations Anti-Cancer Drugs 16 IssueID4 423–433 Occurrence Handle15746579 Occurrence Handle1:CAS:528:DC%2BD2MXhslyqsrw%3D Occurrence Handle10.1097/00001813-200504000-00009

    Article  PubMed  CAS  Google Scholar 

  9. R. Cheung Y. Ying A. M. Rauth N. Marcon X. Y. Wu (2005) ArticleTitleBiodegradable dextran-based microspheres for delivery of anticancer drug mitomycin C Biomaterials 26 5375–5385 Occurrence Handle15814136 Occurrence Handle1:CAS:528:DC%2BD2MXjt1agsLo%3D Occurrence Handle10.1016/j.biomaterials.2005.01.050

    Article  PubMed  CAS  Google Scholar 

  10. Z. Liu R. Cheung X. Y. Wu J. R. Ballinger R. Bendayan A. M. Rauth (2001) ArticleTitleA study of doxorubicin loading onto and release from sulfopropyl dextran ion-exchange microspheres J. Control. Release 77 213–224 Occurrence Handle11733089 Occurrence Handle1:CAS:528:DC%2BD3MXoslGnt7k%3D Occurrence Handle10.1016/S0168-3659(01)00473-4

    Article  PubMed  CAS  Google Scholar 

  11. S. C. J. Steiniger J. Kreuter A. S. Khalansky I. N. Skidan A. I. Bobruskin Z. S. Smirnova S. E. Severin R. Uhl M. Kock K. D. Geiger S. E. Gelperina (2004) ArticleTitleChemotherapy of glioblastoma in rats using doxorubicin-loaded nanoparticles Int. J. Cancer 109 759–767 Occurrence Handle14999786 Occurrence Handle1:CAS:528:DC%2BD2cXivFClu7Y%3D Occurrence Handle10.1002/ijc.20048

    Article  PubMed  CAS  Google Scholar 

  12. S. E. Gelperina A. S. Khalansky I. N. Skidan Z. S. Smirnova A. I. Bobruskin S. E. Severin B. Turowski F. E. Zanella J. Kreuter (2002) ArticleTitleToxicological studies of doxorubicin bound to polysorbate 80-coated poly(butyl cyanoacrylate) nanoparticles in healthy rats and rats with intracranial glioblastoma Toxicol. Lett. 126 131–141 Occurrence Handle11751017 Occurrence Handle1:CAS:528:DC%2BD3MXptFyntLs%3D Occurrence Handle10.1016/S0378-4274(01)00456-8

    Article  PubMed  CAS  Google Scholar 

  13. M. I. Koukourakis S. Koukouraki I. Fezoulidis G. Kurias S. Archimandritis N. Karkavitsas (2000) ArticleTitleHigh intratumoral accumulation of stealth liposomal doxorubicin (Caelyx) in glioblastomas and in metastatic tumours Br. J. Cancer 83 1281–1286 Occurrence Handle11044350 Occurrence Handle1:CAS:528:DC%2BD3cXos12hu74%3D Occurrence Handle10.1054/bjoc.2000.1459

    Article  PubMed  CAS  Google Scholar 

  14. U. Massing S. Fuxius (2000) ArticleTitleLiposomal formulations of anticancer drugs: selectivity and effectiveness Drug Resist. Updat. 3 171–177 Occurrence Handle11498382 Occurrence Handle1:CAS:528:DC%2BD3cXmsVSitLg%3D Occurrence Handle10.1054/drup.2000.0138

    Article  PubMed  CAS  Google Scholar 

  15. Z. Liu J. R. Ballinger A. M. Rauth R. Bendayan X. Y. Wu (2003) ArticleTitleDelivery of an anticancer drug and a chemosensitizer to murine breast sarcoma by intratumoral injection of sulfopropyl dextran microspheres J. Pharm. Pharmacol. 55 1063–1073 Occurrence Handle12956895 Occurrence Handle1:CAS:528:DC%2BD3sXmvFGnsb0%3D Occurrence Handle10.1211/0022357021567

    Article  PubMed  CAS  Google Scholar 

  16. Z. Liu R. Bendayan X. Y. Wu (2001) ArticleTitleTriton-X-100-modified polymer and microspheres for reversal of multidrug resistance J. Pharm. Pharmacol. 53 1–12

    Google Scholar 

  17. Z. Liu X. Y. Wu R. Bendayan (1999) ArticleTitleIn vitro investigation of ionic polysaccharide microspheres for simultaneous delivery of chemosensitizer and antineoplastic agent to multidrug-resistant cells J. Pharm. Sci. 88 412–418 Occurrence Handle10187751 Occurrence Handle1:CAS:528:DyaK1MXhslersLk%3D Occurrence Handle10.1021/js9803353

    Article  PubMed  CAS  Google Scholar 

  18. J. Huwyler A. Cerletti G. Fricker A. N. Eberle J. Drewe (2002) ArticleTitleBy-passing of P-glycoprotein using immunoliposomes J. Drug Target. 10 73–79 Occurrence Handle11996089 Occurrence Handle1:CAS:528:DC%2BD38Xis1Oht7g%3D Occurrence Handle10.1080/10611860290007559

    Article  PubMed  CAS  Google Scholar 

  19. C. Mamot D. C. Drummond K. Hong D. B. Kirpotin J. W. Park (2003) ArticleTitleLiposome-based approaches to overcome anticancer drug resistance Drug Resist. Updat. 6 271–279 Occurrence Handle14643297 Occurrence Handle1:CAS:528:DC%2BD3sXptF2ru70%3D Occurrence Handle10.1016/S1368-7646(03)00082-7

    Article  PubMed  CAS  Google Scholar 

  20. C. E. Soma C. Dubernet D. Bentolila S. Benita P. Couvreur (2000) ArticleTitleReversion of multidrug resistance by co-encapsulation of doxorubicin and cyclosporin A in polyalkylcyanoacrylate nanoparticles Biomaterials 21 1–7 Occurrence Handle10619673 Occurrence Handle1:CAS:528:DC%2BD3cXjtVeqsQ%3D%3D Occurrence Handle10.1016/S0142-9612(99)00125-8

    Article  PubMed  CAS  Google Scholar 

  21. L. Fenart A. Casanova B. Dehouck C. Duhem S. Slupek R. Cecchelli D. Betbeder (1999) ArticleTitleEvaluation of effect of charge and lipid coating on ability of 60 nm nanoparticles to cross an in vitro model of the blood–brain barrier J. Pharmacol. Exp. Ther. 291 1017–1022 Occurrence Handle10565819 Occurrence Handle1:CAS:528:DyaK1MXnslygtLY%3D

    PubMed  CAS  Google Scholar 

  22. A. C. Verdiere Particlede C. Dubernet F. Nemati E. Soma M. Appel J. Ferte S. Bernard F. Puisieux P. Couvreur (1997) ArticleTitleReversion of multidrug resistance with polyalkylcyanoacrylate nanoparticles: towards a mechanism of action Br. J. Cancer 76 198–205 Occurrence Handle9231919

    PubMed  Google Scholar 

  23. C. E. Soma C. Dubernet G. Barratt F. Nemati M. Appel S. Benita P. Couvreur (1999) ArticleTitleAbility of doxorubicin-loaded nanoparticles to overcome multidrug resistance of tumor cells after their capture by macrophages Pharm. Res. 16 1710–1716 Occurrence Handle10571276 Occurrence Handle1:CAS:528:DyaK1MXnt1Ggs7Y%3D Occurrence Handle10.1023/A:1018902031370

    Article  PubMed  CAS  Google Scholar 

  24. A. R. Thierry D. Vige S. S. Coughlin J. A. Belli A. Dritschilo A. Rahman (1993) ArticleTitleModulation of doxorubicin resistance in multidrug-resistant cells by liposomes FASEB J. 7 572–579 Occurrence Handle8097173 Occurrence Handle1:CAS:528:DyaK3sXisVSktbk%3D

    PubMed  CAS  Google Scholar 

  25. Y. Romsicki F. J. Sharom (1999) ArticleTitleThe membrane lipid environment modulates drug interactions with the P-glycoprotein multidrug transporter Biochemistry 38 6887–6896 Occurrence Handle10346910 Occurrence Handle1:CAS:528:DyaK1MXislyju74%3D Occurrence Handle10.1021/bi990064q

    Article  PubMed  CAS  Google Scholar 

  26. Y. L. Lo (2000) ArticleTitlePhospholipids as multidrug resistance modulators of the transport of epirubicin in human intestinal epithelial Caco-2 cell layers and everted gut sacs of rats Biochem. Pharmacol. 60 1381–1390 Occurrence Handle11008132 Occurrence Handle1:CAS:528:DC%2BD3cXmslOjtL0%3D Occurrence Handle10.1016/S0006-2952(00)00451-2

    Article  PubMed  CAS  Google Scholar 

  27. R. H. Muller K. Mader S. Gohla (2000) ArticleTitleSolid lipid nanoparticles (SLN) for controlled drug delivery—a review of the state of the art Eur. J. Pharm. Biopharm. 50 161–177 Occurrence Handle10840199 Occurrence Handle1:CAS:528:DC%2BD3cXjslyisrg%3D Occurrence Handle10.1016/S0939-6411(00)00087-4

    Article  PubMed  CAS  Google Scholar 

  28. R. H. Muller D. Ruhl S. Runge K. Schulze-Forster W. Mehnert (1997) ArticleTitleCytotoxicity of solid lipid nanoparticles as a function of the lipid matrix and the surfactant Pharm. Res. 14 458–462 Occurrence Handle9144731 Occurrence Handle1:STN:280:ByiB1cbpsVI%3D Occurrence Handle10.1023/A:1012043315093

    Article  PubMed  CAS  Google Scholar 

  29. J. M. Koziara P. R. Lockman D. D. Allen R. J. Mumper (2004) ArticleTitlePaclitaxel nanoparticles for the potential treatment of brain tumors J. Control. Release 99 259–269 Occurrence Handle15380635 Occurrence Handle1:CAS:528:DC%2BD2cXns1Chur4%3D Occurrence Handle10.1016/j.jconrel.2004.07.006

    Article  PubMed  CAS  Google Scholar 

  30. R. Cavalli O. Caputo M. R. Gasco (1993) ArticleTitleSolid lipospheres of doxorubicin and idarubicin Int. J. Pharm. 89 R9–R12 Occurrence Handle1:CAS:528:DyaK3sXms1Oksw%3D%3D Occurrence Handle10.1016/0378-5173(93)90313-5

    Article  CAS  Google Scholar 

  31. L. Serpe M. G. Catalano R. Cavalli E. Ugazio O. Bosco R. Canaparo E. Muntoni R. Frairia M. R. Gasco M. Eandi G. P. Zara (2004) ArticleTitleCytotoxicity of anticancer drugs incorporated in solid lipid nanoparticles on HT-29 colorectal cancer cell line Eur. J. Pharm. Biopharm. 58 673–680 Occurrence Handle15451544 Occurrence Handle1:CAS:528:DC%2BD2cXnvFagurc%3D Occurrence Handle10.1016/j.ejpb.2004.03.026

    Article  PubMed  CAS  Google Scholar 

  32. A. Miglietta R. Cavalli C. Bocca L. Gabriel M. R. Gasco (2000) ArticleTitleCellular uptake and cytotoxicity of solid lipid nanospheres (SLN) incorporating doxorubicin or paclitaxel Int. J. Pharm. 210 61–67 Occurrence Handle11163988 Occurrence Handle1:CAS:528:DC%2BD3MXhsVyrtQ%3D%3D Occurrence Handle10.1016/S0378-5173(00)00562-7

    Article  PubMed  CAS  Google Scholar 

  33. S. M. Hahn A. Russo J. A. Cook J. B. Mitchell (1999) ArticleTitleA multidrug-resistant breast cancer line induced by weekly exposure to doxorubicin Int. J. Oncol. 14 273–279 Occurrence Handle9917502 Occurrence Handle1:CAS:528:DyaK1MXhtFKjtb8%3D

    PubMed  CAS  Google Scholar 

  34. H. L. Wong R. Bendayan A. M. Rauth X. Y. Wu (2004) ArticleTitleDevelopment of solid lipid nanoparticles containing ionically-complexed chemotherapeutic drugs and chemosensitizers J. Pharm. Sci. 93 1993–2004 Occurrence Handle15236449 Occurrence Handle1:CAS:528:DC%2BD2cXmvVKktL8%3D Occurrence Handle10.1002/jps.20100

    Article  PubMed  CAS  Google Scholar 

  35. F. Leonessa D. Green T. Licht A. Wright K. Wingate-Legette J. Lippman M. M. Gottesman R. Clarke (1996) ArticleTitleMDA435/LCC6 and MDA435/LCC6MDR1: ascites models of human breast cancer Br. J. Cancer 73 154–161 Occurrence Handle8546900 Occurrence Handle1:STN:280:BymC2M%2FhtlI%3D

    PubMed  CAS  Google Scholar 

  36. R.G. Bristow R.P. Hill (1998) Molecular and cellular basis of radiotherapy I. F. Tannock R. P. Hill (Eds) The Basic Science of Oncology McGraw-Hill Toronto 295–321

    Google Scholar 

  37. Z. Liu and S. Erhan. Synthesis and properties of new soybean oil based polymers, US patent application.

  38. D. Z. Hou C. S. Xie K. J. Huang C. H. Zhu (2003) ArticleTitleThe production and characteristics of solid lipid nanoparticles (SLNs) Biomaterials 24 1781–1785 Occurrence Handle12593960 Occurrence Handle1:CAS:528:DC%2BD3sXht1Wnt7k%3D Occurrence Handle10.1016/S0142-9612(02)00578-1

    Article  PubMed  CAS  Google Scholar 

  39. J. Moselhy X. Y. Wu R. Nicholov K. Kodaria (2000) ArticleTitleIn vitro characterization of interaction of poly(NIPAm/MAA) nanoparticles with proteins and cells J. Biomater. Sci. Polym. Ed. 11 123–147 Occurrence Handle10718475 Occurrence Handle1:CAS:528:DC%2BD3cXhsF2htrc%3D Occurrence Handle10.1163/156856200743616

    Article  PubMed  CAS  Google Scholar 

  40. S. L. Abrahamse B. L. Pool-Zobel G. Rechkemmer (1999) ArticleTitlePotential of short chain fatty acids to modulate the induction of DNA damage and changes in the intracellular calcium concentration by oxidative stress in isolated rat distal colon cells Carcinogenesis 20 629–634 Occurrence Handle10223191 Occurrence Handle1:CAS:528:DyaK1MXis1Crtb8%3D Occurrence Handle10.1093/carcin/20.4.629

    Article  PubMed  CAS  Google Scholar 

  41. A. V. Kabanov E. V. Batrakova V. Y. Alakhov (2002) ArticleTitlePluronic block copolymers for overcoming drug resistance in cancer Adv. Drug Deliv. Rev. 54 759–779 Occurrence Handle12204601 Occurrence Handle1:CAS:528:DC%2BD38XmsVeqt74%3D Occurrence Handle10.1016/S0169-409X(02)00047-9

    Article  PubMed  CAS  Google Scholar 

  42. E. V. Batrakova S. Lee S. Li A. Venn V. Alakhov A. Kabanov (1999) ArticleTitleFundamental relationships between the composition of pluronic block copolymers and their hypersensitization effect in MDR cancer cells Pharm. Res. 16 1373–1379 Occurrence Handle10496652 Occurrence Handle1:CAS:528:DyaK1MXmtVKktb4%3D Occurrence Handle10.1023/A:1018942823676

    Article  PubMed  CAS  Google Scholar 

  43. J. Kreuter P. Ramge V. Petrov S. Hamm S. E. Gelperina B. Engelhardt R. Alyautdin H. Briesen Particlevon D. J. Begley (2003) ArticleTitleDirect evidence that polysorbate-80-coated poly(butylcyanoacrylate) nanoparticles deliver drugs to the CNS via specific mechanisms requiring prior binding of drug to the nanoparticles Pharm. Res. 20 409–416 Occurrence Handle12669961 Occurrence Handle1:CAS:528:DC%2BD3sXhslGrtr8%3D Occurrence Handle10.1023/A:1022604120952

    Article  PubMed  CAS  Google Scholar 

  44. A. Tang P. Kopeckova J. Kopecek (2003) ArticleTitleBinding and cytotoxicity of HPMA copolymer conjugates to lymphocytes mediated by receptor-binding epitopes Pharm. Res. 20 360–367 Occurrence Handle12669954 Occurrence Handle1:CAS:528:DC%2BD3sXhslGrsbo%3D Occurrence Handle10.1023/A:1022639701388

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

The authors sincerely thank the Canadian Institutes of Health Research for sponsoring this project, Dr. R. Clarke for providing the cancer cell lines, and Mr. B. Calvieri from Microscopy Imaging Laboratory, University of Toronto, for the technical assistance in electron microscopy. The Canadian Graduate Scholarship from Natural Sciences and Engineering Research Council of Canada, Pharmacy Postgraduate Fellowship from the Merck Frosst Inc., and Ben Cohen Fund from the University of Toronto to H. L. Wong are also gratefully acknowledged.

Author information

Authors and Affiliations

  1. Leslie Dan Faculty of Pharmacy, University of Toronto, 19 Russell Street, Toronto, Ontario, Canada, M5S 2S2

    Ho Lun Wong, Reina Bendayan, Janet L. Manias, Manisha Ramaswamy & Xiao Yu Wu

  2. Ontario Cancer Institute, 610 University Avenue, Toronto, Ontario, Canada, M5G 2M9

    Andrew M. Rauth

  3. Food and Industrial Oil Research, USDA/ARS/NCAUR, 1815 N. University Street, Peoria, Illinois, 61604, USA

    Zengshe Liu & Sevim Z. Erhan

Authors
  1. Ho Lun Wong
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Andrew M. Rauth
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Reina Bendayan
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Janet L. Manias
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Manisha Ramaswamy
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Zengshe Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Sevim Z. Erhan
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Xiao Yu Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Xiao Yu Wu.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Wong, H.L., Rauth, A.M., Bendayan, R. et al. A New Polymer–Lipid Hybrid Nanoparticle System Increases Cytotoxicity of Doxorubicin Against Multidrug-Resistant Human Breast Cancer Cells. Pharm Res 23, 1574–1585 (2006). https://doi.org/10.1007/s11095-006-0282-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11095-006-0282-x

Key Words

Search

Navigation