Skip to main content

Advertisement

Log in

Lipid-functionalized Dextran Nanosystems to Overcome Multidrug Resistance in Cancer: A Pilot Study

  • Symposium: Highlights from the First Combined 2011 Meeting of the Musculoskeletal Tumor Society and Connective Tissue Oncology Society
  • Published:
Clinical Orthopaedics and Related Research®

Abstract

Background

The toxicity of anticancer agents and the difficulty in delivering drugs selectively to tumor cells pose a challenge in overcoming multidrug resistance (MDR). Recently, nanotechnology has emerged as a powerful tool in addressing some of the barriers to drug delivery, including MDR in cancer, by utilizing alternate routes of cellular entry and targeted delivery of drugs and genes. However, it is unclear whether doxorubicin (Dox) can be delivered by nanotechnologic approaches.

Questions/Purposes

We asked whether (1) Dox-loaded lipid-functionalized dextran-based biocompatible nanoparticles (Dox/NP) can reverse MDR, (2) Dox/NP has more potent cytotoxic effect on MDR tumors than poly(ethylene glycol)-modified liposomal Dox (PLD), and (3) multidrug resistance protein 1 (MDR1) small interfering RNA loaded in these nanoparticles (siMDR1/NP) can modulate MDR.

Methods

To create stable Dox/NP and siMDR1/NP, we used two different lipid-modified dextran derivatives. The effect of Dox or Dox/NP was tested on drug-sensitive osteosarcoma (KHOS) and ovarian cancer (SKOV-3) cell cultures in triplicate and their respective MDR counterparts KHOSR2 and SKOV-3TR in triplicate. We determined the effects on drug retention, transfection efficacy of siMDR1/NP, and P-glycoprotein expression and the antiproliferative effect between Dox/NP and PLD in MDR tumor cells.

Results

Fluorescence microscopy revealed efficient uptake of the Dox/NP and fluorescently tagged siMDR1/NP. Dox/NP showed five- to 10-fold higher antiproliferative activity at the 50% inhibitory concentration than free Dox in tumor cells. Dox/NP showed twofold higher activity than PLD in MDR tumor cells. siMDR1/NP (100 nM) suppressed P-glycoprotein expression in KHOSR2.

Conclusions

Dextran-lipid nanoparticles are a promising platform for delivering Dox and siRNAs.

Clinical Relevance

Biocompatible dextran-based nanoparticles that are directly translatable to clinical medicine may lead to new potential therapeutics for reversing MDR in patients with cancer.

This is a preview of subscription content, log in via an institution to check access.

Access this article

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. 3A–E
Fig. 4A–B
Fig. 5
Fig. 6A–B

Similar content being viewed by others

References

  1. Abeylath SC, Amiji MM. “Click” synthesis of dextran macrostructures for combinatorial-designed self-assembled nanoparticles encapsulating diverse anticancer therapeutics. Bioorg Med Chem. 2011;19:6167–6173.

    Article  PubMed  CAS  Google Scholar 

  2. Agarwal R, Kaye SB. Ovarian cancer: strategies for overcoming resistance to chemotherapy. Nat Rev Cancer. 2003;3:502–516.

    Article  PubMed  CAS  Google Scholar 

  3. Baldini N, Scotlandi K, Barbanti-Brodano G, Manara MC, Maurici D, Bacci G, Bertoni F, Picci P, Sottili S, Campanacci M, et al. Expression of P-glycoprotein in high-grade osteosarcomas in relation to clinical outcome. N Engl J Med. 1995;333:1380–1385.

    Article  PubMed  CAS  Google Scholar 

  4. Belpomme D, Gauthier S, Pujade-Lauraine E, Facchini T, Goudier MJ, Krakowski I, Netter-Pinon G, Frenay M, Gousset C, Marie FN, Benmiloud M, Sturtz F. Verapamil increases the survival of patients with anthracycline-resistant metastatic breast carcinoma. Ann Oncol. 2000;11:1471–1476.

    Article  PubMed  CAS  Google Scholar 

  5. Bhavsar MD, Amiji MM. Gastrointestinal distribution and in vivo gene transfection studies with nanoparticles-in-microsphere oral system (NiMOS). J Control Release. 2007;119:339–348.

    Article  PubMed  CAS  Google Scholar 

  6. Bielack SS, Kempf-Bielack B, Delling G, Exner GU, Flege S, Helmke K, Kotz R, Salzer-Kuntschik M, Werner M, Winkelmann W, Zoubek A, Jurgens H, Winkler K. Prognostic factors in high-grade osteosarcoma of the extremities or trunk: an analysis of 1,702 patients treated on neoadjuvant cooperative osteosarcoma study group protocols. J Clin Oncol. 2002;20:776–790.

    Article  PubMed  Google Scholar 

  7. Chaudhary PM, Roninson IB. Expression and activity of P-glycoprotein, a multidrug efflux pump, in human hematopoietic stem cells. Cell. 1991;66:85–94.

    Article  PubMed  CAS  Google Scholar 

  8. Chen AM, Zhang M, Wei D, Stueber D, Taratula O, Minko T, He H. Co-delivery of doxorubicin and Bcl-2 siRNA by mesoporous silica nanoparticles enhances the efficacy of chemotherapy in multidrug-resistant cancer cells. Small. 2009;5:2673–2677.

    Article  PubMed  CAS  Google Scholar 

  9. Devalapally H, Duan Z, Seiden MV, Amiji MM. Modulation of drug resistance in ovarian adenocarcinoma by enhancing intracellular ceramide using tamoxifen-loaded biodegradable polymeric nanoparticles. Clin Cancer Res. 2008;14:3193–3203.

    Article  PubMed  CAS  Google Scholar 

  10. Dillen K, Vandervoort J, Van den Mooter G, Ludwig A. Evaluation of ciprofloxacin-loaded Eudragit RS100 or RL100/PLGA nanoparticles. Int J Pharm. 2006;314:72–82.

    Article  PubMed  CAS  Google Scholar 

  11. Duan Z, Brakora KA, Seiden MV. Inhibition of ABCB1 (MDR1) and ABCB4 (MDR3) expression by small interfering RNA and reversal of paclitaxel resistance in human ovarian cancer cells. Mol Cancer Ther. 2004;3:833–838.

    PubMed  CAS  Google Scholar 

  12. Ferrandina G, Corrado G, Licameli A, Lorusso D, Fuoco G, Pisconti S, Scambia G. Pegylated liposomal doxorubicin in the management of ovarian cancer. Ther Clin Risk Manag. 2010;6:463–483.

    PubMed  CAS  Google Scholar 

  13. Fletcher JI, Haber M, Henderson MJ, Norris MD. ABC transporters in cancer: more than just drug efflux pumps. Nat Rev Cancer. 2010;10:147–156.

    Article  PubMed  CAS  Google Scholar 

  14. Geller DS, Gorlick R. Osteosarcoma: a review of diagnosis, management, and treatment strategies. Clin Adv Hematol Oncol. 2010;8:705–718.

    PubMed  Google Scholar 

  15. Gillet JP, Gottesman MM. Mechanisms of multidrug resistance in cancer. Methods Mol Biol. 2010;596:47–76.

    Article  PubMed  CAS  Google Scholar 

  16. Han HK. Role of transporters in drug interactions. Arch Pharm Res. 2011;34:1865–1877.

    Article  PubMed  CAS  Google Scholar 

  17. Hindenburg AA, Baker MA, Gleyzer E, Stewart VJ, Case N, Taub RN. Effect of verapamil and other agents on the distribution of anthracyclines and on reversal of drug resistance. Cancer Res. 1987;47:1421–1425.

    PubMed  CAS  Google Scholar 

  18. Hornicek FJ, Gebhardt MC, Wolfe MW, Kharrazi FD, Takeshita H, Parekh SG, Zurakowski D, Mankin HJ. P-glycoprotein levels predict poor outcome in patients with osteosarcoma. Clin Orthop Relat Res. 2000;373:11–17.

    Article  PubMed  Google Scholar 

  19. Iyer AK, Khaled G, Fang J, Maeda H. Exploiting the enhanced permeability and retention effect for tumor targeting. Drug Discov Today. 2006;11:812–818.

    Article  PubMed  CAS  Google Scholar 

  20. Kandel RA, Campbell S, Noble-Topham S, Bell R, Andrulis IL. Correlation of p-glycoprotein detection by immunohistochemistry with mdr-1 mRNA levels in osteosarcomas: pilot study. Diagn Mol Pathol. 1995;4:59–65.

    Article  PubMed  CAS  Google Scholar 

  21. Kaye SB. Reversal of drug resistance in ovarian cancer: where do we go from here? J Clin Oncol. 2008;26:2616–2618.

    Article  PubMed  Google Scholar 

  22. Keizer HG, Schuurhuis GJ, Broxterman HJ, Lankelma J, Schoonen WG, van Rijn J, Pinedo HM, Joenje H. Correlation of multidrug resistance with decreased drug accumulation, altered subcellular drug distribution, and increased P-glycoprotein expression in cultured SW-1573 human lung tumor cells. Cancer Res. 1989;49:2988–2993.

    PubMed  CAS  Google Scholar 

  23. Klimecki WT, Futscher BW, Grogan TM, Dalton WS. P-glycoprotein expression and function in circulating blood cells from normal volunteers. Blood. 1994;83:2451–2458.

    PubMed  CAS  Google Scholar 

  24. Kolitz JE, George SL, Dodge RK, Hurd DD, Powell BL, Allen SL, Velez-Garcia E, Moore JO, Shea TC, Hoke E, Caligiuri MA, Vardiman JW, Bloomfield CD, Larson RA. Dose escalation studies of cytarabine, daunorubicin, and etoposide with and without multidrug resistance modulation with PSC-833 in untreated adults with acute myeloid leukemia younger than 60 years: final induction results of Cancer and Leukemia Group B Study 9621. J Clin Oncol. 2004;22:4290–4301.

    Article  PubMed  CAS  Google Scholar 

  25. Lamendola DE, Duan Z, Yusuf RZ, Seiden MV. Molecular description of evolving paclitaxel resistance in the SKOV-3 human ovarian carcinoma cell line. Cancer Res. 2003;63:2200–2205.

    PubMed  CAS  Google Scholar 

  26. Licht T, Pastan I, Gottesman M, Herrmann F. P-glycoprotein-mediated multidrug resistance in normal and neoplastic hematopoietic cells. Ann Hematol. 1994;69:159–171.

    Article  PubMed  CAS  Google Scholar 

  27. MacDiarmid JA, Amaro-Mugridge NB, Madrid-Weiss J, Sedliarou I, Wetzel S, Kochar K, Brahmbhatt VN, Phillips L, Pattison ST, Petti C, Stillman B, Graham RM, Brahmbhatt H. Sequential treatment of drug-resistant tumors with targeted minicells containing siRNA or a cytotoxic drug. Nat Biotechnol. 2009;27:643–651.

    Article  PubMed  CAS  Google Scholar 

  28. Maeda H. The enhanced permeability and retention (EPR) effect in tumor vasculature: the key role of tumor-selective macromolecular drug targeting. Adv Enzyme Regul. 2001;41:189–207.

    Article  PubMed  CAS  Google Scholar 

  29. Meng H, Liong M, Xia T, Li Z, Ji Z, Zink JI, Nel AE. Engineered design of mesoporous silica nanoparticles to deliver doxorubicin and P-glycoprotein siRNA to overcome drug resistance in a cancer cell line. ACS Nano. 2010;4:4539–4550.

    Article  PubMed  CAS  Google Scholar 

  30. Milane L, Duan Z, Amiji M. Development of EGFR-targeted polymer blend nanocarriers for combination paclitaxel/lonidamine delivery to treat multi-drug resistance in human breast and ovarian tumor cells. Mol Pharm. 2010;8:185–203.

    Article  PubMed  Google Scholar 

  31. Minko T, Kopeckova P, Pozharov V, Kopecek J. HPMA copolymer bound adriamycin overcomes MDR1 gene encoded resistance in a human ovarian carcinoma cell line. J Control Release. 1998;54:223–233.

    Article  PubMed  CAS  Google Scholar 

  32. Nieth C, Priebsch A, Stege A, Lage H. Modulation of the classical multidrug resistance (MDR) phenotype by RNA interference (RNAi). FEBS Lett. 2003;545:144–150.

    Article  PubMed  CAS  Google Scholar 

  33. Northfelt DW, Martin FJ, Working P, Volberding PA, Russell J, Newman M, Amantea MA, Kaplan LD. Doxorubicin encapsulated in liposomes containing surface-bound polyethylene glycol: pharmacokinetics, tumor localization, and safety in patients with AIDS-related Kaposi’s sarcoma. J Clin Pharmacol. 1996;36:55–63.

    PubMed  CAS  Google Scholar 

  34. O’Malley DM, Richardson DL, Rheaume PS, Salani R, Eisenhauer EL, McCann GA, Fowler JM, Copeland LJ, Cohn DE, Backes FJ. Addition of bevacizumab to weekly paclitaxel significantly improves progression-free survival in heavily pretreated recurrent epithelial ovarian cancer. Gynecol Oncol. 2011;121:269–272.

    Article  PubMed  Google Scholar 

  35. Pecot CV, Calin GA, Coleman RL, Lopez-Berestein G, Sood AK. RNA interference in the clinic: challenges and future directions. Nat Rev Cancer. 2011;11:59–67.

    Article  PubMed  CAS  Google Scholar 

  36. Poveda A, Lopez-Pousa A, Martin J, Del Muro JG, Bernabe R, Casado A, Balana C, Sanmartin O, Menendez MD, Escudero P, Cruz J, Belyakova E, Menendez D, Buesa JM. Phase II clinical trial with pegylated liposomal doxorubicin (Caelyx®/Doxil®) and quality of life evaluation (EORTC QLQ-C30) in adult patients with advanced soft tissue sarcomas: a study of the Spanish Group for Research in Sarcomas (GEIS). Sarcoma. 2005;9:127–132.

    Article  PubMed  CAS  Google Scholar 

  37. Riganti C, Voena C, Kopecka J, Corsetto PA, Montorfano G, Enrico E, Costamagna C, Rizzo AM, Ghigo D, Bosia A. Liposome-encapsulated doxorubicin reverses drug resistance by inhibiting P-glycoprotein in human cancer cells. Mol Pharm. 2011;8:683–700.

    Article  PubMed  CAS  Google Scholar 

  38. Saad M, Garbuzenko OB, Minko T. Co-delivery of siRNA and an anticancer drug for treatment of multidrug-resistant cancer. Nanomedicine (Lond). 2008;3:761–776.

    Article  CAS  Google Scholar 

  39. Schuurhuis GJ, Broxterman HJ, Cervantes A, van Heijningen TH, de Lange JH, Baak JP, Pinedo HM, Lankelma J. Quantitative determination of factors contributing to doxorubicin resistance in multidrug-resistant cells. J Natl Cancer Inst. 1989;81:1887–1892.

    Article  PubMed  CAS  Google Scholar 

  40. Schwartz CL, Gorlick R, Teot L, Krailo M, Chen Z, Goorin A, Grier HE, Bernstein ML, Meyers P. Multiple drug resistance in osteogenic sarcoma: INT0133 from the Children’s Oncology Group. J Clin Oncol. 2007;25:2057–2062.

    Article  PubMed  Google Scholar 

  41. Shapira A, Livney YD, Broxterman HJ, Assaraf YG. Nanomedicine for targeted cancer therapy: towards the overcoming of drug resistance. Drug Resist Updat. 2011;14:150–163.

    Article  PubMed  CAS  Google Scholar 

  42. Shnyder SD, Hayes AJ, Pringle J, Archer CW. P-glycoprotein and metallothionein expression and resistance to chemotherapy in osteosarcoma. Br J Cancer. 1998;78:757–759.

    Article  PubMed  CAS  Google Scholar 

  43. Sikic BI. Pharmacologic approaches to reversing multidrug resistance. Semin Hematol. 1997;34:40–47.

    PubMed  CAS  Google Scholar 

  44. Smeets M, Raymakers R, Vierwinden G, Pennings A, van de Locht L, Wessels H, Boezeman J, de Witte T. A low but functionally significant MDR1 expression protects primitive haemopoietic progenitor cells from anthracycline toxicity. Br J Haematol. 1997;96:346–355.

    Article  PubMed  CAS  Google Scholar 

  45. Sonneveld P, Suciu S, Weijermans P, Beksac M, Neuwirtova R, Solbu G, Lokhorst H, van der Lelie J, Dohner H, Gerhartz H, Segeren CM, Willemze R, Lowenberg B. Cyclosporin A combined with vincristine, doxorubicin and dexamethasone (VAD) compared with VAD alone in patients with advanced refractory multiple myeloma: an EORTC-HOVON randomized phase III study (06914). Br J Haematol. 2001;115:895–902.

    Article  PubMed  CAS  Google Scholar 

  46. Sugawara I, Kataoka I, Morishita Y, Hamada H, Tsuruo T, Itoyama S, Mori S. Tissue distribution of P-glycoprotein encoded by a multidrug-resistant gene as revealed by a monoclonal antibody, MRK 16. Cancer Res. 1988;48:1926–1929.

    PubMed  CAS  Google Scholar 

  47. Sun HW, Wu C, Tan HY, Wang QS. Combination DLL4 with Jagged1-siRNA can enhance inhibition of the proliferation and invasiveness activity of human gastric carcinoma by Notch1/VEGF pathway. Hepatogastroenterology. 2012;59:924–929.

    PubMed  CAS  Google Scholar 

  48. Susa M, Iyer AK, Ryu K, Choy E, Hornicek FJ, Mankin H, Milane L, Amiji MM, Duan Z. Inhibition of ABCB1 (MDR1) expression by an siRNA nanoparticulate delivery system to overcome drug resistance in osteosarcoma. PLoS One. 2010;5:e10764.

    Article  PubMed  Google Scholar 

  49. Susa M, Iyer AK, Ryu K, Hornicek FJ, Mankin H, Amiji MM, Duan Z. Doxorubicin loaded polymeric nanoparticulate delivery system to overcome drug resistance in osteosarcoma. BMC Cancer. 2009;9:399.

    Article  PubMed  Google Scholar 

  50. Talekar M, Kendall J, Denny W, Garg S. Targeting of nanoparticles in cancer: drug delivery and diagnostics. Anticancer Drugs. 2011;22:949–962.

    Article  PubMed  CAS  Google Scholar 

  51. Torchilin VP. Recent advances with liposomes as pharmaceutical carriers. Nat Rev Drug Discov. 2005;4:145–160.

    Article  PubMed  CAS  Google Scholar 

  52. Uhrich KE, Cannizzaro SM, Langer RS, Shakesheff KM. Polymeric systems for controlled drug release. Chem Rev. 1999;99:3181–3198.

    Article  PubMed  CAS  Google Scholar 

  53. van der Valk P, van Kalken CK, Ketelaars H, Broxterman HJ, Scheffer G, Kuiper CM, Tsuruo T, Lankelma J, Meijer CJ, Pinedo HM, et al. Distribution of multi-drug resistance-associated P-glycoprotein in normal and neoplastic human tissues: analysis with 3 monoclonal antibodies recognizing different epitopes of the P-glycoprotein molecule. Ann Oncol. 1990;1:56–64.

    PubMed  Google Scholar 

  54. van Vlerken LE, Duan Z, Seiden MV, Amiji MM. Modulation of intracellular ceramide using polymeric nanoparticles to overcome multidrug resistance in cancer. Cancer Res. 2007;67:4843–4850.

    Article  PubMed  Google Scholar 

  55. van Vlerken LE, Vyas TK, Amiji MM. Poly(ethylene glycol)-modified nanocarriers for tumor-targeted and intracellular delivery. Pharm Res. 2007;24:1405–1414.

    Article  PubMed  Google Scholar 

  56. Whelan JS, Jinks RC, McTiernan A, Sydes MR, Hook JM, Trani L, Uscinska B, Bramwell V, Lewis IJ, Nooij MA, van Glabbeke M, Grimer RJ, Hogendoorn PC, Taminiau AH, Gelderblom H. Survival from high-grade localised extremity osteosarcoma: combined results and prognostic factors from three European Osteosarcoma Intergroup randomised controlled trials. Ann Oncol. 2012;23:1607–1616.

    Article  PubMed  CAS  Google Scholar 

  57. Willingham MC, Cornwell MM, Cardarelli CO, Gottesman MM, Pastan I. Single cell analysis of daunomycin uptake and efflux in multidrug-resistant and -sensitive KB cells: effects of verapamil and other drugs. Cancer Res. 1986;46:5941–5946.

    PubMed  CAS  Google Scholar 

  58. Wunder JS, Bull SB, Aneliunas V, Lee PD, Davis AM, Beauchamp CP, Conrad EU, Grimer RJ, Healey JH, Rock MJ, Bell RS, Andrulis IL. MDR1 gene expression and outcome in osteosarcoma: a prospective, multicenter study. J Clin Oncol. 2000;18:2685–2694.

    PubMed  CAS  Google Scholar 

  59. Zheng L, Ren JQ, Li H, Kong ZL, Zhu HG. Downregulation of wild-type p53 protein by HER-2/neu mediated PI3 K pathway activation in human breast cancer cells: its effect on cell proliferation and implication for therapy. Cell Res. 2004;14:497–506.

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

The authors thank Dr. Michiro Susa and Dr. Henry Mankin for helpful discussions, Dr. Lingling Zhang and Dr. Sampath C. Abeylath for technical assistance, and Dr. Efstathios S. Gonos (National Hellenic Research Foundation, Athens, Greece) for providing the human OS cells line KHOS and the MDR (P-gp)-expressing cell line KHOSR2.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Zhenfeng Duan MD, PhD.

Additional information

The institution of one or more of the authors certifies that they have received during the study period funding from grants from the National Cancer Institute/NIH (UO1-CA 151452) (MMA, ZD), Gattegno and Wechsler Funds (FJH, ZD), Kenneth Stanton Fund for Sarcoma (Nashua, NH, USA) (FJH, ZD), Sarcoma Foundation of America (Damascus, MD, USA) (ZD), and The Chordoma Foundation (Durham, NC, USA) (ZD). Each author certifies that he or she, or a member of his or her immediate family, has no commercial associations (eg, consultancies, stock ownership, equity interest, patent/licensing arrangements, etc) that might pose a conflict of interest in connection with the submitted article.

All ICMJE Conflict of Interest Forms for authors and Clinical Orthopaedics and Related Research editors and board members are on file with the publication and can be viewed on request.

This work was performed at Massachusetts General Hospital (Boston, MA, USA) and Northeastern University (Boston, MA, USA).

About this article

Cite this article

Kobayashi, E., Iyer, A.K., Hornicek, F.J. et al. Lipid-functionalized Dextran Nanosystems to Overcome Multidrug Resistance in Cancer: A Pilot Study. Clin Orthop Relat Res 471, 915–925 (2013). https://doi.org/10.1007/s11999-012-2610-2

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11999-012-2610-2

Keywords

Navigation