Skip to main content

Advertisement

SpringerLink
Log in

Co-delivery of Adenovirus and Carmustine by Anionic Liposomes with Synergistic Anti-tumor Effects

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

ABSTRACT

Purpose

To improve gene transducibility mediated by adenovirus (Ad) in cancer cells and further enhance anti-tumor effects by co-delivery.

Methods

Calcium-induced phase change method was used to prepare the complex of anionic liposomes and adenovirus (AL/Ad5). Gene expression was qualitatively detected by X-gal staining and quantitatively detected by ELISA. Taking adenovirus-mediated stromal cell-derived factor-1α (Ad5-SDF1α) as therapeutic gene and carmustine (BCNU) as chemotherapeutic agent, a co-delivering system of AL/Ad5-SDF1α/BCNU was prepared and administered to tumor-bearing mice by intratumor injection.

Results

Enhanced LacZ gene transduction was obtained in B16 and Lewis lung carcinoma cells in vitro and in vivo. Complexes of AL/Ad5-SDF1α improved SDF1α gene expression and led to accumulation of dendritic cells among the murine B16 melanoma cells in vivo. This co-delivery system of AL/Ad5-SDF1α/BCNU could significantly suppress tumor growth and prolong survival of tumor-bearing mice.

Conclusions

Through the co-delivering system, AL/Ad5-SDF1α could synergize with BCNU to improve the antitumor effect. It may be a promising strategy for solid tumor therapy.

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

Similar content being viewed by others

Abbreviations

Ad5-SDF1α:

adenovirus-mediated stromal cell-derived factor-1α

Ad-SOD:

adenovirus-mediated superoxide dismutases

AL:

anionic liposomes

AL/Ad5:

complexes of anionic liposomes and adenovirus

AL/Ad5-SDF1α/BCNU:

complexes of adenovirus and carmustine (BCNU) co-delivered by aninoic liposomes

BCNU:

carmustine [1, 3-bis(2-chloroethyl)-1-nitrosourea]

CAR:

coxsackie-adenovirus receptor

DCs:

dendritic cells

ELISA:

enzyme-linked immunosorbent assay

LacZ:

β-galactosidase gene Z

LLC:

Lewis lung carcinoma

MOI:

multiplicity of infection

Pfu:

plaque-forming unit

Q-PCR:

quantitative-PCR

RGD:

arginine-glycine-aspartate

X-gal:

5-bromo-4-chloro-3-indolyl β-D-galactopyranoside

REFERENCES

  1. Hatefi A, Cappello J, Ghandehari H. Adenoviral gene delivery to solid tumors by recombinant silk-elastinlike protein polymers. Pharm Res. 2007;24:773–9.

    Article  PubMed  CAS  Google Scholar 

  2. Seidman MA, Hogan SM, Wendland RL, Worgall S, Crystal RG, Leopold PL. Variation in adenovirus receptor expression and adenovirus vector-mediated transgene expression at defined stages of the cell cycle. Mol Ther. 2001;4:13–21.

    Article  PubMed  CAS  Google Scholar 

  3. Okegawa T, Li Y, Pong RC, Bergelson JM, Zhou J, Hsieh JT. The dual impact of coxsackie and adenovirus receptor expression on human prostate cancer gene therapy. Cancer Res. 2000;60:5031–6.

    PubMed  CAS  Google Scholar 

  4. Kanerva A, Hemminki A. Modified adenoviruses for cancer gene therapy. Int J Cancer. 2004;110:475–80.

    Article  PubMed  CAS  Google Scholar 

  5. Mizuno M, Ryuke Y, Yoshida J. Cationic liposomes conjugation to recombinant adenoviral vectors containing herpes simplex virus thymidine kinase gene followed by ganciclovir treatment reduces viral antigenicity and maintains antitumor activity in mouse experimental glioma models. Cancer Gene Ther. 2002;9:825–9.

    Article  PubMed  CAS  Google Scholar 

  6. Kim J, Smith T, Idamakanti N, Mulgrew K, Kaloss M, Kylefjord H, et al. Targeting adenoviral vectors by using the extracellular domain of the coxsackie-adenovirus receptor: improved potency via trimerization. J Virol. 2002;76:1892–903.

    Article  PubMed  CAS  Google Scholar 

  7. O’Riordan CR, Lachapelle A, Delgado C, Parkes V, Wadsworth SC, Smith AE, et al. PEGylation of adenovirus with retention of infectivity and protection from neutralizing antibody in vitro and in vivo. Hum Gene Ther. 1999;10:1349–58.

    Article  PubMed  Google Scholar 

  8. Pearce OM, Fisher KD, Humphries J, Seymour LW, Smith A, Davis BG. Glycoviruses: chemical glycosylation retargets adenoviral gene transfer. Angew Chem Int Ed Engl. 2005;44:1057–61.

    Article  PubMed  CAS  Google Scholar 

  9. Ma Z, Mi Z, Wilson A, Alber S, Robbins PD, Watkins S, et al. Redirecting adenovirus to pulmonary endothelium by cationic liposomes. Gene Ther. 2002;9:176–82.

    Article  PubMed  CAS  Google Scholar 

  10. Tavitian B, Marzabal S, Boutet V, Kuhnast B, Terrazzino S, Moynier M, et al. Characterization of a synthetic anionic vector for oligonucleotide delivery using in vivo whole body dynamic imaging. Pharm Res. 2002;19:367–76.

    Article  PubMed  CAS  Google Scholar 

  11. Srinivasan C, Burgess DJ. Optimization and characterization of anionic lipoplexes for gene delivery. J Control Release. 2009;136:62–70.

    Article  PubMed  CAS  Google Scholar 

  12. Patil SD, Rhodes DG, Burgess DJ. DNA-based therapeutics and DNA delivery systems: a comprehensive review. AAPS J. 2005;7:E61–77.

    Article  PubMed  CAS  Google Scholar 

  13. Patil SD, Rhodes DG, Burgess DJ. Anionic liposomal delivery system for DNA transfection. AAPS J. 2004;6:e29.

    Article  PubMed  Google Scholar 

  14. Liang H, Harries D, Wong GC. Polymorphism of DNA-anionic liposome complexes reveals hierarchy of ion-mediated interactions. Proc Natl Acad Sci USA. 2005;102:11173–8.

    Article  PubMed  CAS  Google Scholar 

  15. Patil SD, Rhodes DG, Burgess DJ. Biophysical characterization of anionic lipoplexes. Biochim Biophys Acta. 2005;1711:1–11.

    Article  PubMed  CAS  Google Scholar 

  16. Zhong ZR, Shi SJ, Han JF, Zhang ZR, Sun X. Anionic liposomes increase the efficiency of adenovirus-mediated gene transfer to coxsackie-adenovirus receptor deficient cells. Mol Pharm. 2010;1:105–15.

    Article  Google Scholar 

  17. Han J, Zhao D, Zhong Z, Zhang Z, Gong T, Sun X. Combination of adenovirus and cross-linked low molecular weight PEI improves efficiency of gene transduction. Nanotechnology. 2010;21:105106.

    Article  PubMed  Google Scholar 

  18. Yamashita M, Ino A, Kawabata K, Sakurai F, Mizuguchi H. Expression of coxsackie and adenovirus receptor reduces the lung metastatic potential of murine tumor cells. Int J Cancer. 2007;121:1690–6.

    Article  PubMed  CAS  Google Scholar 

  19. Parney IF, Chang LJ. Cancer immunogene therapy: a review. J Biomed Sci. 2003;10:37–43.

    Article  PubMed  CAS  Google Scholar 

  20. Lee HK, Iwasaki A. Innate control of adaptive immunity: dendritic cells and beyond. Semin Immunol. 2007;19:48–55.

    Article  PubMed  CAS  Google Scholar 

  21. Banchereau J, Steinman RM. Dendritic cells and the control of immunity. Nature. 1998;392:245–52.

    Article  PubMed  CAS  Google Scholar 

  22. Hattermann K, Held-Feindt J, Lucius R, Muerkoster SS, Penfold ME, Schall TJ, et al. The chemokine receptor CXCR7 is highly expressed in human glioma cells and mediates antiapoptotic effects. Cancer Res. 2010;70:3299–308.

    Article  PubMed  CAS  Google Scholar 

  23. Fushimi T, O’Connor TP, Crystal RG. Adenoviral gene transfer of stromal cell-derived factor-1 to murine tumors induces the accumulation of dendritic cells and suppresses tumor growth. Cancer Res. 2006;66:3513–22.

    Article  PubMed  CAS  Google Scholar 

  24. Machiels JP, Reilly RT, Emens LA, Ercolini AM, Lei RY, Weintraub D, et al. Cyclophosphamide, doxorubicin, and paclitaxel enhance the antitumor immune response of granulocyte/macrophage-colony stimulating factor-secreting whole-cell vaccines in HER-2/neu tolerized mice. Cancer Res. 2001;61:3689–97.

    PubMed  CAS  Google Scholar 

  25. Jones AL, Millar JL, Millar BC, Powell B, Selby P, Winkley A, et al. Enhanced anti-tumour activity of carmustine (BCNU) with tumour necrosis factor in vitro and in vivo. Br J Cancer. 1990;62:776–80.

    Article  PubMed  CAS  Google Scholar 

  26. Marsh JC. The effects of cancer chemotherapeutic agents on normal hematopoietic precursor cells: a review. Cancer Res. 1976;36:1853–82.

    PubMed  CAS  Google Scholar 

  27. Weisel KC, Bautz F, Seitz G, Yildirim S, Kanz L, Mohle R. Modulation of CXC chemokine receptor expression and function in human neutrophils during aging in vitro suggests a role in their clearance from circulation. Mediat Inflamm. 2009;2009:790174.

    Article  Google Scholar 

  28. Mohle R, Failenschmid C, Bautz F, Kanz L. Overexpression of the chemokine receptor CXCR4 in B cell chronic lymphocytic leukemia is associated with increased functional response to stromal cell-derived factor-1 (SDF-1). Leukemia. 1999;13:1954–9.

    Article  PubMed  CAS  Google Scholar 

  29. Kalinkovich A, Tavor S, Avigdor A, Kahn J, Brill A, Petit I, et al. Functional CXCR4-expressing microparticles and SDF-1 correlate with circulating acute myelogenous leukemia cells. Cancer Res. 2006;66:11013–20.

    Article  PubMed  CAS  Google Scholar 

  30. Leopold PL, Crystal RG. Intracellular trafficking of adenovirus: many means to many ends. Adv Drug Deliv Rev. 2007;59:810–21.

    Article  PubMed  CAS  Google Scholar 

  31. Arcasoy SM, Latoche J, Gondor M, Watkins SC, Henderson RA, Hughey R, et al. MUC1 and other sialoglycoconjugates inhibit adenovirus-mediated gene transfer to epithelial cells. Am J Respir Cell Mol Biol. 1997;17:422–35.

    PubMed  CAS  Google Scholar 

  32. Zhong Z, Song Y, Engbersen JF, Lok MC, Hennink WE, Feijen J. A versatile family of degradable non-viral gene carriers based on hyperbranched poly(ester amine)s. J Control Release. 2005;109:317–29.

    Article  PubMed  CAS  Google Scholar 

  33. Kamiya H, Tsuchiya H, Yamazaki J, Harashima H. Intracellular trafficking and transgene expression of viral and non-viral gene vectors. Adv Drug Deliv Rev. 2001;52:153–64.

    Article  PubMed  CAS  Google Scholar 

  34. Natsume A, Mizuno M, Ryuke Y, Yoshida J. Cationic liposome conjugation to recombinant adenoviral vector reduces viral antigenicity. Jpn J Cancer Res. 2000;91:363–7.

    Article  PubMed  CAS  Google Scholar 

  35. Steel JC, Cavanagh HM, Burton MA, Abu-Asab MS, Tsokos M, Morris JC, et al. Increased tumor localization and reduced immune response to adenoviral vector formulated with the liposome DDAB/DOPE. Eur J Pharm Sci. 2007;30:398–405.

    Article  PubMed  CAS  Google Scholar 

  36. Paczesny S, Ueno H, Fay J, Banchereau J, Palucka AK. Dendritic cells as vectors for immunotherapy of cancer. Semin Cancer Biol. 2003;13:439–47.

    Article  PubMed  CAS  Google Scholar 

  37. Sun X, Zhang HW, Zhang ZR. Growth inhibition of the pulmonary metastatic tumors by systemic delivery of the p27 kip1 gene using lyophilized lipid-polycation-DNA complexes. J Gene Med. 2009;11:535–44.

    Article  PubMed  CAS  Google Scholar 

  38. Teicher BA, Holden SA, Ara G, Korbut T, Menon K. Comparison of several antiangiogenic regimens alone and with cytotoxic therapies in the Lewis lung carcinoma. Cancer Chemother Pharmacol. 1996;38:169–77.

    Article  PubMed  CAS  Google Scholar 

  39. Weydert CJ, Zhang Y, Sun W, Waugh TA, Teoh ML, Andringa KK, et al. Increased oxidative stress created by adenoviral MnSOD or CuZnSOD plus BCNU (1,3-bis(2-chloroethyl)-1-nitrosourea) inhibits breast cancer cell growth. Free Radic Biol Med. 2008;44:856–67.

    Article  PubMed  CAS  Google Scholar 

Download references

ACKNOWLEDGMENTS & DISCLOSURES

We are thankful for the financial support of the National Natural and Science Foundation of China (No. 30973657) and the National Science and Technology Major Project of China (No. 2009ZX09310-002).

Author information

Author notes

  1. Zhirong Zhong

    Present address: Luzhou Medical College, Luzhou, Sichuan, China, 646000

Authors and Affiliations

  1. Drug Targeting and Novel Drug Delivery Systems Ministry of Education, West China School of Pharmacy, Sichuan University, Chengdu, Sichuan, China, 610041

    Yu Wan, Sanjun Shi, Jianfeng Han & Zhirong Zhang

  2. West China School of Pharmacy, Sichuan University, No.17, Block 3, Southern Renmin Road, Chengdu, China, 610041

    Xun Sun

Authors
  1. Zhirong Zhong
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yu Wan
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Sanjun Shi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jianfeng Han
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Zhirong Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Xun Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Xun Sun.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Zhong, Z., Wan, Y., Shi, S. et al. Co-delivery of Adenovirus and Carmustine by Anionic Liposomes with Synergistic Anti-tumor Effects. Pharm Res 29, 145–157 (2012). https://doi.org/10.1007/s11095-011-0521-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11095-011-0521-7

KEY WORDS

Search

Navigation