Skip to main content

Advertisement

SpringerLink
Log in

The effect of AZD2171- or sTRAIL/Apo2L-loaded polylactic-co-glycolic acid microspheres on a subcutaneous glioblastoma model

  • Published:
Biomedical Microdevices Aims and scope Submit manuscript

Abstract

Studies with AZD2171—a new anti-angiogenic inhibitor of tyrosine kinases associated with VEGF signaling—have shown great promise for treating glioblastoma. Unfortunately, AZD2171 success is limited by low permeability through the blood–brain barrier. Due to AZD2171’s short half-life and high toxicity, its local administration will require multiple intracranial procedures, making this approach clinically unfeasible. In this study, we investigated the potential of the highly hydrophobic AZD2171, released from modified polylactic-co-glycolic acid microspheres (PLGA-MS), to treat glioblastoma. To further demonstrate the versatile loading capacity of this system, the same PLGA formulation, which was found optimal for the loading and release of AZD2171, was tested with sTRAIL/Apo2L—a biologic drug that is very different than AZD2171 in its molecular weight, solubility, and charge. AZD2171 released from PLGA-MS was at least effective as the free drug in inhibiting endothelial growth and proliferation (in vitro), and, surprisingly, had a profound cytotoxic effect also towards in vitro cultured glioblastoma cell-lines (U87 and A172). Complete tumor inhibition was achieved following a single treatment with AZD2171-loaded PLGA-MS (6 mg/kg) administered locally adjacent to human U87 glioma tumors inoculated subcutaneously in nude mice. This improved effect, compared to other therapeutic approaches involving AZD2171, was shown to affect both tumor vasculature and the glioma cells. sTRAIL-loaded microspheres, administered at very low doses (0.3 mg/kg), led to 35 % inhibition of tumor growth in 2 weeks. Collectively, our results provide pre-clinical evidence for the potential of PLGA formulations of AZD2171 and sTRAIL to serve as an effective treatment for glioblastoma.

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

Similar content being viewed by others

References

  • M.S. Ahluwalia, 2010 Society for Neuro-Oncology Annual Meeting: a report of selected studies. Expert. Rev. Anticancer. Ther. 11(2), 161–163 (2011)

    Article  Google Scholar 

  • A. Arshady, Preparation of biodegradable microspheres and microcapsules: polyactides and related polyester. J. Control. Release 17, 1–21 (1991)

    Article  Google Scholar 

  • B. Auffinger, B. Thaci, P. Nigam, E. Rincon, Y. Cheng, M.S. Lesniak, New therapeutic approaches for malignant glioma: in search of the Rosetta stone. F1000 Med. Rep. 4, 18 (2012)

    Article  Google Scholar 

  • T.T. Batchelor, A.G. Sorensen, E. di Tomaso, W.T. Zhang, D.G. Duda, K.S. Cohen, K.R. Kozak, D.P. Cahill, P.J. Chen, M. Zhu, M. Ancukiewicz, M.M. Mrugala, S. Plotkin, J. Drappatz, D.N. Louis, P. Ivy, D.T. Scadden, T. Benner, J.S. Loeffler, P.Y. Wen, R.K. Jain, AZD2171, a pan-VEGF receptor tyrosine kinase inhibitor, normalizes tumor vasculature and alleviates edema in glioblastoma patients. Cancer Cell 11(1), 83–95 (2007)

    Article  Google Scholar 

  • O. Benny, P. Pakneshan, Novel technologies for antiangiogenic drug delivery in the brain. Cell Adhes. Migr. 3(2), 224–229 (2009)

    Article  Google Scholar 

  • O. Benny, M. Duvshani-Eshet, T. Cargioli, L. Bello, A. Bikfalvi, R.S. Carroll, M. Machluf, Continuous delivery of endogenous inhibitors from poly(lactic-co-glycolic acid) polymeric microspheres inhibits glioma tumor growth. Clin. Cancer Res. 11(2 Pt 1), 768–776 (2005)

    Google Scholar 

  • O. Benny, S.K. Kim, K. Gvili, I.S. Radzishevsky, A. Mor, L. Verduzco, L.G. Menon, P.M. Black, M. Machluf, R.S. Carroll, In vivo fate and therapeutic efficacy of PF-4/CTF microspheres in an orthotopic human glioblastoma model. FASEB J. 22(2), 488–499 (2008)

    Article  Google Scholar 

  • O. Benny, L.G. Menon, G. Ariel, E. Goren, S.K. Kim, C. Stewman, P.M. Black, R.S. Carroll, M. Machluf, Local delivery of poly lactic-co-glycolic acid microspheres containing imatinib mesylate inhibits intracranial xenograft glioma growth. Clin. Cancer Res. 15(4), 1222–1231 (2009)

    Article  Google Scholar 

  • C. Berkland, M. King, A. Cox, K. Kim, D.W. Pack, Precise control of PLG microsphere size provides enhanced control of drug release rate. J. Control. Release 82(1), 137–147 (2002)

    Article  Google Scholar 

  • C. Berkland, K. Kim, D.W. Pack, PLG microsphere size controls drug release rate through several competing factors. Pharm. Res. 20(7), 1055–1062 (2003)

    Article  Google Scholar 

  • F. Cui, D. Cun, A. Tao, M. Yang, K. Shi, M. Zhao, Y. Guan, Preparation and characterization of melittin-loaded poly (DL-lactic acid) or poly (DL-lactic-co-glycolic acid) microspheres made by the double emulsion method. J. Control. Release 107(2), 310–319 (2005)

    Article  Google Scholar 

  • J.F. de Groot, G. Fuller, A.J. Kumar, Y. Piao, K. Eterovic, Y. Ji, C.A. Conrad, Tumor invasion after treatment of glioblastoma with bevacizumab: radiographic and pathologic correlation in humans and mice. Neuro. Oncol. 12(3), 233–242 (2010)

    Article  Google Scholar 

  • J. Dietrich, R. Han, Y. Yang, M. Mayer-Proschel, M. Noble, CNS progenitor cells and oligodendrocytes are targets of chemotherapeutic agents in vitro and in vivo. J. Biol. 5(7), 22 (2006)

    Article  Google Scholar 

  • J. Dietrich, M. Monje, J. Wefel, C. Meyers, Clinical patterns and biological correlates of cognitive dysfunction associated with cancer therapy. Oncologist 13(12), 1285–1295 (2008)

    Article  Google Scholar 

  • J. Dietrich, D. Wang, T.T. Batchelor, Cediranib: profile of a novel anti-angiogenic agent in patients with glioblastoma. Expert Opin. Investig. Drugs 18(10), 1549–1557 (2009)

    Article  Google Scholar 

  • R. Dillman, in Biological Therapy of Glioblastoma. Principles of Cancer Biotherapy, ed. by R. Oldham, R. Dillman (Springer, Netherlands, 2009), pp. 723–732

    Chapter  Google Scholar 

  • U. Edlund, A. Albertsson, Degradable polymer microspheres for controlled drug delivery. Adv. Polym. Sci. 157, 67–112 (2002)

    Article  Google Scholar 

  • F.A. Eskens, J. Verweij, The clinical toxicity profile of vascular endothelial growth factor (VEGF) and vascular endothelial growth factor receptor (VEGFR) targeting angiogenesis inhibitors; a review. Eur. J. Cancer 42(18), 3127–3139 (2006)

    Article  Google Scholar 

  • R. Francescone, S. Scully, B. Bentley, W. Yan, S.L. Taylor, D. Oh, L. Moral, R. Shao, Glioblastoma-derived tumor cells induce vasculogenic mimicry through Flk-1 protein activation. J. Biol. Chem. 287(29), 24821–24831 (2012)

    Article  Google Scholar 

  • F. Gomez-Rivera, A.A. Santillan-Gomez, M.N. Younes, S. Kim, D. Fooshee, M. Zhao, S.A. Jasser, J.N. Myers, The tyrosine kinase inhibitor, AZD2171, inhibits vascular endothelial growth factor receptor signaling and growth of anaplastic thyroid cancer in an orthotopic nude mouse model. Clin. Cancer Res. 13(15 Pt 1), 4519–4527 (2007)

    Article  Google Scholar 

  • C. Hagemann, J. Anacker, S. Haas, D. Riesner, B. Schomig, R.I. Ernestus, G.H. Vince, Comparative expression pattern of Matrix-Metalloproteinases in human glioblastoma cell-lines and primary cultures. BMC Res. Notes 3, 293 (2010)

    Article  Google Scholar 

  • X. Hong, F. Jiang, S.N. Kalkanis, Z.G. Zhang, X. Zhang, X. Zheng, T. Mikkelsen, H. Jiang, M. Chopp, Decrease of endogenous vascular endothelial growth factor may not affect glioma cell proliferation and invasion. J. Exp. Ther. Oncol. 6(3), 219–229 (2007)

    Google Scholar 

  • V.L. Jacobs, P.A. Valdes, W.F. Hickey, J.A. De Leo, Current review of in vivo GBM rodent models: emphasis on the CNS-1 tumour model. ASN Neuro 3(3), e00063 (2011)

    Article  Google Scholar 

  • T.H. Kim, H.H. Jiang, C.W. Park, Y.S. Youn, S. Lee, X. Chen, K.C. Lee, PEGylated TNF-related apoptosis-inducing ligand (TRAIL)-loaded sustained release PLGA microspheres for enhanced stability and antitumor activity. J. Control. Release 150(1), 63–69 (2011)

    Article  Google Scholar 

  • R. Lakomy, P. Burkon, D. Burkonova, R. Jancalek, New therapeutic options in therapy of glioblastoma multiforme. Klin. Onkol. 23(6), 381–387 (2010)

    Google Scholar 

  • Y. Liu, F. Lang, X. Xie, S. Prabhu, J. Xu, D. Sampath, K. Aldape, G. Fuller, V.K. Puduvalli, Efficacy of adenovirally expressed soluble TRAIL in human glioma organotypic slice culture and glioma xenografts. Cell Death Dis. 2, e121 (2011)

    Article  Google Scholar 

  • M.R. Lobo, S.C. Green, M.C. Schabel, G.Y. Gillespie, R.L. Woltjer, M.M. Pike, Quinacrine synergistically enhances the antivascular and antitumor efficacy of cediranib in intracranial mouse glioma. Neuro. Oncol. 15(12), 1673–1683 (2013)

    Article  Google Scholar 

  • S. Loges, T. Schmidt, P. Carmeliet, Mechanisms of resistance to anti-angiogenic therapy and development of third-generation anti-angiogenic drug candidates. Genes Cancer 1(1), 12–25 (2010)

    Article  Google Scholar 

  • T.J. MacDonald, K.M. Brown, B. LaFleur, K. Peterson, C. Lawlor, Y. Chen, R.J. Packer, P. Cogen, D.A. Stephan, Expression profiling of medulloblastoma: PDGFRA and the RAS/MAPK pathway as therapeutic targets for metastatic disease. Nat. Genet. 29(2), 143–152 (2001a)

    Article  Google Scholar 

  • T.J. MacDonald, T. Taga, H. Shimada, P. Tabrizi, B.V. Zlokovic, D.A. Cheresh, W.E. Laug, Preferential susceptibility of brain tumors to the antiangiogenic effects of an alpha(v) integrin antagonist. Neurosurgery 48(1), 151–157 (2001b)

    Google Scholar 

  • J.M. Maris, J. Courtright, P.J. Houghton, C.L. Morton, R. Gorlick, E.A. Kolb, R. Lock, M. Tajbakhsh, C.P. Reynolds, S.T. Keir, J. Wu, M.A. Smith, Initial testing of the VEGFR inhibitor AZD2171 by the pediatric preclinical testing program. Pediatr. Blood Cancer 50(3), 581–587 (2008)

    Article  Google Scholar 

  • O. Martinho, R. Silva-Oliveira, V. Miranda-Goncalves, C. Clara, J.R. Almeida, A.L. Carvalho, J.T. Barata, R.M. Reis, In vitro and in vivo analysis of RTK inhibitor efficacy and identification of its novel targets in glioblastomas. Transl. Oncol. 6(2), 187–196 (2013)

    Article  Google Scholar 

  • L.G. Menon, K. Kelly, H.W. Yang, S.K. Kim, P.M. Black, R.S. Carroll, Human bone marrow-derived mesenchymal stromal cells expressing S-TRAIL as a cellular delivery vehicle for human glioma therapy. Stem Cells 27(9), 2320–2330 (2009)

    Article  Google Scholar 

  • J.C. Olivier, Drug transport to brain with targeted nanoparticles. NeuroRx 2(1), 108–119 (2005)

    Article  Google Scholar 

  • M. Onishi, T. Ichikawa, K. Kurozumi, I. Date, Angiogenesis and invasion in glioma. Brain Tumor Pathol. 28(1), 13–24 (2011)

    Article  Google Scholar 

  • M. O’Reilly, Angiostatin: an endogenous inhibitor of angiogenesis and of tumor growth. EXS 79, 273–294 (1997)

    Google Scholar 

  • T.P. Padera, A.H. Kuo, T. Hoshida, S. Liao, J. Lobo, K.R. Kozak, D. Fukumura, R.K. Jain, Differential response of primary tumor versus lymphatic metastasis to VEGFR-2 and VEGFR-3 kinase inhibitors cediranib and vandetanib. Mol. Cancer Ther. 7(8), 2272–2279 (2008)

    Article  Google Scholar 

  • P. Perugini, I. Genta, B. Conti, T. Modena, F. Pavanetto, Long-term release of clodronate from biodegradable microspheres. AAPS PharmSciTech 2(3), E10 (2001)

    Article  Google Scholar 

  • J.M. Ruiz, J.P. Busnel, J.P. Benoit, Influence of average molecular weights of poly(DL-lactic acid-co-glycolic acid) copolymers 50/50 on phase separation and in vitro drug release from microspheres. Pharm. Res. 7(9), 928–934 (1990)

    Article  Google Scholar 

  • A.J. Sawyer, J.M. Piepmeier, W.M. Saltzman, New methods for direct delivery of chemotherapy for treating brain tumors. Yale J. Biol. Med. 79(3-4), 141–152 (2006)

    Google Scholar 

  • P. Secchiero, A. Gonelli, E. Carnevale, F. Corallini, C. Rizzardi, S. Zacchigna, M. Melato, G. Zauli, Evidence for a proangiogenic activity of TNF-related apoptosis-inducing ligand. Neoplasia 6(4), 364–373 (2004)

    Article  Google Scholar 

  • K. Shah, C.H. Tung, X.O. Breakefield, R. Weissleder, In vivo imaging of S-TRAIL-mediated tumor regression and apoptosis. Mol. Ther. 11(6), 926–931 (2005)

    Article  Google Scholar 

  • D.W. Siemann, W.D. Brazelle, J.M. Jurgensmeier, The vascular endothelial growth factor receptor-2 tyrosine kinase inhibitor cediranib (Recentin; AZD2171) inhibits endothelial cell function and growth of human renal tumor xenografts. Int. J. Radiat. Oncol. Biol. Phys. 73(3), 897–903 (2009)

    Article  Google Scholar 

  • N.R. Smith, N.H. James, I. Oakley, A. Wainwright, C. Copley, J. Kendrew, L.M. Womersley, J.M. Jurgensmeier, S.R. Wedge, S.T. Barry, Acute pharmacodynamic and antivascular effects of the vascular endothelial growth factor signaling inhibitor AZD2171 in Calu-6 human lung tumor xenografts. Mol. Cancer Ther. 6(8), 2198–2208 (2007)

    Article  Google Scholar 

  • R. Stupp, J.C. Tonn, M. Brada, G. Pentheroudakis, E.G.W. Group, High-grade malignant glioma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann. Oncol. 21(Suppl 5), v190–v193 (2010)

    Article  Google Scholar 

  • E. Timotheadou, New agents targeting angiogenesis in glioblastoma. Chemother Res Pract 2011, 878912 (2011)

    Google Scholar 

  • N.E. Toledano Furman, Y. Lupu-Haber, T. Bronshtein, L. Kaneti, N. Letko, E. Weinstein, L. Baruch, M. Machluf, Reconstructed stem cell nanoghosts: a natural tumor targeting platform. Nano Lett. 13(7), 3248–3255 (2013)

    Article  Google Scholar 

  • T. Uchida, K. Yoshida, S. Goto, Preparation and characterization of polylactic acid microspheres containing water-soluble dyes using a novel w/o/w emulsion solvent evaporation method. J. Microencapsul. 13(2), 219–228 (1996)

    Article  Google Scholar 

  • M.M. Valter, O.D. Wiestler, T. Pietsche, Differential control of VEGF synthesis and secretion in human glioma cells by IL-1 and EGF. Int. J. Dev. Neurosci. 17(5-6), 565–577 (1999)

    Article  Google Scholar 

  • W.J. van Heeckeren, J. Ortiz, M.M. Cooney, S.C. Remick, Hypertension, proteinuria, and antagonism of vascular endothelial growth factor signaling: clinical toxicity, therapeutic target, or novel biomarker? J. Clin. Oncol. 25(21), 2993–2995 (2007)

    Article  Google Scholar 

  • G. Vilar, J. Tulla-Puche, F. Albericio, Polymers and drug delivery systems. Curr. Drug Deliv. 9(4), 367–394 (2012)

    Article  Google Scholar 

  • T. Wang, S. Agarwal, W.F. Elmquist, Brain distribution of cediranib is limited by active efflux at the blood-brain barrier. J. Pharmacol. Exp. Ther. 341(2), 386–395 (2012)

    Article  Google Scholar 

  • S.R. Wedge, J. Kendrew, L.F. Hennequin, P.J. Valentine, S.T. Barry, S.R. Brave, N.R. Smith, N.H. James, M. Dukes, J.O. Curwen, R. Chester, J.A. Jackson, S.J. Boffey, L.L. Kilburn, S. Barnett, G.H. Richmond, P.F. Wadsworth, M. Walker, A.L. Bigley, S.T. Taylor, L. Cooper, S. Beck, J.M. Jurgensmeier, D.J. Ogilvie, AZD2171: a highly potent, orally bioavailable, vascular endothelial growth factor receptor-2 tyrosine kinase inhibitor for the treatment of cancer. Cancer Res. 65(10), 4389–4400 (2005)

    Article  Google Scholar 

  • W. Wick, M. Weller, M. Weiler, T. Batchelor, A.W. Yung, M. Platten, Pathway inhibition: emerging molecular targets for treating glioblastoma. Neuro. Oncol. 13(6), 566–579 (2011)

    Article  Google Scholar 

  • X.S. Wu, Synthesis, characterization, biodegradation, and drug delivery application of biodegradable lactic/glycolic acid polymers: part III. Drug delivery application. Artif. Cells Blood Substit. Immobil. Biotechnol. 32(4), 575–591 (2004)

    Article  Google Scholar 

  • X.S. Wu, N. Wang, Synthesis, charactarization, biodegradable lactic/glycolic acid polymer. J. Biomater. Sci. Polym. Ed. 12, 21–34 (2001)

    Article  Google Scholar 

  • K. Yonesaka, K. Zejnullahu, I. Okamoto, T. Satoh, F. Cappuzzo, J. Souglakos, D. Ercan, A. Rogers, M. Roncalli, M. Takeda, Y. Fujisaka, J. Philips, T. Shimizu, O. Maenishi, Y. Cho, J. Sun, A. Destro, K. Taira, K. Takeda, T. Okabe, J. Swanson, H. Itoh, M. Takada, E. Lifshits, K. Okuno, J.A. Engelman, R.A. Shivdasani, K. Nishio, M. Fukuoka, M. Varella-Garcia, K. Nakagawa, P.A. Janne, Activation of ERBB2 signaling causes resistance to the EGFR-directed therapeutic antibody cetuximab. Sci. Transl. Med. 3(99), 99ra86 (2011)

    Article  Google Scholar 

  • H. Zhao, J. Gagnon, U.O. Hafeli, Process and formulation variables in the preparation of injectable and biodegradable magnetic microspheres. Biomagn. Res. Technol. 5, 2 (2007)

    Article  Google Scholar 

Download references

Acknowledgments

A172 human glioblastoma cells were kindly provided by Prof. David Givol, Weizmann Institute of Science, Rehovot, Israel. bFGF was kindly donated by Prof. Gera Neufeld, Technion—Israel Institute of Technology, Haifa, Israel. The financial support of the Russell Berrie Nanotechnology Institute (RBNI) and The Lorry I. Lokey Center is thankfully acknowledged. The financial support and contribution of the Bert Richardson Foundation is greatly appreciated.

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. All procedures performed in studies involving animals were in accordance with the ethical standards of the institution or practice at which the studies were conducted. All animal experiments were performed in compliance with the Ministry of Health’s guidelines for the care and use of laboratory animals (Ethics Committee approval No. IL-089-09-2006).

Author information

Authors and Affiliations

  1. Faculty of Biotechnology and Food Engineering, Technion – Israel Institute of Technology (IIT), Haifa, 3200003, Israel

    Anna Shivinsky, Tomer Bronshtein, Tom Haber & Marcelle Machluf

Authors
  1. Anna Shivinsky
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Tomer Bronshtein
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Tom Haber
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Marcelle Machluf
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Marcelle Machluf.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Shivinsky, A., Bronshtein, T., Haber, T. et al. The effect of AZD2171- or sTRAIL/Apo2L-loaded polylactic-co-glycolic acid microspheres on a subcutaneous glioblastoma model. Biomed Microdevices 17, 69 (2015). https://doi.org/10.1007/s10544-015-9969-2

Download citation

  • Published:

  • DOI: https://doi.org/10.1007/s10544-015-9969-2

Keywords

Search

Navigation