Pharmaceutical Research

, Volume 29, Issue 12, pp 3312–3324 | Cite as

Mechanisms of Tumor Vascular Priming by a Nanoparticulate Doxorubicin Formulation

  • Tista Roy Chaudhuri
  • Robert D. Arnold
  • Jun Yang
  • Steven G. Turowski
  • Yang Qu
  • Joseph A. Spernyak
  • Richard Mazurchuk
  • Donald E. Mager
  • Robert M. Straubinger
Research Paper

ABSTRACT

Purpose

Tumor vascular normalization by antiangiogenic agents may increase tumor perfusion but reestablish vascular barrier properties in CNS tumors. Vascular priming via nanoparticulate carriers represents a mechanistically distinct alternative. This study investigated mechanisms by which sterically-stabilized liposomal doxorubicin (SSL-DXR) modulates tumor vascular properties.

Methods

Functional vascular responses to SSL-DXR were investigated in orthotopic rat brain tumors using deposition of fluorescent permeability probes and dynamic contrast-enhanced magnetic resonance imaging. Microvessel density and tumor burden were quantified by immunohistochemistry (CD-31) and quantitative RT-PCR (VE-cadherin).

Results

Administration of SSL-DXR (5.7 mg/kg iv) initially (3–4 days post-treatment) decreased tumor vascular permeability, ktrans (vascular exchange constant), vascular endothelial cell content, microvessel density, and deposition of nanoparticulates. Tumor vasculature became less chaotic. Permeability and perfusion returned to control values 6–7 days post-treatment, but intratumor SSL-DXR depot continued to effect tumor vascular endothelial compartment 7–10 days post-treatment, mediating enhanced permeability.

Conclusions

SSL-DXR ultimately increased tumor vascular permeability, but initially normalized tumor vasculature and decreased tumor perfusion, permeability, and nanoparticulate deposition. These temporal changes in vascular integrity resulting from a single SSL-DXR dose have important implications for the design of combination therapies incorporating nanoparticle-based agents for tumor vascular priming.

KEY WORDS

brain tumors nanoparticulate drug carriers sterically-stabilized liposomes tumor priming tumor vascular permeability 

ABBREVIATIONS

DCE-MRI

dynamic contrast-enhanced magnetic resonance imaging

dNTP

deoxynucleotide triphosphate

DSPC

distearoylphosphatidylcholine

DXR

doxorubicin

eGFP

enhanced green fluorescent protein

PEG-DSPE

distereoylphosphatidylethanolamine derivatized with polyethylene glycol

PK

pharmacokinetic

qRT-PCR

quantitative reverse transcriptase—polymerase chain reaction

SSL

sterically stabilized liposomes

SSL-DXR

sterically stabilized liposomes containing doxorubicin

REFERENCES

  1. 1.
    Jemal A, Siegel R, Ward E, Hao Y, Xu J, Thun MJ. Cancer statistics, 2009. CA Cancer J Clin. 2009;59:225–49.PubMedCrossRefGoogle Scholar
  2. 2.
    Ries LAG, Kosary CL, Hankey BF, Miller BA, Clegg L, Edwards BK. Surveillance epidemiology end result (SEER) cancer statistics review 1973–1996. Bethesda: National Cancer Institute; 1999.Google Scholar
  3. 3.
    Packer RJ. Brain tumors in children. Arch Neurol. 1999;56:421–5.PubMedCrossRefGoogle Scholar
  4. 4.
    Fathallah-Shaykh H. New molecular strategies to cure brain tumors. Arch Neurol. 1999;56:449–53.PubMedCrossRefGoogle Scholar
  5. 5.
    Demuth T, Rennert JL, Hoelzinger DB, Reavie LB, Nakada M, Beaudry C, et al. Glioma cells on the run—the migratory transcriptome of 10 human glioma cell lines. BMC Genomics. 2008;9:54.PubMedCrossRefGoogle Scholar
  6. 6.
    Jain RK. Vascular and interstitial barriers to delivery of therapeutic agents in tumors. Cancer Metastasis Rev. 1990;9:253–66.PubMedCrossRefGoogle Scholar
  7. 7.
    Jain RK. Haemodynamic and transport barriers to the treatment of solid tumours. Int J Radiat Biol. 1991;60:85–100.PubMedCrossRefGoogle Scholar
  8. 8.
    Jang SH, Wientjes MG, Lu D, Au JL. Drug delivery and transport to solid tumors. Pharm Res. 2003;20:1337–50.PubMedCrossRefGoogle Scholar
  9. 9.
    Tredan O, Galmarini CM, Patel K, Tannock IF. Drug resistance and the solid tumor microenvironment. J Natl Cancer Inst. 2007;99:1441–54.PubMedCrossRefGoogle Scholar
  10. 10.
    Brem SS, Bierman PJ, Black P, Brem H, Chamberlain MC, Chiocca EA, et al. Central nervous system cancers. J Natl Compr Canc Netw. 2008;6:456–504.PubMedGoogle Scholar
  11. 11.
    Avgeropoulos NG, Batchelor TT. New treatment strategies for malignant gliomas. Oncologist. 1999;4:209–24.PubMedGoogle Scholar
  12. 12.
    Venturoli D, Rippe B. Ficoll and dextran vs. globular proteins as probes for testing glomerular permselectivity: effects of molecular size, shape, charge, and deformability. Am J Physiol Renal Physiol. 2005;288:F605–13.PubMedCrossRefGoogle Scholar
  13. 13.
    Dreher MR, Liu W, Michelich CR, Dewhirst MW, Yuan F, Chilkoti A. Tumor vascular permeability, accumulation, and penetration of macromolecular drug carriers. J Natl Cancer Inst. 2006;98:335–44.PubMedCrossRefGoogle Scholar
  14. 14.
    Drummond DC, Meyer O, Hong K, Kirpotin DB, Papahadjopoulos D. Optimizing liposomes for delivery of chemotherapeutic agents to solid tumors. Pharmacol Rev. 1999;51:691–743.PubMedGoogle Scholar
  15. 15.
    Gabizon A, Papahadjopoulos D. Liposome formulations with prolonged circulation time in blood and enhanced uptake by tumors. Proc Natl Acad Sci USA. 1988;85:6949–53.PubMedCrossRefGoogle Scholar
  16. 16.
    Gabizon A, Shiota R, Papahadjopoulos D. Pharmacokinetics and tissue distribution of doxorubicin encapsulated in stable liposomes with long circulation times. J Natl Canc Inst. 1989;81:1484–8.CrossRefGoogle Scholar
  17. 17.
    Allen TM, Chonn A. Large unilamellar liposomes with low uptake into the reticuloendothelial system. FEBS Lett. 1987;223:42–6.PubMedCrossRefGoogle Scholar
  18. 18.
    Davis ME, Chen ZG, Shin DM. Nanoparticle therapeutics: an emerging treatment modality for cancer. Nat Rev Drug Discov. 2008;7:771–82.PubMedCrossRefGoogle Scholar
  19. 19.
    Torchilin VP. Targeted pharmaceutical nanocarriers for cancer therapy and imaging. AAPS J. 2007;9:E128–47.PubMedCrossRefGoogle Scholar
  20. 20.
    Li SD, Huang L. Pharmacokinetics and biodistribution of nanoparticles. Mol Pharm. 2008;5:496–504.PubMedCrossRefGoogle Scholar
  21. 21.
    Muggia FM. Liposomal encapsulated anthracyclines: new therapeutic horizons. Curr Oncol Rep. 2001;3:156–62.PubMedCrossRefGoogle Scholar
  22. 22.
    Gabizon AA. Pegylated liposomal doxorubicin: metamorphosis of an old drug into a new form of chemotherapy. Canc Investig. 2001;19:424–36.CrossRefGoogle Scholar
  23. 23.
    Zhou R, Mazurchuk R, Straubinger RM. Antivasculature effects of doxorubicin-containing liposomes in an intracranial rat brain tumor model. Cancer Res. 2002;62:2561–6.PubMedGoogle Scholar
  24. 24.
    Sharma US, Sharma A, Chau RI, Straubinger RM. Liposome-mediated therapy of intracranial brain tumors in a rat model. Pharm Res. 1997;14:992–8.PubMedCrossRefGoogle Scholar
  25. 25.
    Arnold RD, Mager DE, Slack JE, Straubinger RM. Effect of repetitive administration of doxorubicin-containing liposomes on plasma pharmacokinetics and drug biodistribution in a rat brain tumor model. Clin Cancer Res. 2005;11:8856–65.PubMedCrossRefGoogle Scholar
  26. 26.
    Mayer LD, Bally MB, Cullis PR. Uptake of adriamycin into large unilamellar vesicles in response to a pH gradient. Biochim Biophys Acta. 1986;857:123–6.PubMedCrossRefGoogle Scholar
  27. 27.
    Haran G, Cohen R, Bar LK, Barenholz Y. Transmembrane ammonium sulfate gradients in liposomes produce efficient and stable entrapment of amphipathic weak bases. Biochim Biophys Acta. 1993;1151:201–15.PubMedCrossRefGoogle Scholar
  28. 28.
    Lasic DD, Frederik PM, Stuart MC, Barenholz Y, McIntosh TJ. Gelation of liposome interior. A novel method for drug encapsulation. FEBS Lett. 1992;312:255–8.PubMedCrossRefGoogle Scholar
  29. 29.
    Tailor TD, Hanna G, Yarmolenko PS, Dreher MR, Betof AS, Nixon AB, et al. Effect of pazopanib on tumor microenvironment and liposome delivery. Mol Cancer Ther. 2010;9:1798–808.PubMedCrossRefGoogle Scholar
  30. 30.
    Baker JH, Lam J, Kyle AH, Sy J, Oliver T, Co SJ, et al. Irinophore C, a novel nanoformulation of irinotecan, alters tumor vascular function and enhances the distribution of 5-fluorouracil and doxorubicin. Clin Cancer Res. 2008;14:7260–71.PubMedCrossRefGoogle Scholar
  31. 31.
    Verreault M, Strutt D, Masin D, Anantha M, Yung A, Kozlowski P, et al. Vascular normalization in orthotopic glioblastoma following intravenous treatment with lipid-based nanoparticulate formulations of irinotecan (Irinophore C), doxorubicin (Caelyx) or vincristine. BMC Cancer. 2011;11:124.PubMedCrossRefGoogle Scholar
  32. 32.
    Weidensteiner C, Rausch M, McSheehy PM, Allegrini PR. Quantitative dynamic contrast-enhanced MRI in tumor-bearing rats and mice with inversion recovery TrueFISP and two contrast agents at 4.7 T. J Magn Reson Imaging. 2006;24:646–56.PubMedCrossRefGoogle Scholar
  33. 33.
    Choyke PL, Dwyer AJ, Knopp MV. Functional tumor imaging with dynamic contrast-enhanced magnetic resonance imaging. J Magn Reson Imaging. 2003;17:509–20.PubMedCrossRefGoogle Scholar
  34. 34.
    Trummer BJ, Iyer VS, Balu-Iyer SV, O’Connor R, Straubinger RM. Physicochemical properties of EGF receptor inhibitors and development of a nanoliposomal formulation of gefitinib. Journal of Pharmaceutical Sciences. 2012;in press.Google Scholar
  35. 35.
    Oh Y-K, Nix DE, Straubinger RM. Formulation and efficacy of liposome-encapsulated antibiotics for therapy of intracellular M. avium infection. Antimicrob Agents Chemother. 1995;39:2104–11.PubMedCrossRefGoogle Scholar
  36. 36.
    Madden TD, Harrigan PR, Tai LC, Bally MB, Mayer LD, Redelmeier TE, et al. The accumulation of drugs within large unilamellar vesicles exhibiting a proton gradient: a survey. Chem Phys Lipids. 1990;53:37–46.PubMedCrossRefGoogle Scholar
  37. 37.
    Harrigan PR, Wong KF, Redelmeier TE, Wheeler JJ, Cullis PR. Accumulation of doxorubicin and other lipophilic amines into large unilamellar vesicles in response to transmembrane pH-gradients. Biochim Biophys Acta. 1993;1149:329–48.PubMedCrossRefGoogle Scholar
  38. 38.
    Li X, Hirsh DJ, Cabral-Lilly D, Zirkel A, Gruner SM, Janoff AS, et al. Doxorubicin physical state in solution and inside liposomes loaded via a pH gradient. Biochim Biophys Acta. 1998;1415:23–40.PubMedCrossRefGoogle Scholar
  39. 39.
    Bartlett GR. Phosphorus assay in column chromatography. J Biol Chem. 1959;234:466–8.PubMedGoogle Scholar
  40. 40.
    Ghods AJ, Irvin D, Liu G, Yuan X, Abdulkadir IR, Tunici P, et al. Spheres isolated from 9L gliosarcoma rat cell line possess chemoresistant and aggressive cancer stem-like cells. Stem Cells. 2007;25:1645–53.PubMedCrossRefGoogle Scholar
  41. 41.
    Schmitt P, Griswold MA, Jakob PM, Kotas M, Gulani V, Flentje M, et al. Inversion recovery TrueFISP: quantification of T(1), T(2), and spin density. Magn Reson Med. 2004;51:661–7.PubMedCrossRefGoogle Scholar
  42. 42.
    Shih SC, Robinson GS, Perruzzi CA, Calvo A, Desai K, Green JE, et al. Molecular profiling of angiogenesis markers. Am J Pathol. 2002;161:35–41.PubMedCrossRefGoogle Scholar
  43. 43.
    Vandesompele J, De Preter K, Pattyn F, Poppe B, Van Roy N, De Paepe A, et al. Accurate normalization of real-time quantitative RT-PCR data by geometric averaging of multiple internal control genes. Genome Biol. 2002;3:RESEARCH0034.PubMedCrossRefGoogle Scholar
  44. 44.
    Meers P, Ali S, Erukulla R, Janoff AS. Novel inner monolayer fusion assays reveal differential monolayer mixing associated with cation-dependent membrane fusion. Biochim Biophys Acta. 2000;1467:227–43.PubMedCrossRefGoogle Scholar
  45. 45.
    Saito R, Bringas JR, McKnight TR, Wendland MF, Mamot C, Drummond DC, et al. Distribution of liposomes into brain and rat brain tumor models by convection-enhanced delivery monitored with magnetic resonance imaging. Cancer Res. 2004;64:2572–9.PubMedCrossRefGoogle Scholar
  46. 46.
    Lyass O, Uziely B, Ben-Yosef R, Tzemach D, Heshing NI, Lotem M, et al. Correlation of toxicity with pharmacokinetics of pegylated liposomal doxorubicin (Doxil) in metastatic breast carcinoma. Cancer. 2000;89:1037–47.PubMedCrossRefGoogle Scholar
  47. 47.
    Jain RK. Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy. Science. 2005;307:58–62.PubMedCrossRefGoogle Scholar
  48. 48.
    Batchelor TT, Sorensen AG, di Tomaso E, Zhang WT, Duda DG, Cohen KS, et al. AZD2171, a pan-VEGF receptor tyrosine kinase inhibitor, normalizes tumor vasculature and alleviates edema in glioblastoma patients. Cancer Cell. 2007;11:83–95.PubMedCrossRefGoogle Scholar
  49. 49.
    Escorcia FE, Henke E, McDevitt MR, Villa CH, Smith-Jones P, Blasberg RG, et al. Selective killing of tumor neovasculature paradoxically improves chemotherapy delivery to tumors. Cancer Res. 2010;70:9277–86.PubMedCrossRefGoogle Scholar
  50. 50.
    Gabizon A, Price DC, Huberty J, Bresalier RS, Papahadjopoulos D. Effect of liposome composition and other factors on the targeting of liposomes to experimental tumors: biodistribution and imaging studies. Cancer Res. 1990;50:6371–8.PubMedGoogle Scholar
  51. 51.
    Huang S, Lee K-D, Hong K, Friend D, Papahadjopoulos D. Microscopic localization of sterically-stabilized liposomes in colon-carcinoma-bearing mice. Cancer Res. 1992;52:5135–43.PubMedGoogle Scholar
  52. 52.
    Chen Q, Tong S, Dewhirst MW, Yuan F. Targeting tumor microvessels using doxorubicin encapsulated in a novel thermosensitive liposome. Mol Cancer Ther. 2004;3:1311–7.PubMedGoogle Scholar
  53. 53.
    Wu N, Da D, Rudoll T, Needham D, Whorton A, Dewhirst M. Increased microvascular permeability contributes to preferential accumulation of Stealth™ liposomes in tumor tissue. Cancer Res. 1993;53:3766–70.Google Scholar
  54. 54.
    Paez-Ribes M, Allen E, Hudock J, Takeda T, Okuyama H, Vinals F, et al. Antiangiogenic therapy elicits malignant progression of tumors to increased local invasion and distant metastasis. Cancer Cell. 2009;15:220–31.PubMedCrossRefGoogle Scholar
  55. 55.
    Ebos JM, Lee CR, Cruz-Munoz W, Bjarnason GA, Christensen JG, Kerbel RS. Accelerated metastasis after short-term treatment with a potent inhibitor of tumor angiogenesis. Cancer Cell. 2009;15:232–9.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  • Tista Roy Chaudhuri
    • 1
    • 2
  • Robert D. Arnold
    • 1
    • 4
  • Jun Yang
    • 1
  • Steven G. Turowski
    • 2
  • Yang Qu
    • 1
  • Joseph A. Spernyak
    • 2
  • Richard Mazurchuk
    • 2
    • 5
  • Donald E. Mager
    • 1
  • Robert M. Straubinger
    • 1
    • 2
    • 3
  1. 1.Department of Pharmaceutical SciencesUniversity at Buffalo, State University of New YorkBuffaloUSA
  2. 2.Department of Molecular and Cellular Biophysics and BiochemistryRoswell Park Cancer InstituteBuffaloUSA
  3. 3.New York State Center of Excellence in Bioinformatics and Life SciencesBuffaloUSA
  4. 4.Department of Pharmacal, Harrison School of PharmacyAuburn UniversityAuburnUSA
  5. 5.Division of Cancer PreventionNational Cancer InstituteBethesdaUSA

Personalised recommendations