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Nanoparticulate Delivery System Targeted to Tumor Neovasculature for Combined Anticancer and Antiangiogenesis Therapy

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ABSTRACT

Purpose

Herein, we designed a nanoparticulate combined delivery system decorated on the surface with RGD peptide, and encapsulating paclitaxel (PTX) and combretastatin A4 (CA4) as the respective anticancer and antiangiogenesis agent in the nanoparticle.

Methods

PTX and CA4 were co-encapsulated into the biocompatible PLGA, followed by solvent evaporation to form solid nanoparticle. The cRGDfK peptide was then conjugated onto the nanoparticle surface with EDC/NHS chemistry.

Results

The developed nanoparticles (NPs) were found uniform in size and well dispersed in buffers. The cellular uptake of such NPs could be efficiently detected as early as 20 min after incubation. In 24-h incubation, the encapsulated PTX could induce caspase 3/7-dependent apoptosis at 50 nM, whereas the CA4-loaded NPs could disrupt tubulin structure at 2.5 μM. The targeted dual drug-loaded nanoparticle achieved significant tumor growth suppression in vivo compared to the control from day 8 (P < 0.05). Histological results revealed that the targeted dual drug nanoparticle led to dramatic tumor vasculature disruption, significant cancer cell apoptosis and cell proliferation inhibition in the mouse model.

Conclusion

These findings indicate that the targeted dual drug nanoparticulate delivery system encompassing both antiangiogenesis and anticancer effects can be a potential candidate in cancer therapy.

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REFERENCES

  1. Coultas L, Chawengsaksophak K, Rossant J. Endothelial cells and VEGF in vascular development. Nature. 2005;438:937–45.

    Article  CAS  PubMed  Google Scholar 

  2. Shojaei F, Ferrara N. Antiangiogenesis to treat cancer and intraocular neovascular disorders. Lab Invest. 2007;87:227–30.

    Article  CAS  PubMed  Google Scholar 

  3. Carmeliet P. Angiogenesis in life, disease and medicine. Nature. 2005;438:932–6.

    Article  CAS  PubMed  Google Scholar 

  4. Holmgren L, Oreilly MS, Folkman J. Dormancy of micrometastases—balanced proliferation and apoptosis in the presence of angiogenesis suppression. Nat Med. 1995;1:149–53.

    Article  CAS  PubMed  Google Scholar 

  5. Kerbel RS, Kamen BA. The anti-angiogenic basis of metronomic chemotherapy. Nat Rev Cancer. 2004;4:423–36.

    Article  CAS  PubMed  Google Scholar 

  6. Dorrell MI, Aguilar E, Scheppke L, Barnett FH, Friedlander M. Combination angiostatic therapy completely inhibits ocular and tumor angiogenesis. Proc Natl Acad Sci USA. 2007;104:967–72.

    Article  CAS  PubMed  Google Scholar 

  7. Uno T, Takeda K, Kojima Y, Yoshizawa H, Akiba H, Mittler RS, et al. Eradication of established tumors in mice by a combination antibody-based therapy. Nat Med. 2006;12:693–8.

    Article  CAS  PubMed  Google Scholar 

  8. Klement G, Baruchel S, Rak J, Man S, Clark K, Hicklin DJ, et al. Continuous low-dose therapy with vinblastine and VEGF receptor-2 antibody induces sustained tumor regression without overt toxicity. J Clin Invest. 2000;105:R15–24.

    Article  CAS  PubMed  Google Scholar 

  9. Hurwitz H, Fehrenbacher L, Novotny W, Cartwright T, Hainsworth J, Heim W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. New Engl J Med. 2004;350:2335–42.

    Article  CAS  PubMed  Google Scholar 

  10. Thorpe PE. Vascular targeting agents as cancer therapeutics. Clin Cancer Res. 2004;10:415–27.

    Article  PubMed  Google Scholar 

  11. Yeung SCJ, She MR, Yang HL, Pan JX, Sun LL, Chaplin D. Combination chemotherapy including combretastatin A4 phosphate and paclitaxel is effective against anaplastic thyroid cancer in a nude mouse xenograft model. J Clin Endocrinol Metab. 2007;92:2902–9.

    Article  CAS  PubMed  Google Scholar 

  12. Farokhzad OC, Cheng JJ, Teply BA, Sherifi I, Jon S, Kantoff PW, et al. Targeted nanoparticle-aptamer bioconjugates for cancer chemotherapy in vivo. Proc Natl Acad Sci USA. 2006;103:6315–20.

    Article  CAS  PubMed  Google Scholar 

  13. Wang Z, Chui WK, Ho PC. Design of a multifunctional PLGA nanoparticulate drug delivery system: evaluation of its physicochemical properties and anticancer activity to malignant cancer cells. Pharm Res. 2009;26:1162–71.

    Article  CAS  PubMed  Google Scholar 

  14. Green JJ, Chiu E, Leshchiner ES, Shi J, Langer R, Anderson DG. Electrostatic ligand coatings of nanoparticles enable ligand-specific gene delivery to human primary cells. Nano Lett. 2007;7:874–9.

    Article  CAS  PubMed  Google Scholar 

  15. Devalapally H, Duan ZF, Seiden MV, Amiji MM. Paclitaxel and ceramide co-administration in biodegradable polymeric nanoparticulate delivery system to overcome drug resistance in ovarian cancer. Int J Cancer. 2007;121:1830–8.

    Article  CAS  PubMed  Google Scholar 

  16. Kumar P, Benedict R, Urzua F, Fischbach C, Mooney D, Polverini P. Combination treatment significantly enhances the efficacy of antitumor therapy by preferentially targeting angiogenesis. Lab Invest. 2005;85:756–67.

    Article  CAS  PubMed  Google Scholar 

  17. Minischetti M, Vacca A, Ribatti D, Iurlaro M, Ria R, Pellegrino A, et al. TNP-470 and recombinant human interferon-alpha 2a inhibit angiogenesis synergistically. Br J Haematol. 2000;109:829–37.

    Article  CAS  PubMed  Google Scholar 

  18. Abdollahi A, Griggs DW, Zieher H, Roth A, Lipson KE, Saffrich R, et al. Inhibition of alpha(v)beta(3) integrin survival signaling enhances antiangiogenic and antitumor effects of radiotherapy. Clin Cancer Res. 2005;11:6270–9.

    Article  CAS  PubMed  Google Scholar 

  19. Poeck H, Besch R, Maihoefer C, Renn M, Tormo D, Morskaya SS, et al. 5′-triphosphate-siRNA: turning gene silencing and Rig-I activation against melanoma. Nat Med. 2008;14:1256–63.

    Article  CAS  PubMed  Google Scholar 

  20. McCarron PA, Marouf WM, Quinn DJ, Fay F, Burden RE, Olwill SA, et al. Antibody targeting of camptothecin-loaded PLGA nanoparticles to tumor cells. Bioconjug Chem. 2008;19:1561–9.

    Article  CAS  PubMed  Google Scholar 

  21. Dhar S, Gu FX, Langer R, Farokhzad OC, Lippard SJ. Targeted delivery of cisplatin to prostate cancer cells by aptamer functionalized Pt(IV) prodrug-PLGA-PEG nanoparticles. Proc Natl Acad Sci USA. 2008;105:17356–61.

    Article  CAS  PubMed  Google Scholar 

  22. McGown AT, Fox BW. Structural and biochemical-comparison of the anti-mitotic agents colchicine, Combretastatin-A4 AND amphethinile. Anticancer Drug Des. 1989;3:249–54.

    PubMed  Google Scholar 

  23. Kanthou C, Tozer GM. The tumor vascular targeting agent combretastatin A-4-phosphate induces reorganization of the actin cytoskeleton and early membrane blebbing in human endothelial cells. Blood. 2002;99:2060–9.

    Article  CAS  PubMed  Google Scholar 

  24. Winkler F, Kozin SV, Tong RT, Chae SS, Booth MF, Garkavtsev I, et al. Kinetics of vascular normalization by VEGFR2 blockade governs brain tumor response to radiation: role of oxygenation, angiopoietin-1, and matrix metal loproteinases. Cancer Cell. 2004;6:553–63.

    CAS  PubMed  Google Scholar 

  25. Tozer GM, Kanthou C, Baguley BC. Disrupting tumour blood vessels. Nat Rev Cancer. 2005;5:423–35.

    Article  CAS  PubMed  Google Scholar 

  26. Liu Z, Chen K, Davis C, Sherlock S, Cao QZ, Chen XY, et al. Drug delivery with carbon nanotubes for in vivo cancer treatment. Cancer Res. 2008;68:6652–60.

    Article  CAS  PubMed  Google Scholar 

  27. Henke E, Perk J, Vider J, de Candia P, Chin Y, Solit DB, et al. Peptide-conjugated antisense oligonucleotides for targeted inhibition of a transcriptional regulator in vivo. Nat Biotechnol. 2008;26:91–100.

    Article  CAS  PubMed  Google Scholar 

  28. Stoeltzing O, Liu WB, Reinmuth N, Fan F, Parry GC, Parikh AA, et al. Inhibition of integrin alpha(5)beta(1) function with a small peptide (ATN-161) plus continuous 5-FU infusion reduces colorectal liver metastases and improves survival in mice. Int J Cancer. 2003;104:496–503.

    Article  CAS  PubMed  Google Scholar 

  29. Bozec A, Formento P, Lassalle S, Lippens C, Hofman P, Milano G. Dual inhibition of EGFR and VEGFR pathways in combination with irradiation: antitumour supra-additive effects on human head and neck cancer xenografts. B J Cancer. 2007;97:65–72.

    Article  CAS  Google Scholar 

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Authors and Affiliations

  1. Laboratory for Experimental and Applied Pharmacokinetics and Pharmacodynamics (LEAP2), Department of Pharmacy, National University of Singapore, 18 Science Drive 4, Singapore, 117543, Singapore

    Zhe Wang & Paul C. Ho

  2. Medicinal Chemistry Research Laboratory, Department of Pharmacy, National University of Singapore, 18 Science Drive 4, Singapore, 117543, Singapore

    Wai-Keung Chui

Authors
  1. Zhe Wang
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  2. Wai-Keung Chui
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  3. Paul C. Ho
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Correspondence to Paul C. Ho.

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Wang, Z., Chui, WK. & Ho, P.C. Nanoparticulate Delivery System Targeted to Tumor Neovasculature for Combined Anticancer and Antiangiogenesis Therapy. Pharm Res 28, 585–596 (2011). https://doi.org/10.1007/s11095-010-0308-2

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  • DOI: https://doi.org/10.1007/s11095-010-0308-2

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