Advertisement

Heart and Vessels

, Volume 34, Issue 1, pp 167–176 | Cite as

Sustained delivery of vascular endothelial growth factor using a dextran/poly(lactic-co-glycolic acid)-combined microsphere system for therapeutic neovascularization

  • Zhen Dong Zhang
  • Ying Qi Xu
  • Feng ChenEmail author
  • Jun Fu Luo
  • Chong Dong Liu
Original Article
  • 85 Downloads

Abstract

We hypothesize that the controlled delivery of vascular endothelial growth factor (VEGF) using a novel protein sustained-release system based on the combination of protein-loaded dextran microparticles and PLGA microspheres could be useful to achieve mature vessel formation in a rat hind-limb ischemic model. VEGF-loaded dextran microparticles were fabricated and then encapsulated into poly(lactic-co-glycolic acid) (PLGA) microspheres to prepare VEGF–dextran–PLGA microspheres. The release behavior and bioactivity in promoting endothelial cell proliferation of VEGF from PLGA microspheres were monitored in vitro. VEGF–dextran–PLGA microsphere-loaded fibrin gel was injected into an ischemic rat model, and neovascularization at the ischemic site was evaluated. The release of VEGF from PLGA microspheres was in a sustained manner for more than 1 month in vitro with low level of initial burst release. The released VEGF enhanced the proliferation of endothelial cells in vitro, and significantly promoted the capillaries and smooth muscle α-actin positive vessels formation in vivo. The retained bioactivity of VEGF released from VEGF–dextran–PLGA microspheres potentiated the angiogenic efficacy of VEGF. This sustained-release system may be a promising vehicle for delivery of multiple angiogenic factors for therapeutic neovascularization.

Keywords

Vascular endothelial growth factor Microsphere Sustained release Ischemia Neovascularization 

Notes

Acknowledgements

This study was funded by National Natural Science Foundation of China (grant number 81460083), Natural Science Foundation of Jiangxi Province (grant number 20141BBG70032, 20152ACB21026 and 20142BAB215034).

Compliance with ethical standards

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.

References

  1. 1.
    Layman H, Sacasa M, Murphy AE, Murphy AM, Pham SM, Andreopoulos FM (2009) Co-delivery of FGF-2 and G-CSF from gelatin-based hydrogels as angiogenic therapy in a murine critical limb ischemic model. Acta Biomater 5:230–239CrossRefGoogle Scholar
  2. 2.
    Li L, Okada H, Takemura G, Esaki M, Kobayashi H, Kanamori H, Kawamura I, Maruyama R, Fujiwara T, Fujiwara H, Tabata Y, Minatoguchi S (2009) Sustained release of erythropoietin using biodegradable gelatin hydrogel microspheres persistently improves lower leg ischemia. J Am Coll Cardiol 53:2378–2388CrossRefGoogle Scholar
  3. 3.
    Bao H, Lv F, Liu T (2017) A pro-angiogenic degradable Mg-poly(lactic-co-glycolic acid) implant combined with rhbFGF in a rat limb ischemia model. Acta Biomater 64:279–289CrossRefGoogle Scholar
  4. 4.
    Ylä-Herttuala S (2013) Cardiovascular gene therapy with vascular endothelial growth factors. Gene 525:217–219CrossRefGoogle Scholar
  5. 5.
    Helisch A, Schaper W (2003) Arteriogenesis: the development and growth of collateral arteries. Microcirculation 10:83–97CrossRefGoogle Scholar
  6. 6.
    Heil M, Eitenmüller I, Schmitz-Rixen T, Schaper W (2006) Arteriogenesis versus angiogenesis: similarities and differences. J Cell Mol Med 10:45–55CrossRefGoogle Scholar
  7. 7.
    Troidl K, Schaper W (2012) Arteriogenesis versus angiogenesis in peripheral artery disease. Diabetes Metab Res Rev 28(Suppl 1):27–29CrossRefGoogle Scholar
  8. 8.
    Simons M (2005) Angiogenesis: where do we stand now. Circulation 111:1556–1566CrossRefGoogle Scholar
  9. 9.
    Nair KL, Jagadeeshan S, Nair SA, Kumar GS (2011) Biological evaluation of 5-fluorouracil nanoparticles for cancer chemotherapy and its dependence on the carrier, PLGA. Int J Nanomedicine 6:1685–1697Google Scholar
  10. 10.
    El-Hammadi MM, Delgado ÁV, Melguizo C, Prados JC, Arias JL (2017) Folic acid-decorated and PEGylated PLGA nanoparticles for improving the antitumour activity of 5-fluorouracil. Int J Pharm 516:61–70CrossRefGoogle Scholar
  11. 11.
    Kumari A, Yadav SK, Yadav SC (2010) Biodegradable polymeric nanoparticles based drug delivery systems. Colloids Surf B Biointerfaces 75:1–18CrossRefGoogle Scholar
  12. 12.
    Raza K, Kumar N, Misra C, Kaushik L, Guru SK, Kumar P, Malik R, Bhushan S, Katare OP (2016) Dextran-PLGA-loaded docetaxel micelles with enhanced cytotoxicity and better pharmacokinetic profile. Int J Biol Macromol 88:206–212CrossRefGoogle Scholar
  13. 13.
    Suarez SL, Muñoz A, Mitchell A, Braden RL, Luo C, Cochran JR, Almutairi A, Christman KL (2016) Degradable acetalated dextran microparticles for tunable release of an engineered hepatocyte growth factor fragment. ACS Biomater Sci Eng 2:197–204CrossRefGoogle Scholar
  14. 14.
    Ribeiro MP, Morgado PI, Miguel SP, Coutinho P, Correia IJ (2013) Dextran-based hydrogel containing chitosan microparticles loaded with growth factors to be used in wound healing. Mater Sci Eng C Mater Biol Appl 33:2958–2966CrossRefGoogle Scholar
  15. 15.
    Schwendeman SP (2002) Recent advances in the stabilization of proteins encapsulated in injectable PLGA delivery systems. Crit Rev Ther Drug Carrier Syst 19:73–98CrossRefGoogle Scholar
  16. 16.
    Zhu G, Mallery SR, Schwendeman SP (2000) Stabilization of proteins encapsulated in injectable poly (lactide- co-glycolide). Nat Biotechnol 18:52–57CrossRefGoogle Scholar
  17. 17.
    Schellekens H (2005) Immunologic mechanisms of EPO-associated pure red cell aplasia. Best Pract Res Clin Haematol 18:473–480CrossRefGoogle Scholar
  18. 18.
    Maas C, Hermeling S, Bouma B, Jiskoot W, Gebbink MF (2007) A role for protein misfolding in immunogenicity of biopharmaceuticals. J Biol Chem 282:2229–2236CrossRefGoogle Scholar
  19. 19.
    Jiang W, Schwendeman SP (2001) Stabilization and controlled release of bovine serum albumin encapsulated in poly(d, l-lactide) and poly(ethylene glycol) microsphere blends. Pharm Res 18:878–885CrossRefGoogle Scholar
  20. 20.
    Kang J, Wu F, Cai Y, Xu M, He M, Yuan W (2014) Development of recombinant human growth hormone (rhGH) sustained-release microspheres by a low temperature aqueous phase/aqueous phase emulsion method. Eur J Pharm Sci 62:141–147CrossRefGoogle Scholar
  21. 21.
    Wu F, Dai L, Geng L, Zhu H, Jin T (2017) Practically feasible production of sustained-release microspheres of granulocyte-macrophage colony-stimulating factor (rhGM–CSF). J Control Release 259:195–202CrossRefGoogle Scholar
  22. 22.
    Geng Y, Yuan W, Wu F, Chen J, He M, Jin T (2008) Formulating erythropoietin-loaded sustained-release PLGA microspheres without protein aggregation. J Control Release 130:259–265CrossRefGoogle Scholar
  23. 23.
    Yuan W, Wu F, Guo M, Jin T (2009) Development of protein delivery microsphere system by a novel S/O/O/W multi-emulsion. Eur J Pharm Sci 36:212–218CrossRefGoogle Scholar
  24. 24.
    Yang S, Yuan W, Jin T (2009) Formulating protein therapeutics into particulate forms. Expert Opin Drug Deliv 6:1123–1133CrossRefGoogle Scholar
  25. 25.
    Kwak HH, Shim WS, Choi MK, Son MK, Kim YJ, Yang HC, Kim TH, Lee GI, Kim BM, Kang SH, Shim CK (2009) Development of a sustained-release recombinant human growth hormone formulation. J Control Release 137:160–165CrossRefGoogle Scholar
  26. 26.
    Kim SJ, Hahn SK, Kim MJ, Kim DH, Lee YP (2005) Development of a novel sustained release formulation of recombinant human growth hormone using sodium hyaluronate microparticles. J Control Release 104:323–335CrossRefGoogle Scholar
  27. 27.
    Jordan F, Naylor A, Kelly CA, Howdle SM, Lewis A, Illum L (2010) Sustained release hGH microsphere formulation produced by a novel supercritical fluid technology: in vivo studies. J Control Release 141:153–160CrossRefGoogle Scholar
  28. 28.
    Kakizawa Y, Nishio R, Hirano T, Koshi Y, Nukiwa M, Koiwa M, Michizoe J, Ida N (2010) Controlled release of protein drugs from newly developed amphiphilic polymer-based microparticles composed of nanoparticles. J Control Release 142:8–13CrossRefGoogle Scholar
  29. 29.
    Giacca M, Zacchigna S (2012) VEGF gene therapy: therapeutic angiogenesis in the clinic and beyond. Gene Ther 19:622–629CrossRefGoogle Scholar
  30. 30.
    Ouma GO, Zafrir B, Mohler ER, Flugelman MY (2013) Therapeutic angiogenesis in critical limb ischemia. Angiology 64:466–480CrossRefGoogle Scholar
  31. 31.
    Marsano A, Maidhof R, Luo J, Fujikara K, Konofagou EE, Banfi A, Vunjak-Novakovic G (2013) The effect of controlled expression of VEGF by transduced myoblasts in a cardiac patch on vascularization in a mouse model of myocardial infarction. Biomaterials 34:393–401CrossRefGoogle Scholar
  32. 32.
    Jin T, Zhu J, Wu F, Yuan W, Geng LL, Zhu H (2008) Preparing polymer-based sustained-release systems without exposing proteins to water–oil or water–air interfaces and cross-linking reagents. J Control Release 128:50–59CrossRefGoogle Scholar
  33. 33.
    Yancopoulos GD, Davis S, Gale NW, Rudge JS, Wiegand SJ, Holash J (2000) Vascular-specific growth factors and blood vessel formation. Nature 407:242–248CrossRefGoogle Scholar
  34. 34.
    Dor Y, Djonov V, Abramovitch R, Itin A, Fishman GI, Carmeliet P, Goelman G, Keshet E (2002) Conditional switching of VEGF provides new insights into adult neovascularization and pro-angiogenic therapy. EMBO J 21:1939–1947CrossRefGoogle Scholar
  35. 35.
    Ozawa CR, Banfi A, Glazer NL, Thurston G, Springer ML, Kraft PE, McDonald DM, Blau HM (2004) Microenvironmental VEGF concentration, not total dose, determines a threshold between normal and aberrant angiogenesis. J Clin Invest 113:516–527CrossRefGoogle Scholar
  36. 36.
    Springer ML, Ozawa CR, Banfi A, Kraft PE, Ip TK, Brazelton TR, Blau HM (2003) Localized arteriole formation directly adjacent to the site of VEGF-induced angiogenesis in muscle. Mol Ther 7:441–449CrossRefGoogle Scholar
  37. 37.
    Kalka C, Masuda H, Takahashi T, Gordon R, Tepper O, Gravereaux E, Pieczek A, Iwaguro H, Hayashi SI, Isner JM, Asahara T (2000) Vascular endothelial growth factor(165) gene transfer augments circulating endothelial progenitor cells in human subjects. Circ Res 86:1198–1202CrossRefGoogle Scholar
  38. 38.
    Asahara T, Takahashi T, Masuda H, Kalka C, Chen D, Iwaguro H, Inai Y, Silver M, Isner JM (1999) VEGF contributes to postnatal neovascularization by mobilizing bone marrow-derived endothelial progenitor cells. EMBO J 18:3964–3972CrossRefGoogle Scholar
  39. 39.
    Grunewald M, Avraham I, Dor Y, Bachar-Lustig E, Itin A, Jung S, Yung S, Chimenti S, Landsman L, Abramovitch R, Keshet E (2006) VEGF-induced adult neovascularization: recruitment, retention, and role of accessory cells. Cell 124:175–189CrossRefGoogle Scholar
  40. 40.
    Li B, Sharpe EE, Maupin AB, Teleron AA, Pyle AL, Carmeliet P, Young PP (2006) VEGF and PlGF promote adult vasculogenesis by enhancing EPC recruitment and vessel formation at the site of tumor neovascularization. FASEB J 20:1495–1497CrossRefGoogle Scholar
  41. 41.
    Hattori K, Dias S, Heissig B, Hackett NR, Lyden D, Tateno M, Hicklin DJ, Zhu Z, Witte L, Crystal RG, Moore MA, Rafii S (2001) Vascular endothelial growth factor and angiopoietin-1 stimulate postnatal hematopoiesis by recruitment of vasculogenic and hematopoietic stem cells. J Exp Med 193:1005–1014CrossRefGoogle Scholar
  42. 42.
    Iwaguro H, Yamaguchi J, Kalka C, Murasawa S, Masuda H, Hayashi S, Silver M, Li T, Isner JM, Asahara T (2002) Endothelial progenitor cell vascular endothelial growth factor gene transfer for vascular regeneration. Circulation 105:732–738CrossRefGoogle Scholar
  43. 43.
    Avraham-Davidi I, Yona S, Grunewald M, Landsman L, Cochain C, Silvestre JS, Mizrahi H, Faroja M, Strauss-Ayali D, Mack M, Jung S, Keshet E (2013) On-site education of VEGF-recruited monocytes improves their performance as angiogenic and arteriogenic accessory cells. J Exp Med 210:2611–2625CrossRefGoogle Scholar

Copyright information

© Springer Japan KK, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of PathologyThe First Affiliated Hospital, Nanchang UniversityNanchangPeople’s Republic of China
  2. 2.Department of Vascular SurgeryThe Second Affiliated Hospital, Nanchang UniversityNanchangPeople’s Republic of China
  3. 3.Medical CollegeNanchang UniversityNanchangPeople’s Republic of China

Personalised recommendations