The iron chelator deferoxamine is a hypoxia biomimicry and has received interest as a potential therapeutic in tissue engineering and regenerative medicine. Recently, local injection of this iron chelator deferoxamine has proven to increase bone healing through the activation of the hypoxia-inducible factor-1 signaling pathway that augments angiogenesis and osteogenesis. Repeated injections of deferoxamine are required to achieve local therapeutic levels at fracture site. To achieve local therapeutic levels at fracture site without the use of multiples injections and associated pain and infection issues, we designed and prepared polymeric microspheres made of polycaprolactone and poly(ethylene oxide), in which deferoxamine was encapsulated, via a melting process. The application of this process has enabled to obtain spheres of different poly(ethylene oxide) concentrations for optimizing the drug release rate. The effective local release carrier offers a predetermined rate that can mimic the effect of repeated deferoxamine injections over a 14-day period to selectively stimulate bone repair and thus improve the biological performance to the point where ideally synthetics begin to challenge autograft dominance as the bone replacement of choice.
FayazHCGiannoudisPVVrahasMS, et al.
The role of stem cells in fracture healing and nonunion. Int Orthop (Sicot)2011;
35: 1587–1597.
2.
FilipowskaJTomaszewskiKANiedźwiedzkiŁ, et al.
The role of vasculature in bone development, regeneration and proper systemic functioning. Angiogenesis2017;
20: 291–302.
3.
MurnaghanMLiGMarshDR.Nonsteroidal anti-inflammatory drug-induced fracture nonunion: An inhibition of angiogenesis?J Bone Joint Surg Am2006;
88: 140–147.
4.
HouZNieCSiZ, et al.
Deferoxamine enhances neovascularization and accelerates wound healing in diabetic rats via the accumulation of hypoxia-inducible factor-1alpha. Diabetes Res Clin Pract2013;
101: 62–71.
5.
RiddleRCKhatriRSchipaniE, et al.
Role of hypoxia-inducible factor-1alpha in angiogenic-osteogenic coupling. J Mol Med (Berl)2009;
87: 583–590.
6.
PouysségurJDayanFMazureNM.Hypoxia signalling in cancer and approaches to enforce tumour regression. Nature2006;
441: 437–443.
7.
SiegertISchödelJNairzM, et al.
Ferritin-mediated iron sequestration stabilizes hypoxia-inducible factor-1α upon LPS activation in the presence of ample oxygen. Cell Rep2015;
13: 2048–2055.
8.
HertzbergBPHoltJBGraffRD, et al.
An evaluation of carrier agents for deferoxamine, an up-regulator of vascular endothelial growth factor. J Biomater Appl2013;
27: 1046–1054.
9.
KomatsuDEHadjiargyrouM.Activation of the transcription factor HIF-1 and its target genes, VEGF, HO-1, iNOS, during fracture repair. Bone2004;
34: 680–688.
10.
ShenXWanCRamaswamyG, et al.
Prolyl hydroxylase inhibitors increase neoangiogenesis and callus formation following femur fracture in mice. J Orthop Res2009;
27: 1298–1305.
11.
HuangLEGuJSchauM, et al.
Regulation of hypoxia-inducible factor 1alpha is mediated by an O2-dependent degradation domain via the ubiquitin-proteasome pathway. Proc Natl Acad Sci U S A1998;
95: 7987–7992.
12.
WengerRH.Cellular adaptation to hypoxia: O2-sensing protein hydroxylases, hypoxia-inducible transcription factors, and O2-regulated gene expression. FASEB J2002;
16: 1151–1162.
13.
FlanaganRJonesAMaynardRL.Antidotes: Principles and clinical applications.
Boca Raton:
CRC Press, 2003.
14.
MartinDW.Harper’s review of biochemistry.
Los Altos:
Lange Medical Publications, 1981.
15.
WarburgO. Annual review of biochemistry. Prefatory chapter. Annu Rev Biochem 1964; 33: 1–14.
16.
FarbergASSarhaddiDDonneysA, et al.
Deferoxamine enhances bone regeneration in mandibular distraction osteogenesis. Plast Reconstr Surg2014;
133: 666–671.
17.
DonneysAWeissDMDeshpandeSS, et al.
Localized deferoxamine injection augments vascularity and improves bony union in pathologic fracture healing after radiotherapy. Bone2013;
52: 318–325.
18.
DonneysAAhsanSPeroskyJE, et al.
Deferoxamine restores callus size, mineralization, and mechanical strength in fracture healing after radiotherapy. Plast Reconstr Surg2013;
131: 711e–719e.
19.
DonneysABloughJTNelsonNS, et al.
Translational treatment paradigm for managing non-unions secondary to radiation injury utilizing adipose derived stem cells and angiogenic therapy. Head Neck2016;
38: E837–E843.
20.
DragerJRamirez-GarciaLunaJLKumarA, et al.
Hypoxia biomimicry to enhance monetite bone defect repair. Tissue Eng Part A2017;
23: 1372–1381.
21.
HuKOlsenBR.The roles of vascular endothelial growth factor in bone repair and regeneration. Bone2016;
91: 30–38.
22.
HamiltonJLKizhakkedathuJN.Polymeric nanocarriers for the treatment of systemic iron overload. Mol Cell Ther2015;
3: 3.
23.
RanQYuYChenW, et al.
Deferoxamine loaded titania nanotubes substrates regulate osteogenic and angiogenic differentiation of MSCs via activation of HIF-1α signaling. Mater Sci Eng C2018;
91: 44–54.
24.
GuoCYangKYanY, et al.
SF-deferoxamine, a bone-seeking angiogenic drug, prevents bone loss in estrogen-deficient mice. Bone2019;
120: 156–165.
25.
RassuGSodduECossuM, et al.
Solid microparticles based on chitosan or methyl-β-cyclodextrin: A first formulative approach to increase the nose-to-brain transport of deferoxamine mesylate. J Control Release2015;
201: 68–77.
26.
UlubayramKKiziltayAYilmazE, et al.
Desferrioxamine release from gelatin-based systems. Biotechnol Appl Biochem2005;
42: 237–245.
27.
YaoQLiuYSelvaratnamB, et al.
Mesoporous silicate nanoparticles/3D nanofibrous scaffold-mediated dual-drug delivery for bone tissue engineering. J Control Release2018;
279: 69–78.
28.
YanYChenHZhangH, et al.
Vascularized 3D printed scaffolds for promoting bone regeneration. Biomaterials2019;
190–191: 97–110.
29.
DonneysAYangQForrestML, et al.
Implantable hyaluronic acid-deferoxamine conjugate prevents nonunions through stimulation of neovascularization. Regen Med2019;
4: 11.
30.
ToliyatTJorjaniMKhorasaniradZ.An extended-release formulation of desferrioxamine for subcutaneous administration. Drug Deliv2009;
16: 416–421.
31.
YouLHWangJLiuTQ, et al.
Targeted brain delivery of rabies virus glycoprotein 29-modified deferoxamine-loaded nanoparticles reverses functional deficits in Parkinsonian mice. ACS Nano2018;
12: 4123–4139.
32.
VigneshSSivashanmugamAMohandasA, et al.
Injectable deferoxamine nanoparticles loaded chitosan-hyaluronic acid coacervate hydrogel for therapeutic angiogenesis. Colloids Surf B Biointerfaces2018;
161: 129–138.
33.
RassuGSalisAPorcuEP, et al.
Composite chitosan/alginate hydrogel for controlled release of deferoxamine: A system to potentially treat iron dysregulation diseases. Carbohyd Polym2016;
136: 1338–1347.
34.
O’NeillHSHerronCCHastingsCL, et al.
A stimuli responsive liposome loaded hydrogel provides flexible on-demand release of therapeutic agents. Acta Biomater2017;
48: 110–119.
35.
WoodruffMAHutmacherDW.The return of a forgotten polymer—Polycaprolactone in the 21st century. Prog Polym Sci2010;
35: 1217–1256.
36.
SinhaVRBansalKKaushikR, et al.
Poly-epsilon-caprolactone microspheres and nanospheres: An overview. Int J Pharm2004;
278: 1–23.
37.
AllenCJ. Polycaprolactone-b-poly(ethylene oxide) copolymer micelles: Physico-chemical characterization and application in drug delivery. Thesis, McGill University, Canada, 1999.
38.
AllenCYuYMaysingerD, et al.
Polycaprolactone-b-poly(ethylene oxide) block copolymer micelles as a novel drug delivery vehicle for neurotrophic agents FK506 and L-685,818. Bioconjugate Chem1998;
9: 564–572.
39.
ChenCCaiGZhangH, et al.
Chitosan-poly(epsilon-caprolactone)-poly(ethylene glycol) graft copolymers: Synthesis, self-assembly, and drug release behavior. J Biomed Mater Res A2011;
96: 116–124.
40.
ZhangYZhuoR-X.Synthesis and in vitro drug release behavior of amphiphilic triblock copolymer nanoparticles based on poly (ethylene glycol) and polycaprolactone. Biomaterials2005;
26: 6736–6742.
41.
AhmedFDischerDE.Self-porating polymersomes of PEG–PLA and PEG–PCL: Hydrolysis-triggered controlled release vesicles. J Control Release2004;
96: 37–53.
42.
LepoittevinBDevalckenaereMPantoustierN, et al.
Poly(ε-caprolactone)/clay nanocomposites prepared by melt intercalation: Mechanical, thermal and rheological properties. Polymer2002;
43: 4017–4023.
43.
ShojaMKamyarSAhmadM, et al.Preparation and characterization of poly (ε- caprolactone)/Tio2 micro-composites. Dig J Nanomater Bios2015:
10(2): 471–477.
44.
Herrera-KaoWALoría-BastarracheaMIPérez-PadillaY, et al.
Thermal degradation of poly(caprolactone), poly(lactic acid), and poly(hydroxybutyrate) studied by TGA/FTIR and other analytical techniques. Polym Bull2018;
75: 4191–4205.
45.
UmemuraMKimJHAoyamaH, et al.
The iron chelating agent, deferoxamine detoxifies Fe(Salen)-induced cytotoxicity. J Pharmacol Sci2017;
134: 203–210.
46.
FuYKaoWJ.Drug release kinetics and transport mechanisms of non-degradable and degradable polymeric delivery systems. Expert Opin Drug Deliv2010;
7: 429–444.
