Sustained Delivery of IL-1Ra from Pluronic F127-Based Thermosensitive Gel Prolongs its Therapeutic Potentials
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Pluronic F-127 (PF127) has previously shown to prolong the sustained release of various proteinous drugs and their serum half-lives. Subsequently, we have extended this approach to look at in vitro release, in vivo efficacy and pharmacokinetics of interleukin-1 receptor antagonist (IL-1Ra).
Various concentrations of PF127 gels were prepared using cold method. In vitro drug release kinetic studies were performed using membraneless dissolution method. Stability of IL-1Ra was assessed by SDS-PAGE. In vivo studies and in vivo bioactivity of IL-1Ra were also performed on wistar rats.
IL-1Ra loaded PF127 gels showed in vitro sustained release of IL-1Ra, depending on the concentration of gel used. SDS-PAGE confirmed the stability of protein during its in vitro release. PF127 gel also exhibited prolonged release of IL-1Ra in rats as compared to that of IL-1Ra aq. solution. In vivo bioactivity of IL-1Ra loaded in gel was confirmed by its ability to inhibit IL-1β-stimulated induction of IL-6.
When compared directly, IL-1Ra loaded PF127 gel exhibited prolonged in vitro and in vivo release, greater efficacy to induce hypoglycemia and inhibited IL-1β-stimulated production of IL-6 as compared to IL-1Ra aq. solution. We believe that this methodology for sustained delivery of IL-1Ra probably be suitable for the convenience of patients to achieve desired therapeutic potentials without exceeding dose limits and frequent administration.
Key WordsAkaike information criterion controlled release interleukin-1 receptor antagonist in vitro study in vivo study pharmacokinetics
Acknowledgments and Disclosures
In vivo results presented here are not efficacy data. They can only be considered as animal-based pharmacokinetic and pharmacodynamic results.
This work was financially supported by the grant (No. 2010C13006) from the Science and Technology Department of Zhejiang Province, China.
We acknowledge the China Scholarship Council to award scholarship for PhD to Muhammad Sajid Hamid Akash and Kanwal Rehman. IL-1Ra was generously provided by Hisun Pharmaceuticals but the company was not involved in the design, conduct and/or analysis of experiments. One of the authors would like to admire his wife Kanwal Rehman for her motivation and support.
- 14.Pichika R, Betre H, Setton LA, An HS, Masuda K. Bioactivity of IL-1 receptor antagonist (IL-1Ra) and a related fusion protein in inhibiting IL-1–mediated effects in human intervertebral disc cells. Trans Orthop Res Soc. 2006;52.Google Scholar
- 16.Shamji MF, Betre H, Kraus VB, Chen J, Chilkoti A, Pichika R, et al. Development and characterization of a fusion protein between thermally responsive elastin-like polypeptide and interleukin-1 receptor antagonist: sustained release of a local anti-inflammatory therapeutic. Arthritis Rheum. 2007;56:3650–61.PubMedCrossRefGoogle Scholar
- 18.Dai SF, Shen Q, Chen S. Inhomogeneous expression of fusion protein HSA/IL-1Ra pichia pastoris. J Zhejiang Univ (Medical Sci). 2008;37:134–8.Google Scholar
- 19.Jun JB, Kim JK, Kim TH, Na Y, Choi CH, Kim YH. Inhibition of the IL-1β-induced expression of matrix metalloproteinases by controlled release of IL-1 receptor antagonist using injectable and thermo-reversible gels in human osteoarthritis chondrocytes. J Rheum Dis. 2011;18:85–93.CrossRefGoogle Scholar
- 32.Khan SA, Ahmad M, Murtaza G, Shehnaz G, Aamir MN, Rasool F. Design of nimesulide-chitosan microparticles by pH change coacervation. Lat Am J Pharmacy. 2011;30:1260–6.Google Scholar
- 35.Wannachaiyasit S, Phaechamud T. Development of chlorhexidine thermosensitive gels as a mouth antiseptic. J Metals Mater Miner. 2010;20:165–8.Google Scholar
- 36.Nie S, Hsiao WW, Pan W, Yang Z. Thermosensitive pluronic® F127-based hydrogel containing liposomes for the controlled delivery of paclitaxel: in vitro drug release, cell cytotoxicity, and uptake studies. Int J Nanomed. 2011;6:151–61.Google Scholar
- 43.Akash MSH, Rehman K, Rasool F, Sethi A, Abrar MA, Irshad A, et al. Alternate therapy of Type 2 diabetes mellitus (T2DM) with Nigella (Ranunculaceae). J Med Plants Res. 2011;5:6885–9.Google Scholar
- 46.Banerjee PS, Hosny EA, Robinson JR. Parenteral delivery of peptides and protein drugs. In: Lee VHL, editor. Peptide and protein drug delivery. New York: Marcel Dekker; 1991. p. 487–543.Google Scholar
- 49.McIntyre KW, Stepan GJ, Kolinsky KD, Benjamin WR, Plocinski JM, Kaffka KL, et al. Inhibition of interleukin 1 (IL-1) binding and bioactivity in vitro and modulation of acute inflammation in vivo by IL-1 receptor antagonist and anti-IL-1 receptor monoclonal antibody. J Exp Med. 1991;173:931–9.PubMedCrossRefGoogle Scholar