Transforming growth factor β-3 crystals as reservoirs for slow release of active TGF-β3

Transforming growth factor betas (TGF-betas) play critical roles in many diseased states and injury repair processes. Exogenous delivery of TGF-beta may thus have therapeutic applications. Here, crystals of TGF-beta3 (TGF-beta3) are being evaluated as protected reservoirs for sustained local release. A sensitive Mv1Lu cell growth inhibition assay established that in vitro, active TGF-beta3 can be delivered from physically stable crystals. Non-sink release experiments revealed that crystal solubility at pH 7.4 was higher in cell culture medium (2.7+/-0.1 mug/ml) than in saline buffers (similar to1-1.5 mug/ml, P<0.05). Addition of serum induced a five-fold delay in equilibration of soluble-crystal TGF-beta 3. Semi-sink experiments cumulated in higher TGF-beta 3 release than under non-sink conditions; the observed steady states correlated with crystal solubility and the frequency of buffer exchange. Release of TGF-beta 3 from crystals was also strongly dependent on solubility changes as affected by pH. At neutral pH the solubilities were the lowest, and increased with both higher and lower pH. The results indicate that TGF-beta 3 crystals may have promising features for local pH-triggered sustained-release applications. (C) 2002 Elsevier Science B.V. All rights reserved.