CALCIUM-ALGINATE BEADS FOR THE ORAL DELIVERY OF TRANSFORMING GROWTH FACTOR-BETA(1) (TGF-BETA(1)) - STABILIZATION OF TGF-BETA(1) BY THE ADDITION OF POLYACRYLIC-ACID WITHIN ACID-TREATED BEADS

The susceptibility of the gastrointestinal tract to the toxic effects of chemotherapeutic drugs remains a complication in chemotherapy. Rece nt studies have suggested that transforming growth factor-beta1 (TGF-b eta1) can be used as a cytoprotectant against cell cycle specific drug s. This work describes the use of alginate beads as a potential oral d elivery system for TGF-beta1 designed to release the drug in the lumen of the small intestine. TGF-beta1 encapsulation and extent of release from alginate beads approached 100% as determined by I-125-labelled T GF-beta1. However, when assayed by ELISA and a growth inhibition assay , nearly all immunoreactivity and bioactivity was lost, apparently due to a very high affinity of the alginate for TGF-beta1. This limitatio n was overcome by two novel methods: (1) incorporation of selected pol yanions within the alginate beads to 'shield' TGF-beta1 from interacti on with alginate and (2) exposure of the alginate beads containing TGF -beta1 to 0.1 N Ha (acid treatment) to simultaneously reduce the molec ular weight of the alginate and its ability to interact with TGF-beta1 . If the beads were only acid treated, just 8% of the immunoreactivity of TGF-beta1 was retained. If polyacrylic acid (90 kDa) was added to the beads, 50% of the immunoreactivity of TGF-beta1 was retained. Howe ver, when TGF-beta1 was released from acid-treated beads also containi ng polyacrylic acid, more than 80% of the TGF-beta1 remained immunorea ctive and bioactive. The retained TGF-beta1 activity after release fro m the beads was found to continue to increase with increasing concentr ations of polyacrylic acid, until a concentration was reached where be ads would not form. The dramatic increase in retained TGF-beta1 activi ty is attributed to the ability of polyacrylic acid to shield TGF-beta 1 from interaction with lower molecular fragments of alginate.