Evaluation of hyaluronic acid–protein conjugates for polymer masked–unmasked protein therapy

详细信息    查看全文

• 作者：Elaine L. Ferguson ; Alshame M.J. Alshame ; David W. Thomas
• 关键词：Polymer therapeutics ; Hyaluronic acid ; Bioresponsive ; Nanomedicines ; PUMPT
• 刊名：International Journal of Pharmaceutics
• 出版年：2010
• 出版时间：15 December 2010
• 年：2010
• 卷：402
• 期：1-2
• 页码：95-102
• 全文大小：1000 K

文摘

Bioresponsive polymers may effectively be utilized to enhance the circulation time and stability of biologically active proteins and peptides, while reducing their immunogenicity and toxicity. Recently, dextrin-epidermal growth factor (EGF) conjugates, which make use of the Polymer-masked UnMasked Protein Therapy (PUMPT) concept, have been developed and shown potential as modulators of impaired wound healing. This study investigated the potential of PUMPT using hyaluronic acid (HA) conjugates to mask activity and enhance protein stability, while allowing restoration of biological activity following triggered degradation. HA fragments (Mw 90,000 g/mol), obtained by acid hydrolysis of Rooster comb HA, were conjugated to trypsin as a model enzyme or to EGF as a model growth factor. Conjugates contained 2.45 and 0.98 % (w/w) trypsin or EGF, respectively, and contained <5 % free protein. HA conjugation did not significantly alter trypsin's activity. However, incubation of the conjugate with physiological concentrations of HAase increased its activity to 145 % (p < 0.001) that of the free enzyme. In contrast, when HA–EGF conjugates were tested in vitro, no effect on cell proliferation was seen, even in the presence of HAase. HA conjugates did not display typical masking/unmasking behavior, HA–trypsin conjugates exhibited 52 % greater stability in the presence of elastase, compared to free trypsin, demonstrating the potential of HA conjugates for further development as modulators of tissue repair.