Enzymatically-responsive pro-angiogenic peptide-releasing poly(ethylene glycol) hydrogels promote vascularization in vivo

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• 作者：Amy H. Van Hove^a ; ^{amy.h.vanhove@rochester.edu" class="auth_mail" title="E-mail the corresponding author} ; Kathleen Burke^a ; ^{kathleen_Burke@URMC.Rochester.edu" class="auth_mail" title="E-mail the corresponding author} ; Erin Antonienko^a ; ^{eantonie@u.rochester.edu" class="auth_mail" title="E-mail the corresponding author} ; Edward Brown III^a ; ^b ; ^{Edward_Brown@URMC.Rochester.edu" class="auth_mail" title="E-mail the corresponding author} ; Danielle S.W. Benoit^a ; ^c ; ^d ; ^e ; ^{benoit@bme.rochester.edu" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Angiogenesis ; Enzyme ; Peptide ; Hydrogel ; Controlled drug release
• 刊名：Journal of Controlled Release
• 出版年：2015
• 出版时间：10 November 2015
• 年：2015
• 卷：217
• 期：Complete
• 页码：191-201
• 全文大小：1582 K

文摘

Therapeutic angiogenesis holds great potential for a myriad of tissue engineering and regenerative medicine approaches. While a number of peptides have been identified with pro-angiogenic behaviors, therapeutic efficacy is limited by poor tissue localization and persistence. Therefore, poly(ethylene glycol) hydrogels providing sustained, enzymatically-responsive peptide release were exploited for peptide delivery. Two pro-angiogenic peptide drugs, SPARC₁₁₃ and SPARC₁₁₈, from the Secreted Protein Acidic and Rich in Cysteine, were incorporated into hydrogels as crosslinking peptides flanked by matrix metalloproteinase (MMP) degradable substrates. In vitro testing confirmed peptide drug bioactivity requires sustained delivery. Furthermore, peptides retain bioactivity with residual MMP substrates present after hydrogel release. Incorporation into hydrogels achieved enzymatically-responsive bulk degradation, with peptide release in close agreement with hydrogel mass loss and released peptides retaining bioactivity. Interestingly, SPARC₁₁₃ and SPARC₁₁₈-releasing hydrogels had significantly different degradation time constants in vitro (1.16 and 8.77 × 10^− 2 h^− 1, respectively), despite identical MMP degradable substrates. However, upon subcutaneous implantation, both SPARC₁₁₃ and SPARC₁₁₈ hydrogels exhibited similar degradation constants of ~ 1.45 × 10^− 2 h^− 1, and resulted in significant ~ 1.65-fold increases in angiogenesis in vivo compared to controls. Thus, these hydrogels represent a promising pro-angiogenic approach for applications such as tissue engineering and ischemic tissue disorders.