Formulation of In Situ Chemically Cross-Linked Hydrogel Depots for Protein Release: From the Blob Model Perspective

Abstract

The fast release rate and the undesirable covalent binding are two major problems often encountered in formulating in situ chemically cross-linked hydrogel as protein release depot, particularly when prolonged release over months is desirable. In this study, we applied the De Gennes' blob theory to analyze and tackle these two problems using a vinylsulfone-thiol (VS-SH) reaction based in situ hydrogel system. We showed that the simple scaling relation ξb ≈ Rg(c/c*)(-v/(3v-1)) is applicable to the in situ hydrogel and the mesh size estimated from the precursor polymer parameters is a reasonable match to experimental results. On the other hand, as predicted by the theory and confirmed by experiments, the drug diffusion within hydrogel depends mainly on polymer concentration but not the degree of modification (DM). The covalent binding was found to be caused by the mismatch of location between the reactive groups and the entanglement points. The mismatch and, thus, the protein binding were minimized by increasing the DM and concentration of the SH polymer relative to the VS polymer, as predicted by theory. Using these principles, an in situ hydrogel system for the controlled release of an antiangiogenic antibody therapeutics bevacizumab for 3 months was developed.

Injectable Chemically Crosslinked Hydrogel for the Controlled Release of Bevacizumab in Vitreous: A 6-Month In Vivo Study

“…5,11 Briefly, HA-VS of 20% DM was made by reacting with 1.253 (DVS:OH) molar excess of DVS with HA at 0.1 M NaOH for 2 minutes 45 seconds and stopped by neutralizing with HCl. After purification with tangential flow filtration (TFF, mPES MidiKros TFF Filter, NMWL ¼ 3 kDa, D02-E003-05-N, Spectrum Laboratory, Inc., CA), the polymers were adjusted to pH 5.2, sterilized by filtering through a 0.…”

“…The adjustable network structure can be used to control the drug release at a desirable rate. 5 Chemical crosslinking from polymer-polymer reaction also allows the choice of a wide range of biocompatible and degradable polymer. In recent years, this type of hydrogel has been approved for clinical use in various applications including cardiovascular diseases and lung diseases.…”

“…6 Previously, we have developed a simple model to predict hydrogel properties from the precursor polymer properties. 5 Using this model as a guideline, we have designed a hyaluronic acid (HA)/dextranbased in situ gel system for the controlled release of bevacizumab. 5 This system is composed of vinylsulfone functionalized HA (HA-VS) and thiolated dextran (Dex-SH).…”

“…5 Using this model as a guideline, we have designed a hyaluronic acid (HA)/dextranbased in situ gel system for the controlled release of bevacizumab. 5 This system is composed of vinylsulfone functionalized HA (HA-VS) and thiolated dextran (Dex-SH). HA was chosen as one of the main components because of its degradability in the eye.…”

“…By controlling the concentration and degree of modification (DM) of these two polymers, we were able to construct a transparent hydrogel to release bevacizumab for at least 3 months. 5 In this study, the cyto and in vivo biocompatibility of this gel, as well as the in vivo release of gelformulated bevacizumab after intravitreal injection to rabbits, were evaluated.…”