Modified dextran, heparin-based triggered release microspheres for cardiovascular delivery of therapeutic drugs using protamine as a stimulus

Abstract

In this study, we describe the synthesis of an amine-modified acetalated dextran polymer, which is combined with heparin (HP) as the basis for a novel controlled release system. Dextran-amine (DEXAM) conjugates, synthesised using reductive amination, were incorporated into DEXAM/HP microspheres. HP binds to positively charged ammonium ions of the DEXAM conjugates, contributing to the structural integrity of the microspheres. Crystal violet (CV) was encapsulated inside DEXAM/HP microspheres as a model drug to test the system. Protamine with a high affinity for HP functioned as a trigger to release CV. DEXAM/HP microspheres were characterised by particle size, encapsulation efficiency, scanning electron microscope images, and in vitro release profile. Release of CV from microspheres varied with primary amine content of DEXAM conjugates, amount of HP, and concentration of protamine added. The system is considered for controlled delivery of agents without the necessity of chemical modification.

Glycosaminoglycan-Inspired Biomaterials for the Development of Bioactive Hydrogel Networks

“…The dextran family comprises branched homopolysaccharides composed of D-glucopyranose units and produced by lactic-acid bacteria. Dextran-GAG combinations are reported for application in vocal fold [201] and cartilage [202] repair and regeneration and drug delivery [203].…”

“…The ability of HEP to interact with positively charged molecules has been explored in a compound release system combining this GAG with a cationic, amine-containing derivative of dextran [203]. In this case, HEP interacted not only with positively charged molecules intended for release but also the vehicle molecules themselves (the cationic dextran derivative) [203].…”

“…The ability of HEP to interact with positively charged molecules has been explored in a compound release system combining this GAG with a cationic, amine-containing derivative of dextran [203]. In this case, HEP interacted not only with positively charged molecules intended for release but also the vehicle molecules themselves (the cationic dextran derivative) [203]. The release profile of microspheres was then evaluated in the presence of protamine, a positively charged protein that inhibits HEP by forming electrostatic complexes with this GAG [203].…”

“…In this case, HEP interacted not only with positively charged molecules intended for release but also the vehicle molecules themselves (the cationic dextran derivative) [203]. The release profile of microspheres was then evaluated in the presence of protamine, a positively charged protein that inhibits HEP by forming electrostatic complexes with this GAG [203]. It was observed that compound release was possible to tune not only by the degree of dextran amination but also the dextran/HEP ratio, with increasing amounts of entrapped HEP leading to higher compound encapsulation efficiency [203].…”

“…The release profile of microspheres was then evaluated in the presence of protamine, a positively charged protein that inhibits HEP by forming electrostatic complexes with this GAG [203]. It was observed that compound release was possible to tune not only by the degree of dextran amination but also the dextran/HEP ratio, with increasing amounts of entrapped HEP leading to higher compound encapsulation efficiency [203]. The presence of protamine induced compound release by competition with dextran/HEP and compound/HEP complexes [203].…”