Acetalated dextran based nano- and microparticles: synthesis, fabrication, and therapeutic applications
Acetalated dextran (Ac-DEX) is a pH-responsive dextran derivative polymer. Prepared by a simple acetalation reaction, Ac-DEX has tunable acid-triggered release profile. Despite its relatively short research history, Ac-DEX has shown great potential in various therapeutic applications. Furthermore, the recent functionalization of Ac-DEX makes versatile derivatives with additional properties.
Herein, we summarize the cutting-edge development of Ac-DEX and related polymers. Specifically, we focus on the chemical synthesis, nano- and micro-particle fabrication techniques, the controlled-release mechanisms, and the rational design Ac-DEX-based of drug delivery systems in various biomedical applications. Finally, we briefly discuss the challenges and future perspectives in the field.
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Introduction
Dextran is a family of natural polysaccharides produced from microbial origins.1 Depending on its origin, dextran has main chains consisting of α-1,6-glucosidic linkages with different lengths and different ratios of branches via 1,3 linkages.2 Dextran is well-known for its biocompatibility and biodegradability, and has been used since the 1940s as a blood volume expander administrated intravenously.3 Recent studies have further explored its potential for drug delivery applications by chemical conjugation and functionalization, which enable dextran to have desirable physicochemical properties and stimuli-responsiveness for controlled drug release behaviour.4–7
Acetalated dextran (Ac-DEX) is one of the most investigated dextran derivatives. It was first reported by Bachelder et al. in 2008,8 synthesized by a simple one-step reaction, between dextran and 2-methoxypropene, catalysed by pyridinium p-toluenesulfonate (PPTS). After acetalation of pendant hydroxyl groups on dextran, the resulted polymer (Ac-DEX) becomes insoluble in water, but soluble in organic solvents such as ethanol, ethyl acetate, and dichloromethane.8 Furthermore, these acetal groups are prone to acidic hydrolysis, which recovers dextran with methanol and acetone as degradation products.8 The hydrophobicity and solubility in organic solvents makes Ac-DEX favourable for drug encapsulation by both precipitation and emulsion techniques, and the acid-triggered degradation makes it possible to release the drug in specific acidified conditions, such as endosomal compartments, tumour microenvironment and inflamed area.9
As a result of its relatively simple preparation, fabrication and controllable degradation, the past decade has witnessed a growing interest in Ac-DEX-based drug delivery systems with a considerable amount of literature published every year. For example, there is a review about Ac-DEX by Bachelder et al. in 2016,10 focusing on the original development of this polymer and its applications especially in vaccine delivery.
In this feature article, we summarize the state-of-the-art progress in this field, and provide a systematic and comprehensive analysis of Ac-DEX, including polymer synthesis, nano- and micro-particles fabrication, controlled release behaviour and therapeutic applications. Especially, we highlight the development of new Ac-DEX derivatives, the fabrication of complex Ac-DEX composite particles using microfluidic techniques, and the emerging therapeutic applications by Ac-DEX based nano- and micro-particles. In the end, we briefly summarize the current challenges in the field, and provide critical insights into the future developments.
Article information: Chem. Commun., 2021, Advance Article. https://doi.org/10.1039/D1CC00811K