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: Shiqi Wang, Flavia Fontana, Mohammad-Ali Shahbazi and Hélder A. Santos. Chem. Commun., 2021, Advance Article. https://doi.org/10.1039/D1CC00811K