Synthesis and Characterization of Acetalated Dextran Polymer and Microparticles with Ethanol as a Degradation Product

Abstract

In the field of drug delivery, pH-sensitive polymeric microparticles can be used to release therapeutic payloads slowly in extracellular conditions (pH 7.4) and faster in more acidic areas in vivo, such as sites of inflammation, tumors, or intracellular conditions. Our group currently uses and is further developing the pH-sensitive polymer acetalated dextran (Ac-DEX), which is a biodegradable polymer with highly tunable degradation kinetics. Ac-DEX has displayed enhanced delivery of vaccine and drug components to immune and other cells, making it an extremely desirable polymer for immune applications. Currently, one of the degradation products of Ac-DEX is methanol, which may cause toxicity issues if applied at high concentrations with repeated doses. Therefore, in this manuscript we report the first synthesis and characterization of an Ac-DEX analog which, instead of a methanol degradation product, has a much safer ethanol degradation product. We abbreviate this ethoxy acetal derivatized acetalated dextran polymer as Ace-DEX, with the 'e' to indicate an ethanol degradation product. Like Ac-DEX, Ace-DEX microparticles have tunable degradation rates at pH 5 (intracellular). These rates range from hours to several days and are controlled simply by reaction time. Ace-DEX microparticles also show minimal cytotoxicity compared to commonly used poly(lactic-co-glycolic acid) (PLGA) microparticles when incubated with macrophages. This study aims to enhance the biocompatibility of acetalated dextran-type polymers to allow their use in high volume clinical applications such as multiple dosing and tissue engineering.

Host-mediated Leishmania donovani treatment using AR-12 encapsulated in acetalated dextran microparticles

“…By extending the reaction time of Ace-DEX, the polymer resists hydrolytic cleavage longer and a more sustained polymer degradation is observed allowing for a large degree of tunability. In the phagosomal compartments, Ace-DEX can have degradation half-lives of minutes to hours allowing for quick intracellular delivery of therapeutics whereas degradation half-lives in pH neutral environments can range from days to weeks (Broaders et al, 2009; Kauffman et al, 2012). PCL and PLGA have much longer degradation half-lives and drug release has been noted to take place over 13 days post phagocytosis (Kalluru et al, 2013).…”

Acetalated dextran encapsulated AR-12 as a host-directed therapy to control Salmonella infection

“…To increase the intracellular concentration of AR-12, we have encapsulated it into a microparticulate carrier comprised of the novel biodegradable polymer acetalated dextran (Ace-DEX) (Bachelder et al, 2008a; Broaders et al, 2009a; Kauffman et al, 2012a). Ace-DEX is unique among other commonly used biodegradable polymers, including polyesters such as poly(lactic-co-glycolic acid) (PLGA) and polycaprolactone (PCL), because it creates pH neutral degradation products of dextran and extremely low levels of both ethanol and acetone, a metabolic product.…”

Sustained Delivery of Doxorubicin via Acetalated Dextran Scaffold Prevents Glioblastoma Recurrence after Surgical Resection

“…32, 33 This reaction generates acyclic and cyclic acetals on the pendent hydroxyl groups of dextran in a time-dependent manner. 34–36 The ratio between cyclic and acyclic acetals can be changed based on the length of reaction time. 34–36 Under aqueous conditions, acetal groups are hydrolyzed, revealing the parent hydroxyl groups of dextran and resulting in Ace-DEX degradation.…”

“…34–36 The ratio between cyclic and acyclic acetals can be changed based on the length of reaction time. 34–36 Under aqueous conditions, acetal groups are hydrolyzed, revealing the parent hydroxyl groups of dextran and resulting in Ace-DEX degradation. Since cyclic acetals are significantly more stable to hydrolysis than acyclic acetals, the time-dependent nature of acetal coverage allows for tight control of Ace-DEX degradation rate.…”