Degradation of acetalated dextran can be broadly tuned based on cyclic acetal coverage and molecular weight

Abstract

Microparticles (MPs) derived from acid-sensitive biopolymers enable rapid degradation and cargo release under acidic conditions, such as at tumor microenvironments, within lysosomal/phagosomal compartments inside phagocytic cells, or at sites of inflammation. One such acid-sensitive biopolymer, acetalated dextran (Ace-DEX), has tunable degradation rates and pH-neutral degradation byproducts consisting of dextran, acetone, and ethanol. By studying the degradation profiles of Ace-DEX MPs with varying cyclic acetal coverage (CAC) and dextran molecular weight (MW), we concluded that MPs composed of low CAC or high MW polymer degraded the fastest at both pH 7.4 and 5.0. To further understand the properties of this unique polymer, we encapsulated a model drug resiquimod, which is a toll-like receptor (TLR) 7/8 agonist, into Ace-DEX MPs of different polymer CAC and dextran MW. It was observed that resiquimod was released faster from MPs of lower CAC or higher MW. By evaluating the activation of RAW macrophages cultured with different types of resiquimod-loaded Ace-DEX MPs, we found that MPs of lower CAC or higher MW promoted greater nitrite production and resulted in more robust cell activation. Our results indicate we can precisely control the degradation profile, release kinetics, and bioactivity of encapsulated cargos by altering CAC and MW, furthering Ace-DEX MPs' novelty as a drug carrier.

Carbohydrate Conjugates in Vaccine Developments

“…A great advantage of Ac-Dex over traditional PLGA is the ease in tuning rate of degradation, providing the possibility to optimize the payload releasing rate for a specific application (Broaders et al, 2009;Chen et al, 2016). During the acetal modification, two types of acetal, cyclic acetal which hydrolyzes more slowly and acyclic acetal with faster degradation rates, would be formed on dextran (Scheme 5).…”

“…Half-life of degradation correlated well with cyclic acetal content, which indicated the hydrolysis of cyclic acetal may be the rate-limiting step in particle degradation. The molecular weight of dextran also influenced the degradation of particles (Chen et al, 2016). With similar cyclic acetal coverage, the Ac-Dex with higher molecular weight degraded faster.…”

Vaccines for the Prevention of Melioidosis and Glanders

“…Vaccine carriers composed of poly-(lactide-co-glycolide) (PLGA) have been extensively characterized in animal models and are currently being evaluated in Phase I clinical trials (Selecta); however, they have not been utilized for vaccines against Burkholderia [66]. Our group utilizes the acid sensitive biopolymer, acetalated dextran (Ac-DEX), because it is immunologically inert, has triggered release in the low pH environments of the phagosome and lysosome, and can be formulated with tunable degradation for formation of a vaccine depot [67–70]. Ac-DEX MPs have been previously shown to enhance cross-presentation of subunit antigens leading to protection in an anthrax vaccine model [71, 72].…”

A pH-Responsive Multifunctional Nanocarrier in the Application of Chemo-Photodynamic Therapy

“…In consideration of biocompatibility and biodegradation, natural materials like polysaccharides and proteins are optimal choices to fabricate all kinds of carriers on account of natural biodegradation and excellent biocompatibility [19][20][21][22][23][24][25][26]. Therefore, pH-sensitive natural polysaccharides have been designed and synthesized through reversible acetylation, which also endow materialhydrophobic groups [27][28][29][30][31][32][33]. The hydrophilic-lipophilic characteristic of polysaccharides is simultaneously altered by acetylation, which benefits the O/W emulsion method for nanoparticle fabrication.…”

“…The hydrophilic-lipophilic characteristic of polysaccharides is simultaneously altered by acetylation, which benefits the O/W emulsion method for nanoparticle fabrication. The pH response property of acetylated materials is attributed to the transition of undissolvable hydrophobic acetal groups to dissolvable hydrophilic hydroxy groups in pH 5.5 aqueous solution [27][28][29][30][31][32][33]. In our previous work, pH-sensitive β-cyclodextrin (β-CD) was synthesized and investigated concerning the effects of reaction condition on pH responsiveness and stability [33].…”