Acid-Sensitive Silylated or Acetalated Polysaccharides for Vaccine Applications

Acid-degradable polymers are well-suited for use as drug delivery vehicles because numerous physiological sites (e.g., intracellular endocytic pathway) are acidic. In particular, our work has concluded that acid-sensitive polymers are advantageous for vaccine and other immune modulatory therapies because once phagocytosed by immune cells, the low pH environment of the phagosome leads to triggered release of the encapsulated cargo. Here we report the synthesis of acid-sensitive silylated or acetalated polysaccharides derived from either dextran or inulin. For the silyl chemistry, various alkyl substitutions on the silicon center were performed, including trimethylsilyl dextran (TMS-DEX), ethyldimethylsilyl dextran (EDMS-DEX), and triethylsilyl dextran (TES-DEX) on dextran. Because dextran and acetalated dextran are not inherently immunogenic, we chemically modified a naturally-occurring, immunostimulatory polysaccharide, inulin, to produce tunable, acid-sensitive biopolymers acetalated inulin (Ace-IN) and trimethylsilyl inulin (TMS-IN). These polymers were then fabricated into microparticles (MPs) via emulsification followed by solvent evaporation. Our data indicates the MPs are stable at extracellular pH 7.4 and display a wide range of degradation half-lives (fifteen minutes to greater than nine days) when exposed to acidic pHs of 2.0 and 5.0. The half-lives are dependent on the extent of silylation/acetalation and steric crowding on the silicon center (trimethyl to ethyldimethyl to triethyl). Silyl-DEX Ace-IN, and Silyl-IN MPs exhibit cytocompatibility when cultured with macrophages. TES-DEX, Ace-IN, and TMS-IN MPs, composed of highly hydrophobic moieties or the parent immunostimulatory inulin, elicited substantial in vitro production of tumor necrosis factor alpha (TNF-α), a cytokine associated with an innate immune response. In vivo immunization with a model ovalbumin antigen encapsulated in silylated or acetalated polysaccharide MPs, without a separate adjuvant, results in a dual humoral and cellular response that is superior to an alum-adjuvanted formulation. Overall, we present Silyl-DEX, Silyl-IN, and Ace-IN as members of the acid-degradable polymer family for potential use in subunit vaccines and other drug delivery applications.