Synthesis Of Poly(Acyclic Orthoesters): Acid-Sensitive Biomaterials For Enhancing Immune Responses Of Protein Vaccine

Poly(orthoesters)are acid-sensitive,surface eroded,degradable polymers that have important applications in the fields of drug delivery and biomaterials.In the past few decades,Professor Jorge Heller has developed four generations of poly(orthoesters),all of which are cyclic orthoesters.The fourth-generation poly(orthoesters)has recently been successfully used in the development of clinically approved sustained-release preparations.Poly(acyclic orthoesters)(PAOEs),which are more acid-sensitive than traditional poly(cyclic orthoesters)and rapidly degraded at lysosomal p H,have great potential for improving cytosolic delivery of membrane-impermeable biopharmaceuticals and are highly desirable.However,their application is significantly hindered by a lack of facile synthetic method.Here we report a simple method for synthesizing PAOEs.With the help of a cationic lipid,ovalbumin,a model vaccine antigen,was efficiently loaded into nanoparticles of PAOEs using a double emulsion method.These nanoparticles efficiently delivered ovalbumin into the cytosol of dendritic cells in vivo and in vitro and demonstrated enhanced antigen presentation over PLGA nanoparticles.In the first part of the work,we report the synthesis of acyclic diketene acetals(a DKAs)from ethyl vinyl ether and diols,and their use to synthesize PAOEs by acid-catalyzed addition polymerization of a diol and a DKA.The hydrolysis kinetics of PAOEs nanoparticles(～250 nm)were studied by NMR.The results show that all PAOEs have excellent acid sensitivity and half-life of PAOEs at p H 5.0 is less than 0.5h,the degree of hydrolysis of PAOEs at p H 7.4 after 24 h is only a dozen percent.In summary,in terms of drug delivery and biomaterials,PAOEs can be rapidly degraded in a lysosomal environment and have great potential to improve the delivery efficiency of biopharmaceutical in the cytoplasm.The second part of the work is about designing a vaccine delivery system(PAOE NPs)based on new acid-sensitive biodegradable materials PAOEs,that is,OVA was loaded into PAOEs to form nanoparticles by a double emulsion method.In vitro,PAOE NPs can be efficiently taken up by dendritic cells and then can quickly escape from the lysosomal compartment to enhance an effective immune response with the help of a cationic lipid.In vivo,after subcutaneous immunization with nanovaccine,PAOE NPs can be captured by antigen-presenting cells and transported to nearby draining lymph nodes,which can interact with immune cells and promote dendritic cell maturation.Moreover PAOE NPs also can promote differentiation spleen cells into OVA-specific CD8~+and secretion of cytokines.PAOEs are promising vehicles for intracellular delivery of biopharmaceuticals and could increase the utility of poly(orthoesters)in biomedical research.