Bioactivity protein has attracted attention as a therapeutic agent of malignant disease, such as cancer due to pharmacological potency. However, since the protein was recognized and engulfed by immune cells as a foreign substance in the blood, the protein exhibited short blood retention. Therefore, the expected pharmacological effects could not be obtained. In this study, we focus on tannic acid (TA) that forms a complex with protein and thus, developed a ternary protein complex utilized TA and boronic acid conjugated-polymer that forms boron ester in water(Fig.1). In the ternary complex, surrounding the core complex between protein and TA are the PEG shell. The ternary complex, with its PEG shell, could reduce protein immunogenicity and prolong blood retention, hence expected to improve tumor accumulation by EPR effect. The ternary complex is expected to be delivered into the cell via endocytosis and release the protein by cleavage of boron ester, which is responsive to low pH in endosome. In this study, we showed both characterization and biodistribution of the ternary complex. We designed boronic acid conjugated polymer, PEG-b-poly(L-lysine)20 (PEG-PLys20) that were modified with 3-fluoro-4-carboxy phenylboronic acid (FPBA), or could also be called, PEG-P[Lys(FPBA)10]20. Using GFP as a model protein, we confirmed the ternary complex and pH-responsiveness by measurement of hydrodynamic diameter using fluorescence correlation spectroscopy(FCS). The result showed that the hydrodynamic diameter of ternary complex was increased compared to GFP and GFP/TA complex in PBS, indicating that the tertiary complex was indeed formed. Meanwhile, the hydrodynamic size of ternary complex decreased to the same size of GFP, as pH decline from 7.4 to 5.5 indicated that the tertiary complex was dissociated in endosome. Finally, we evaluated the biodistribution of the complex in tumor xenografted mouse. The study revealed that the ternary complex showed 10 times higher accumulation in the tumor and longer blood retention compared with GFP. These results thus verified that usefulness of the novel protein delivery system.

Development of intra-tumor-cellular protein delivery system utilizing boronic acid conjugated-polymer and tannic acid

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.