Biopharmaceuticals such as nucleic acids, bioactive peptides and proteins are attracting attention as next-generation drugs, however, there are problems to be solved for practical use. Such problems include (i) low cell membrane permeability, (ii) low blood stability and accumulation at the target, and (iii) occurrence of side effects. In this proposal, we aim to develop advanced DDS technology that solves and accelerates the commercialization of biopharmaceuticals. The problem (i) is a common problem of medium-molecular drugs such as nucleic acids and peptides. The lipid nanoparticles (LNPs) consisting cationic lipids have been developed, but the control of pharmacokinetics and avoidance of systemic toxicity are issues to be solved. In this study, we aim to develop smart polymers containing a pH-responsive betaine structure that switches the electric charges from neutral during the blood circulation to cationic in weakly acidic environments in solid tumors, and apply them to realize tumor environment-responsive nanocarriers. The novel nanocarriers are expected to exhibit excellent blood circulation, but achieve intracellular delivery of cargo molecules to cancer cells after reaching the tumor. Regarding the problem (ii), establishment of DDS technology for bioactive proteins, that realize both the systemic delivery and specific activation at the target site, is highly demanded. In this study, we aim to develop pH-responsive polymeric micelles consisting of ternary systems of proteins, polyphenols and block copolymers containing boronic acids. This system might be applicable to the delivery of various proteins and nanoparticles for their in vivo use. With regard to the problem (iii), we aim to develop the polymer-antibody conjugates that do not show antigen recognition during the circulation but restore the ability to recognize antigen in an acidic environment within tumors. By this technology, it is possible to impart an action site specificity to the therapeutic antibodies, and it is expected to avoid their systemic side effects. Thus, based on the design of functional polymers, we establish the advanced DDS technology of biopharmaceuticals that realizes “simple but smart functionalities” which should be important in the practical use.
Figure 1: Challenges in biopharmaceuticals and development of nanoDDS
Figure 2: Smart shell (pH-responsive betaine polymer) that changes from neutral to cationic in response to intratumoral pH (left) and tumor accumulation of quantum dots (QDs) coated with smart shell (right) (smart shell-coated QDs showed >3 times higher tumor accumulation compared with PEG-coated QDs )
Figure 3: Polymeric micelle composed of ternary system of protein / polyphenols / boronic acid-containing block copolymer (PEG-block copolymer interacts with tannic acid (TA) via pH-responsive boronic ester. GFP-encapsulated micelle showed prolonged blood circulation and enhanced tumor accumulation)