Atoms construct everything. This fact means that if atoms are connected to form molecules and polymers, and these are successively assembled across multiple hierarchical levels in right way, life emerges. This is theoretically true, but it seems too challenging to reproduce this process using synthetic chemistry. However, it might still be feasible to construct structures that is close to life.

With this hope in mind, we designed primary structures of polymers and assemble them with plasmid DNA to construct a structure looked like virus.1,2 The constructed structure packaged a single DNA molecule inside its capsid-like shell with 100 nm size. The polymer-DNA assembled structure permitted protein production from the packaged DNA when they were applied to cultured cells as well as cancer cells in mice via systemic application. The assembly was subsequently employed to systemically target pancreatic cancer in the BxPC3 subcutaneous mouse model, which exhibits highly developed stromal phenotype that closely recapitulates the tumor microenvironment observed in clinical pancreatic cancer. Substantial gene expression was observed in stromal cells, while it was absent in the cancer cells residing within the stroma,3 revealing that the stromal compartment blocks the access of the 100 nm-sized assembly to the cancer cells. Since the stroma is primarily composed of a network of collagen-based extracellular matrix (ECM), reducing the particle size may enable them to traverse through the gaps within the ECM. To this end, it is necessary to overcome the intrinsic rigidity of DNA, which prevents its packaging into a surface-area-minimizing spherical structure. Thus, double-strand of plasmid DNA was dissociated into single strands to impart flexibility and assembled with polymers.4 This size-minimized structure penetrated the stroma, accessed the tumor cells, induced protein expression, and significantly suppressed tumor growth. Collectively, these results demonstrate that polymer-DNA assemblies can induce gene expression specifically in target cells via systemic administration and thus may serve as potential gene delivery vectors for cancer therapy. More intriguingly, virus-like functionality has emerged within the assembly structure.

Keywords: block copolymer assembly, DNA, non-viral gene vector, pancreatic cancer,

References
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