Balancing Biocompatibility, Internalization and Pharmacokinetics of Polycations/siRNA by Structuring the Weak Negative Charged Ternary Complexes with Hyaluronic Acid

Polycations are generally used to work as delivery vector to develop siRNA-based therapy for gene-related diseases. The contradiction between inevitable toxicity, internalization, and pharmacokinetics of polycations/siRNA is a critical challenge for polycations and impedes their further application. Herein, we synthesized the ECMD polycations and constructed ECMD/siRNA/HA complexes with slight negative charge to address the above mentioned issue. We found that equipping with HA could effectively shield the positive charge and dramatically improve cell viability. Moreover, the ternary complexes with slight negative charge exhibited similar cellular uptake efficiency and knockdown efficiency compared with ECMD/siRNA binary complexes because of CD44 protein-mediated endocytosis. Pharmacokinetics experiment and in vivo distribution elucidated that the ternary complexes with negative charge could help to prolong the circulation time of siRNA in blood and affect the organs distribution after i.v. injection. In addition, with time going by, the accumulation amount of siRNA loaded by the ternary complexes was much more in tumor compared with the binary complexes. Therefore, we believed that building the complexes was a feasible method to further develop polycationic vectors for siRNA delivery.