Enhanced nuclear delivery of H1-S6A, F8A peptide by NrTP6-modified polymeric platform

Nucleus is the central regulator of cell metabolism, growth and differentiation, which is considered as an effective target for the treatment of many diseases. To efficiently deliver drugs into nucleus, delivery systems have to bypass a number of barriers especially crossing the cell membrane and nuclear envelope. Here we report a nucleolar targeting peptide (NrTP6) modified polymeric conjugate platform based on N-(2-hydroxypropyl)-methacrylamide (HPMA) copolymers for enhanced nuclear delivery of H1-S6A, F8A peptide to hinder c-Myc from binding to DNA. On one hand, the modification of NrTP6 would promote cellular uptake and nuclear accumulation of the conjugates, and on the other hand, the conjugates can release smaller molecular weight subunits (H1-NrTP6) via cleavage of lysosomally enzyme-sensitive spacer for facilitating nucleus transport. It was found that NrTP6 modified HPMA copolymer-H1 peptide conjugates could improve internalization and nuclear accumulation of H1 peptide by 2.2 and 37.1-fold, respectively, compared to the non-NrTP6 modified ones, in HeLa cells. Moreover, the same trend was found in MDA-MB-231 cells and 4T1 cells. In addition, we found that the nuclear targeting mechanism of NrTP6 peptide mediation may be associated with the importin α/β pathway. Furthermore, the in vivo investigation revealed that NrTP6-modified polymeric platform exhibited the best therapeutic efficacy with a tumor growth inhibition rate of 77.0%. These results indicated that NrTP6 modification was a promising strategy for simultaneously realizing cellular internalization and nuclear targeting, which might provide a new path for intranuclear drug delivery.