Polymeric
prodrugs are of immense interest as anticancer drug-delivery system owing to their superior
drug stability during circulation and satisfactory
drug loading capacity. However, they are usually less effective than free drugs due to imperfect degradable characteristics or active sites blockage. A polymeric
prodrug (HPAA-MTX) with chemotherapeutic self-sensibilization effect consisting of
glutathione (GSH)-triggered hyperbranched poly(amido
amine) (HPAA) and
methotrexate (MTX) was designed and synthesized in this work. This
prodrug not only showed better inhibition effect on the
tumor cells proliferation compared with free MTX, but also displayed selective sensibilization to
tumor cells rather than normal cells. Meanwhile, HPAA-MTX was also explored as a MMP-9
shRNA plasmid delivery vector due to their rich amino group of HPAA, accompanying with MTX for simultaneous inhibiting
tumor cells proliferation and migration. As expected, HPAA-MTX possessed excellent gene delivery capacity with significant down-regulation expression of MMP-9
protein and further inhibition of MCF-7 cells migration. Benefiting from the self-sensibilization effect and MTX/
MMP-9 co-delivery strategy, this HPAA-MTX/
MMP-9 co-delivery system exhibited significantly improved therapeutic efficacy to
breast cancer in a combined manner which was confirmed through in vitro and in vivo assays. The strategy established in this study provided a facile "all-in-one" platform to integrate the
drug/gene co-delivery strategy and self-sensibilization effect into one single nanocomposite for potential
cancer treatment.
STATEMENT OF SIGNIFICANCE: A cationic polymeric
prodrug with chemotherapeutic self-sensibilization effect was designed and showed better inhibition effect on
tumor cells proliferation compared with its free
drug, as well displayed the selective sensibilization effect to
tumor cells rather than normal cells. Moreover, the
prodrug could also deliver MMP-9
shRNA plasmid for a combined
therapy. As expected, the
prodrug possessed excellent gene delivery capacity with significant down-regulation expression of MMP-9
protein and further inhibition of MCF-7 cells migration. Benefiting from the self-sensibilization effect and the
drug/gene co-delivery strategy, this
prodrug exhibited significantly improved therapeutic efficacy to
breast cancer in a combined manner.