The dense extracellular matrix and high interstitial fluid pressure of tumor tissues prevent the ability of anti-tumor agents to penetrate deep into the tumor parenchyma for treatment effects. C-end rule(CendR) peptid...The dense extracellular matrix and high interstitial fluid pressure of tumor tissues prevent the ability of anti-tumor agents to penetrate deep into the tumor parenchyma for treatment effects. C-end rule(CendR) peptides can enhance the permeability of tumor blood vessels and tumor tissues via binding to neuropilin-1(NRP-1), thus aiding in drug delivery. In this study, we selected one of the CendR peptides(sequence RGERPPR) as the parent L-peptide and substituted D-amino acids for the L-amino acids to synthesize its inverso peptide D(RGERPPR). We investigated the NRP-1 binding activity and tumorpenetrating ability of D(RGERPPR). We found that the binding affinity of D(RGERPPR) with NRP-1 and the cellular uptake was significantly higher than that of RGERPPR. Evans Blue tests revealed that D(RGERPPR) exhibited improved tumor-penetrating ability in C6, U87 and A549 tumor-bearing nude mice. Using nude mice bearing A549 xenograft tumors as a model, we found that the rate of tumor growth in the group co-administered with D(RGERPPR) and gemcitabine(Gem) was significantly lower than the gemcitabine-treated group with a tumor suppression rate(TSR%) of 55.4%. Together, our results demonstrate that D(RGERPPR) is a potential tumor-penetrating peptide.展开更多
基金supported by the National Science Foundation of China (Grant Nos.81473148 and 81690263)the Foundation Program of Key Laboratory of Smart Drug Delivery of the Ministry of Education
文摘The dense extracellular matrix and high interstitial fluid pressure of tumor tissues prevent the ability of anti-tumor agents to penetrate deep into the tumor parenchyma for treatment effects. C-end rule(CendR) peptides can enhance the permeability of tumor blood vessels and tumor tissues via binding to neuropilin-1(NRP-1), thus aiding in drug delivery. In this study, we selected one of the CendR peptides(sequence RGERPPR) as the parent L-peptide and substituted D-amino acids for the L-amino acids to synthesize its inverso peptide D(RGERPPR). We investigated the NRP-1 binding activity and tumorpenetrating ability of D(RGERPPR). We found that the binding affinity of D(RGERPPR) with NRP-1 and the cellular uptake was significantly higher than that of RGERPPR. Evans Blue tests revealed that D(RGERPPR) exhibited improved tumor-penetrating ability in C6, U87 and A549 tumor-bearing nude mice. Using nude mice bearing A549 xenograft tumors as a model, we found that the rate of tumor growth in the group co-administered with D(RGERPPR) and gemcitabine(Gem) was significantly lower than the gemcitabine-treated group with a tumor suppression rate(TSR%) of 55.4%. Together, our results demonstrate that D(RGERPPR) is a potential tumor-penetrating peptide.
