新型RGD-Su-AP-PD0325901缀合物的抗肿瘤活性研究

Peptide-drug conjugation is one of the most promising strategies for the targeting delivery of anti-cancer drug to specific group of cells to minimize the undesirable side effects and achieve the therapeutic effects with a low dose. The ideal peptide carriers induce receptor-mediated internalization by binding to special receptors which are only or more present on the tumor cell surfaces. In our study, we found that RGD peptide conjugated PD0325901 (MEK1/2 inhibitor) had good anti-tumor growth activity on both U87 and MCF-7 cell lines. Especially on U87 cells which are the αvβ3 integrin-positive tumor cells, the dimer RGD conjugate W10 (RGD2-Su-AP-PD) and PEGylated conjugate W11 (RGD-PEG4-Su-AP-PD) showed better inhibition effect than PD0325901. Comparing with the RGD targeting moiety, W10 (with dimer RGD peptide) exhibited significantly higher activity than W4(RGD-Su-AP-PD), and W4 much higher than non-RGD-conjugated W3. And this ability to inhibit the active ERK pathway by conjugates W4 or W10 was blocked by monoclonal antibody of integrin αvβ3 on U87 cells. Comparing with the monomer RGD conjugate W4, Dimer analog W10 showed more target-specific and higher anti-tumor activity. In peptide-drug conjugates, the linker between targeting cargo and pharmacophore is important for the conjugates to bind with cell membrane receptor and allosteric pocket of MEK kinase. Modifications with PEG have been used to enhance the bioavailability and the pharmacokinetic properties of RGD-MEKI conjugate. With the PEG4 linker, the conjugate W11 showed the highest anti-proliferation activity in conjugates. W11 inhibited the DNA replication as same as parent drug/PD0325901.