A self-assembling conjugate of SN38 with aminoguanidine for simultaneously suppressing proliferation and migration of breast cancer cells

Abstract

As an active metabolite of irinotecan, 7-ethyl-10-hydroxy-camptothecin (SN38) exhibits significantly stronger anticancer activity compared to irinotecan. However, its poor water solubility restricts its clinical use. Moreover, SN38 has only a weak effect on the metastasis of cancer cells. In the present work, a conjugate of SN38 with aminoguanidine was synthesized via a Cu-catalytic azide–alkyne click (CuAAC) reaction. As the sixth compound synthesized via the synthetic route, we here denoted the SN38-aminoguanidine conjugate as compound 6. Compound 6 is self-assembled into nanoparticles due to its amphiphilic structure. The resulting nanoparticles with a dynamic diameter of 134.05 ± 3.31 nm and a ξ of 1.27 ± 0.10 mV were irregular lumps of around 120 nm, as demonstrated by transmission electron microscopy (TEM), and significantly decreased the level of endogenous nitric oxide via inhibition of inducible nitric oxide synthase (iNOS). Compared with irinotecan, compound 6 showed much stronger cytotoxicity toward triple-negative breast cancer MDA-MB-231 cells while lower cytotoxicity against human normal breast epithelial MCF10A cells. More importantly, compound 6 significantly inhibited the migration of MDA-MB-231 cells while irinotecan did little at a dose of 0.5 μM. Once MDA-MB-231 cells were pretreated with a nitric oxide donor, the inhibitory effects of compound 6 on proliferation and migration of MDA-MB-231 cells both decreased, indicating that iNOS played an important role in proliferation and migration of breast cancer cells. In a molecular docking model, compound 6 formed two hydrogen bonds and one π–H interaction with topo1 in a different binding mode from camptothecin and SN38, while no interaction with the DNA of the topo1–DNA complex was observed. The lower docking score of compound 6 (−9.45), in contrast to that of SN38 (−8.82) suggested that topo1 was still an important target through which compound 6 exerted its antitumor activity. These findings indicated that the incorporation of aminoguanidine into SN38 was an effective strategy to simultaneously address the issue of poor water solubility and endow SN38 with antimigratory activity.