Enhancing Veliparib PARP1 inhibitor stability against UVC degradation via DPPG liposome encapsulation

Abstract

Poly(ADP-ribose) polymerase inhibitors (PARPi) are often used in complementary cancer therapy with radiotherapy and chemotherapy, but present some limitations that encapsulation may circumvent. Since conventional PARPi therapy was proven to increase cell sensitization to UV irradiation, and a shower of particles or radiation with energies equal to or below UV can be created during radiotherapy treatments, this work evaluates the effect of UVC on the degradation process and inhibitory capability of Veliparib encapsulated in 1,2-dipalmitoyl-sn-glycero-3-phospho-rac-(1′-glycerol) sodium salt (DPPG) liposomes, as well as identifies potential degradation products. Results demonstrate that Veliparib is sensitive to UVC radiation, leading to the degradation of the benzamide ring and carbonyl functional group. This coincides with Veliparib's inhibitory capability loss in PARP1's automodification activity. Furthermore, DPPG encapsulation was shown to protect Veliparib from UVC irradiation until 30 min of exposure. This was translated into a delay in the appearance of a degradation band at 330 nm. Infrared analysis revealed that this band is associated with the degradation of the benzamide ring and the carbonyl functional group. The latter presents several CO infrared vibrational bands associated with isomerization and degradation of the functional group. The results allowed us to infer the potential degradation process of Veliparib due to UVC irradiation, which is associated with linear unsaturated aldehyde and conjugated ketone structures that arise from the degradation of the benzamide pharmacophore.