Double-PEGylated Cyclopeptidic Photosensitizer Prodrug Improves Drug Uptake from In Vitro to Hen’s Egg Chorioallantoic Membrane Model

Abstract

Cyclopeptidic photosensitizer prodrugs (cPPPs) are compounds designed to specifically target overexpressed hydrolases such as serine proteases, resulting in their specific activation in close proximity to tumor cells. In this study, we explored a series of conjugates that can be selectively activated by the urokinase plasminogen activator (uPA). They differ from each other by their pheophorbide a (Pha) loading, their number of PEG chains and the eventual presence of black hole quenchers (BHQ3). The involvement of a peptidic linker between the drugs and the cyclopeptidic carrier allows specific cleavage by uPA. Restoration of the photophysical activity was observed in vitro on A549 lung and MCF7 breast cancer cells that exhibited an increase in red fluorescence emission up to 5.1-fold and 7.8-fold, respectively for uPA-cPPQ2+2/5. While these cPPP conjugates do not show dark toxicity, they revealed their phototoxic potential in both cell lines at 5 µM of Phaeq and a blue light fluence of 12.7 J/cm2 that resulted in complete cell death with almost all conjugates. This suggests, in addition to the promising use for cancer diagnosis, a use as a PDT agent. Intravenous injection of tetrasubstituted conjugates in fertilized hen eggs bearing a lung cancer nodule (A549) showed that a double PEGylation was favorable for the selective accumulation of the unquenched Pha moieties in the tumor nodules. Indeed, the diPEGylated uPA-cPPP4/52 induced a 5.2-fold increase in fluorescence, while the monoPEGylated uPA-cPPP4/5 or uPA-cPPQ2+2/5 led to a 0.4-fold increase only.

Development of an Antioxidant, Anti-Aging, and Photoprotective Phytocosmetic from Discarded Agave sisalana Perrine Roots

“…The positive control was the only substance that caused any harmful signals to the membrane. This means that the cream-gel with 5% HER is safe and does not damage the membrane, which is consistent with the results of the MTT test, where only the plant extract was analyzed [25][26][27].…”

“…in their characterization of formulations enriched with Camellia sinensis tea extract, state that there are flavonoids such as thearubigins (TRs), theaflavins (TFs), and theobrownins (TBs), among others, assessed in the same methodology [25,[36][37][38]. Andrade et al [39] valuated the hydroalcoholic extract of Bordeaux grape pomace, observing that this extract achieved an SPF of 12.…”