Pancreatic ductal adenocarcinoma (PDAC) is the most common type of pancreatic cancer, and is among the most aggressive and still incurable cancers. Innovative and successful therapeutic strategies are extremely needed. Peptides represent a versatile and promising tool to achieve tumor targeting, thanks to their ability to recognize specific target proteins (over)expressed on the surface of cancer cells. A7R is one such peptide, binding neuropilin-1 (NRP-1) and VEGFR2. Since PDAC expresses these receptors, the aim of this study was to test if A7R-drug conjugates could represent a PDAC-targeting strategy. PAPTP, a promising mitochondria-targeted anticancer compound, was selected as the cargo for this proof-of-concept study. Derivatives were designed as prodrugs, using a bioreversible linker to connect PAPTP to the peptide. Both the retro-inverso (DA7R) and the head-to-tail cyclic (cA7R) protease-resistant analogs of A7R were tested, and a tetraethylene glycol chain was introduced to improve solubility. Uptake of a fluorescent DA7R conjugate, as well as of the PAPTP-DA7R derivative into PDAC cell lines was found to be related to the expression levels of NRP-1 and VEGFR2. Conjugation of DA7R to therapeutically active compounds or nanovehicles might allow PDAC-targeted drug delivery, improving the efficacy of the therapy and reducing off-target effects.

Pterostilbene (Pt) is a natural phenol found in blueberries and grapes; it shows remarkable biomedical activities similar to those of resveratrol, but its higher bioavailability is a major advantage for possible biomedical applications. Our group has recently demonstrated that long-term (30 weeks) administration of Pt to mice maintained on a high-fat diet counters weight gain and promotes browning of subcutaneous white adipose tissue (sWAT). By Real-time quantitative PCR and Western Blot analysis of the sWAT and visceral white adipose tissue (vWAT) from the same mice used in the previous study, we show here that Pt induced a long-term increase of Adiponectin, Interleukin 10 and of M2 macrophage marker Cd206. The effects were observed in sWAT, while no significant changes were detected in vWAT. The process taking place seems to mimic that occurring in sWAT during cold-induced browning. Analysis of a few pro-inflammatory cytokines (Interleukin 6, Tumor necrosis factor α) and of the NFkB pathway did not reveal marked effects of Pt supplementation. In summary, the mechanisms and processes through which Pt acts in adipose tissue appear to closely mimic those set in motion by cold-induced browning, and point to a possible impact of experimental conditions in the final output of a nutraceutical intervention.