Characterization of a Cell-Penetrating Peptide with Potential Anticancer Activity

Cell-penetrating peptides (CPPs) are still an interesting and viable alternative for drug delivery applications. CPPs contain considerably high amounts of positively charged amino acids, imparting them with cationic character. Tumor cells are characterized by an enhanced anionic nature of their membrane surface, a property that could be used by CPPs to target these cells. We recently identified a branched CPP that displays a high internalization capacity while exhibiting selectivity for certain tumor cell types. In this study we elucidated this observation in greater detail by investigating the underlying mechanism behind the cellular uptake of this peptide. An additional cytotoxicity screen against several cancer cell lines indeed demonstrates high cytotoxic activity against cancer cells over normal fibroblasts. Furthermore, we show that this feature can be used for delivering the anticancer drug actinomycinD with high efficiency in the MCF-7 cancer cell line

Anticancer Potential of (Pentamethylcyclopentadienyl)chloridoiridium(III) Complexes Bearing kappa P and kappa P,kappa S-Coordinated Ph2PCH2CH2CH2S(O)(x)Ph (x=0-2) Ligands

Iridium(III) complexes of the type {[}Ir(eta(5)-C5Me5)Cl-2\{Ph2PCH2-CH2CH2S(O)(x)Ph-kappa P\}] (x=0-2; 1-3) and {[}Ir(eta(5)-C5Me5)Cl\{Ph2PCH2-CH2CH2S(O)(x)Ph-kappa P,kappa S\}]{[}PF6] (x=0-1; 4 and 5) with 3-(diphenyl-phosphino)propyl phenyl sulfide, sulfoxide, and sulfone ligands Ph2PCH2CH2CH2S(O)(x)Ph were designed, synthesized, and characterized fully, including X-ray diffraction analyses for complexes 3 and 4. In vitro studies against human thyroid carcinoma (8505C), submandibular carcinoma (A253), breast adenocarcinoma (MCF-7), colon adenocarcinoma (SW480), and melano-ma (518A2) cell lines provided evidence for the high biological potential of the neutral and cationic iridium(III) complexes. Neutral iridium(III) complex 5 proved to be the most active, with IC50 values up to about 0.1 mu m, representing activities of up to one order of magnitude higher than cisplatin. Using 8505C cells, apoptosis was shown to be the main mechanism through which complex 5 exerts its tumoricidal action. The described iridium(III) complexes represent potential leads in the search for novel metal-based anticancer agents.Graduiertenforderung des Landes Sachsen-Anhalt (Germany); Ministry of Science and Technological Development of the Republic of Serbia {[}173013

Optimizing the enzymatic release of MMAE from isoDGR-based small molecule drug conjugate by incorporation of a GPLG-PABC enzymatically cleavable linker

Zambra M, Randelovic I, Talarico F, et al. Optimizing the enzymatic release of MMAE from isoDGR-based small molecule drug conjugate by incorporation of a GPLG-PABC enzymatically cleavable linker. Frontiers in Pharmacology . 2023;14: 1215694.Antibody-Drug Conjugates (ADCs) and Small Molecule-Drug Conjugates (SMDCs) represent successful examples of targeted drug-delivery technologies for overcoming unwanted side effects of conventional chemotherapy in cancer treatment. In both strategies, a cytotoxic payload is connected to the tumor homing moiety through a linker that releases the drug inside or in proximity of the tumor cell, and that represents a key component for the final therapeutic effect of the conjugate. Here, we show that the replacement of the Val-Ala-p-aminobenzyloxycarbamate linker with the Gly-Pro-Leu-Gly-p-aminobenzyloxycarbamate (GPLG-PABC) sequence as enzymatically cleavable linker in the SMDC bearing the cyclo[DKP-isoDGR] alphaVbeta3 integrin ligand as tumor homing moiety and the monomethyl auristatin E (MMAE) as cytotoxic payload led to a 4-fold more potent anti-tumoral effect of the final conjugate on different cancer cell lines. In addition, the synthesized conjugate resulted to be significantly more potent than the free MMAE when tested following the "kiss-and-run" protocol, and the relative potency were clearly consistent with the expression of the alphaVbeta3 integrin receptor in the considered cancer cell lines. In vitro enzymatic cleavage tests showed that the GPLG-PABC linker is cleaved by lysosomal enzymes, and that the released drug is observable already after 15min of incubation. Although additional data are needed to fully characterize the releasing capacity of GPLG-PABC linker, our findings are of therapeutic significance since we are introducing an alternative to other well-established enzymatically sensitive peptide sequences that might be used in the future for generating more efficient and less toxic drug delivery systems. Copyright © 2023 Zambra, Randelovic, Talarico, Borbely, Svajda, Tovari, Mezo, Bodero, Colombo, Arrigoni, Fasola, Gazzola and Piarulli