Two new Drug Delivery Systems (DDS) cyclo[DKP‐isoDGR]‐PEG‐4‐Val‐Ala‐PTX (2) and cyclo[DKP‐isoDGR]‐PEG‐4‐sC18‐Val‐Ala‐PTX (3), containing the cyclo[DKP‐isoDGR] integrin ligand and the cytotoxic agent Paclitaxel (PTX), were synthesized to investigate the influence of a PEG‐4 chain and of the sC18 cell‐penetrating peptide (CPP) on the cellular uptake and the cytotoxicity of the constructs. A “double click‐reaction strategy” was planned, to realize the connection of cyclo[DKP‐isoDGR] and PTX to the CPP moiety. Anti‐proliferative bioassays were performed on the αVβ3‐positive U87 human glioblastoma cell line using a short contact time (15 min) followed by draining, washing of the cells, and re‐incubation for 72 h. Compound 3 was significantly more potent (IC50=27.6 μM) than compound 2 (IC50>100 μM), and showed a reduced potency loss with respect to PTX (IC50=71 nM).
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] αVβ3 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 αVβ3 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 15 min 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.
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