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

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] αVß3 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 αVß3 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.

Assessing the orbital selective Mott transition with variational wave functions.

We study the Mott metal-insulator transition in the two-band Hubbard model with different hopping amplitudes t1 and t2 for the two orbitals on the two-dimensional square lattice by using non-magnetic variational wave functions, similarly to what has been considered in the limit of infinite dimensions by dynamical mean-field theory. We work out the phase diagram at half filling (i.e. two electrons per site) as a function of R = t2/t1 and the on-site Coulomb repulsion U, for two values of the Hund's coupling J = 0 and J/U = 0.1. Our results are in good agreement with previous dynamical mean-field theory calculations, demonstrating that the non-magnetic phase diagram is only slightly modified from infinite to two spatial dimensions. Three phases are present: a metallic one, for small values of U, where both orbitals are itinerant; a Mott insulator, for large values of U, where both orbitals are localized because of the Coulomb repulsion; and the so-called orbital-selective Mott insulator (OSMI), for small values of R and intermediate Us, where one orbital is localized while the other one is still itinerant. The effect of the Hund's coupling is two-fold: on one side, it favors the full Mott phase over the OSMI; on the other side, it stabilizes the OSMI at larger values of R.