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Pentamidine (PTM) is an aromatic diamidine approved for the treatment of parasitic infections that has been recently proposed for possible repositioning as an anticancer drug. To this aim, efforts have been made to improve its therapeutic efficacy and reduce associated adverse effects through both covalent derivatization and association with nanocarriers. To efficiently encapsulate PTM into biocompatible nanoparticles and to enhance its selectivity toward cancer cells, a squalene (SQ) derivative (1,1',2-tris-norsqualenoic acid, SQ-COOH) was selected to prepare PTM-loaded nanocarriers. Indeed, SQ and its derivatives self-assemble into nanoparticles in aqueous media. Furthermore, SQ-bioconjugates strongly interact with low-density lipoproteins (LDL), thus favoring preferential accumulation in cells overexpressing the LDL receptor (LDLR). We report here the preparation of nanocarriers by ion-pairing between the negatively charged SQ-COOH and the positively charged PTM free base (PTM-B), which allowed the covalent grafting of SQ to PTM to be avoided. The nanoparticles were characterized (mean size < 200 nm and zeta potential < -20 mV for SQ-COOH/PTM-B 3:1 molar ratio) and molecular modelling studies of the SQ-COOH/PTM-B interaction confirmed the nanocarrier stability. Finally, the ability to indirectly target LDLR-overexpressing cancer cells was evaluated by in vitro cell viability assays and confirmed by LDLR silencing, serum privation and simvastatin treatment., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Disulfiram (DSF) is an inhibitor of P-glycoprotein (Pgp), the main obstacle limiting the success of doxorubicin (DOX), but it has poor solubility and stability. With the aim to overcome these limitations we prepared liposomes coencapsulating DSF and DOX (LipoDSF-DOX). Liposome stability, drugs release profile, effects on DOX cytotoxicity, Pgp activity and expression in breast cancer cells were evaluated. We observed that LipoDSF-DOX with a 1:3 weight ratio, with DSF in lipid bilayer and DOX in aqueous core, released DSF faster than DOX. LipoDSF-DOX increased DOX intracellular accumulation and cytotoxicity in Pgp-expressing breast cancer cells, with an efficacy superior to the mixture of free DSF and DOX, thanks to a differential kinetics of release of DSF and DOX when carried by liposomes. The mechanism of the increased DOX retention relied on the DSF-induced sulfhydraton of Pgp and followed by its ubiquitination. These events reduced Pgp expression and catalytic activity in LipoDSF-DOX-treated cells. Our results show that LipoDSF-DOX effectively reversed DOX resistance in Pgp-expressing breast cancer cells, exploiting the temporally different kinetics of release of DSF and DOX, optimized to decrease expression and activity of Pgp., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)