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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.)

Nanoparticles of polymeric complexes made of hyaluronic acid and polyarginine were investigated for the encapsulation of the cationic hydrophilic drug pentamidine isethionate. The interaction between the anionic hyaluronic acid and the cationic pentamidine resulting in the formation of polyelectrolyte complexes was firstly studied. Then, nanoparticles made of hyaluronic acid and polyarginine loaded with pentamidine were developed. These drug delivery systems consist of a monodisperse population of negatively charged pentamidine-loaded nanoparticles with a high drug encapsulation rate (80%). Such high encapsulation efficiency coming from ion exchange was confirmed by measurements of the counterion isethionate released from pentamidine during nanoparticles formation. Besides, freeze-dried pentamidine-loaded nanoparticles kept their integrity after their reconstitution in water. In vitro studies on human lung (A549) and breast (MDA-MB-231) cancer cell lines showed that pentamidine-loaded nanoparticles were more cytotoxic in comparison to the free drug, suggesting an enhanced internalization of encapsulated drug by cancer cells., (Copyright © 2019. Published by Elsevier B.V.)

The work aimed to evaluate the feasibility to design hyaluronic acid (HA) decorated flexible liposomes to enhance the skin penetration of nifedipine. Egg phosphatidylcholine (e-PC) based transfersomes (Tween 80) and transethosomes (ethanol) were prepared. HA was reacted with 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine (HA-DPPE) and two molar ratios (0.5 and 3%) of conjugate with respect to e-PC were tested. The presence of HA significantly increased the packing order of the bilayer (as verified by differential scanning calorimetry), reducing both the encapsulation efficiency and the flexibility of the decorated liposomes in a dose-dependent manner. In fact, at the highest HA content the constant of deformability (K, N/mm) increased and the carriers remained on the skin surface after topical application. The stiffening effect of HA was counterbalanced by the addition of ethanol as fluidizing agent that allowed to maintain the highest HA concentration, meanwhile reducing the K value of the vesicles. HA-transethosomes allowed a suitable nifedipine permeation (J ∼ 30 ng/cm 2 /h) and significantly improved the drug penetration, favouring the formation of a drug depot in the epidermis. These data suggest the potentialities of HA-transethosomes as drug delivery systems intended for the treatment of cutaneous pathologies and underline the importance of studying the effect of surface functionalization on carrier deformability to rationalize the design of such systems., (Copyright © 2017 Elsevier B.V. All rights reserved.)

We have investigated the impact of hyaluronic acid (HA)-coating on the targeting capacity of siRNA lipoplexes to CD44-overexpressing tumor cells. Cellular uptake and localization of HA-lipoplexes were evaluated by flow cytometry and fluorescence microscopy and both methods showed that these lipoplexes were rapidly internalized and localized primarily within the cytoplasm. Inhibition of luciferase expression on the A549-luciferase lung cancer cell line was achieved in vitro using an anti-Luc siRNA. 81% of luciferase gene expression inhibition was obtained in vitro with HA-lipoplexes at +/- ratio 2. In vivo, in a murine A549 metastatic lung cancer model, the treatment with HA-lipoplexes carrying anti-luciferase siRNA led to a statistically significant decrease of luciferase expression as opposed to progressive increase with non-modified lipoplexes or NaCl 0.9%. The reduction of the expression of luciferase mRNA tumor of mice treated with HA-lipoplexes supported the inhibition effect due to siRNA. These results highlight the potential of HA-lipoplexes in CD44-targeting siRNA delivery., (Copyright © 2016 Elsevier B.V. All rights reserved.)

During the last decades, several studies have proposed manganese (Mn) complexes as alternative contrast agents for magnetic resonance imaging (MRI). With the nanotechnology surge in recent years, different types of Mn-based nanoparticles (Nps) have been developed. However, to design effective and safe administration procedures, preliminary studies on target cells, aimed at verifying their full biocompatibility and biodegradability, are mandatory. In this study, MnO containing-Nps encapsulated in a phospholipidic shell (PL-MnO Nps) were tested in cultured cells and flow cytometry; confocal and transmission electron microscopy were combined to understand the Nps uptake mechanism, intracellular distribution and degradation pathways, as well as possible organelle alterations. The results demonstrated that PL-MnO Nps undergo rapid and massive cell internalization, and persist free in the cytoplasm before undergoing lysosomal degradation without being cytotoxic or inducing subcellular damage. Based on the results with this cell model in vitro, PL-MnO Nps thus proved to be suitably biocompatible, and may be envisaged as very promising tools for therapeutic and diagnostic applications, as drug carriers or contrast agent for MRI., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Paclitaxel has been found to be very effective against several human cancers; one of the major problems with its use is its poor solubility, which makes necessary its solubilization with excipients that can determine allergic reactions often severe. The aim of this study is to develop highly water-soluble prodrugs of paclitaxel. For this purpose we prepared a series of new paclitaxel-poly(ethylene glycol) (PEG) conjugates that were characterized and evaluated for their in vitro stability and cytotoxicity. In particular, in order to modulate the release of paclitaxel from prodrugs, we prepared different compounds introducing PEG in the drug C2' and/or C7 positions via ester or carbamate linkage. The conjugates were obtained in high purity and good yield. The carbamate prodrugs were highly stable in different media, while the compounds obtained linking PEG at C2' position through an ester bond showed lower stability. Finally, the cytotoxic activity of the conjugates was evaluated on two cancer cell lines and the results showed that all the derivatives had a reduced cytotoxicity compared to that of paclitaxel., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Transition metal complexes provide a promising avenue for designing new therapeutic and diagnostic agents. In particular, ruthenium(II) polypyridyl complexes are useful for studying cellular uptake, due to their easy synthesis and unique photophysical properties. Dyes are frequently combined with material substrates to modulate their properties, enhance stability, reduce toxicity, and improve delivery. A novel Ru polypyridyl complex linked to a derivative of the natural lipid squalene (Ru-BIPPBI-hx-SQ) is described. Using the solvent displacement method, Ru-BIPPBI-hx-SQ easily self-assembles into nanosized aggregates in aqueous solution, as characterized by dynamic light scattering. The nanoassemblies exhibit long-lived and intense luminescence. Preliminary biological assessment showed them to be non-toxic; they are efficiently and rapidly transported across the cell membrane without requiring its permeabilization. Ru-labeled nanoassemblies are likely to be significant cellular-imaging tools, probing cellular events at very low concentrations. Moreover co-nanoassembly, with drug-derivatives based on squalenoylation technology, including gemcitabine and paclitaxel, has given interesting preliminary results., (Copyright © 2012 Elsevier B.V. All rights reserved.)

The study developed cytotoxic macromolecular conjugates that specifically target the folate receptor and deliver the drug into cell cytoplasm. The anticancer agent paclitaxel was conjugated to human serum albumin (HSA) and this drug-albumin conjugate was further equipped with folic acid, linked via an extended poly(ethylene glycol) spacer. Preparation was carried out in a heterogeneous phase system exploiting the binding ability of Cibacron Blue dye to HSA. Unreacted reagents were easily removed and, after purification by gel filtration, the conjugate was fully characterized. Binding and in vitro cytotoxicity studies on human nasopharyngeal epidermal carcinoma KB and colorectal carcinoma HT-29 cells (as negative control) demonstrated increased selectivity and anti-tumoral activity.

The aim of this study was to develop both a physical and a chemical protection of the anticancer drug gemcitabine, which suffers from a rapid plasmatic metabolization. For this purpose, we used a series of lipophilic derivatives of gemcitabine in which an acyl chain is covalently coupled to the 4-amino group of gemcitabine; moreover, a physical protection of the drug was attempted by incorporating these lipophilic derivatives into poly(H(2)NPEGCA-co-HDCA) nanospheres and nanocapsules. Nanoparticles were prepared by nanoprecipitation of the poly(H(2)NPEGCA-co-HDCA) copolymer and their size, zeta potential and encapsulation efficiency were further characterized. These results have been relied on lipophilicity and flexibility studies. Data showed that only the more lipophilic derivative, 4-(N)-stearoylgemcitabine, was incorporated with a high yield. Thus, 4-(N)-stearoylgemcitabine-containing nanospheres and nanocapsules were further analyzed by differential scanning calorimetry. Their cytotoxicity was tested on two human cancer cell lines and compared to that of gemcitabine and free 4-(N)-stearoylgemcitabine.