In this contribution, we report a strategy to enhance the therapeutic action of the chemotherapeutic Sorafenib (SRB) through its combination with a multifunctional β-cyclodextrin-based polymer able to deliver nitric oxide (NO) and emit green fluorescence upon visible light excitation (PolyCDNO). The basically water-insoluble SRB is effectively encapsulated in the polymeric host (1 mg mL⁻¹) up to a concentration of 18 μg mL⁻¹. The resulting host-guest supramolecular complex is able to release SRB in sink conditions and to preserve very well the photophysical and photochemical properties of the free PolyCDNO, as demonstrated by the similar values of the NO release and fluorescence emission quantum efficiencies found. The complex PolyCDNO/SRB internalizes in HEP-G2 hepatocarcinoma, MCF-7 breast cancer and ACHN kidney adenocarcinoma cells, localizing in all cases mainly at the cytoplasmic level. Biological experiments have been performed at SRB concentrations below the IC₅₀ and with light doses producing NO at nontoxic concentrations. The results demonstrate exceptional mortality levels for PolyCDNO/SRB upon visible light irradiation in all the different cell lines tested, indicating a clear synergistic action between the chemotherapeutic drug and the NO. These findings can open up exciting avenues to potentiate the anticancer action of SRB and, in principle, to reduce its side effects through its use at low dosages when in combination with the photo-regulated release of NO.

The chemotherapeutic Lenvatinib (LVB) and a nitric oxide (NO) photodonor based on a rhodamine antenna (RD-NO) activatable by the highly compatible green light are supramolecularly assembled by a β-cyclodextrin branched polymer (PolyCD). The poorly water-soluble LVB and RD-NO solubilize very well within the polymeric host leading to a ternary supramolecular nanoassembly with a diameter of ~55 nm. The efficiency of the NO photorelease and the typical red fluorescence of RD-NO significantly enhance within the polymer due to its active role in the photochemical and photophysical deactivation pathways. The co-presence of LVB within the same host does not affect either the nature or the efficiency of the photoinduced processes of RD-NO. Besides, irradiation of RD-NO does not lead to the decomposition of LVB, ruling out any intermolecular photoinduced process between the two guests despite sharing the same host. Ad-hoc devised Förster Resonance Energy Transfer experiments demonstrate this to be the result of the not close proximity of the two guests, which are confined in different compartments of the same polymeric host. The supramolecular complex is stable in a culture medium, and its biological activity has been evaluated against HEP-G2 hepatocarcinoma cell lines in the dark and under irradiation with visible green light, using LVB at a concentration well below the IC₅₀. Comparative experiments performed using the polymeric host encapsulating the individual LVB and RD-NO components under the same experimental conditions show that the moderate cell mortality induced by the ternary complex in the dark increases significantly upon irradiation with visible green light, more likely as the result of synergism between the NO photogenerated and the chemotherapeutic.

Au nanostructures exhibiting a localized surface plasmon resonance in the near-infrared spectral window are obtained in a single, green step at room temperature by pomegranate extract in the presence of a highly biocompatible β-cyclodextrin branched polymer, without the need of preformed seeds, external reducing and sacrificial agents, and conventional surfactants. The polymeric component makes the Au nanostructures dispersible in water, stable for weeks and permits their supramolecular assembling with the chemotherapeutic sorafenib and a nitric oxide (NO) photodonor (NOPD), chosen as representative for chemo- and photo-therapeutics. Irradiation of the plasmonic Au nanostructures in the therapeutic window with 808 nm laser light results in a good photothermal response, which (i) is not affected by the presence of either the chemo- or the phototherapeutic guests and (ii) does not lead to their photoinduced decomposition. Besides, irradiation of the hybrid Au nanoassembly with the highly biocompatible green light results in the NO release from the NOPD with efficiency similar to that observed for the free guest. Preliminary biological experiments against Hep-G2 hepatocarcinoma cell lines are also reported.

We have designed and synthesized a novel calix[4]arene derivative bearing four choline appendages, as recognition targeting ligands, and one amino-nitrobenzofurazan, as a fluorescent labeling unit, at the opposite sides of the calixarene molecular scaffold. Due to its amphiphilic character, this compound is well soluble in water, forming supramolecular assemblies that are ca. 170 nm in diameter. The nanoassembly selectively targets cancer cells that overexpress the choline receptors, and it can be visualized thanks to the fluorescent tag. The fluorogenic unit also acts as a green light harvesting center, making the nanoassembly a photo-nanoreactor able to encapsulate a hydrophobic nitric oxide (NO) photodonor, otherwise activatable with blue light, and encouraging the NO release with the more biocompatible green light probably by an intra-cage photoinduced electron transfer.

We have designed and synthesized a novel calix[4]arene derivative bearing four choline appendages as recognition targeting ligands and one amino-nitrobenzofurazan as a fluorescent labelling unit at the opposite sides of the calixarene molecular scaffold. Due to its amphiphilic character, this compound is well soluble in water, forming supramolecular assemblies that are ca. 170 nm in diameter. The nanoassembly selectively targets cancer cells that overexpress the choline transporters, and it can be visualized thanks to the fluorescent tag. The fluorogenic unit also acts as a green light harvesting center, making the nanoassembly a photo-nanoreactor able to encapsulate a hydrophobic nitric oxide (NO) photodonor, otherwise activatable with blue light, and encouraging the NO release with the more biocompatible green light probably by an intra-cage photoinduced electron transfer.