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Water-soluble polymers of cyclodextrins (CyD) can be easily obtained in alkaline media following polycondensation of the naturally occurring monomers in the presence of a crosslinking agent. They can be further modified to customize specifically functionalized architectures. Compared to other macromolecules natural and not, the CyD polymers are endowed with a unique feature, the cone-shaped cavities where they can host guests of various nature. This element has sollicited interest in this class of molecules for a wide range of applications including the biomedical field, in particular drug delivery. The CyD polymers display excellent behavior in terms of water solubility and solubilizing power towards drugs and therapeutic agents that are incompatible with biological fluids. Moreover, they can load more than one type of therapeutic agent in a single system thus allowing to implement combination therapy. In spite of some very promising results as delivery systems, their potentialities remain limited by some intrinsic hurdles. Herein, we comment on their limits mainly related to the production process and the possible solutions to overcome them, giving an outlook on their assets for innovation in disease treatment.

A class of cyclodextrin (CD) dimers has emerged as a potential new treatment for atherosclerosis; they work by forming strong, soluble inclusion complexes with oxysterols, allowing the body to reduce and heal arterial plaques. However, characterizing the interactions between CD dimers and oxysterols presents formidable challenges due to low sterol solubility, the synthesis of modified CDs resulting in varying number and position of molecular substitutions, and the diversity of interaction mechanisms. To address these challenges and illuminate the nuances of CD-sterol interactions, we have used multiple orthogonal approaches for a comprehensive characterization. Results obtained from three independent techniques - metadynamics simulations, competitive isothermal titration calorimetry, and circular dichroism - to quantify CD-sterol binding are presented. The objective of this study is to obtain the binding constants and gain insights into the intricate nature of the system, while accounting for the advantages and limitations of each method. Notably, our findings demonstrate ∼1000× stronger affinity of the CD dimer for 7-ketocholesterol in comparison to cholesterol for the 1:1 complex in direct binding assays. These methodologies and findings not only enhance our understanding of CD dimer-sterol interactions, but could also be generally applicable to prediction and quantification of other challenging host-guest complex systems., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: All authors report financial support, administrative support, equipment, drugs, or supplies, travel, and writing assistance were provided by Cyclarity Therapeutics. Amelia Anderson and Matthew O'Connor have patent Cyclodextrin dimers, compositions thereof, and uses thereof pending to CYCLARITY THERAPUTICS, INC. The authors would like to disclose that AMA, KS, DMC, and MSO have a financial interest in the company Cyclarity Therapeutics. MM has a financial interest in the company CarboHyde; RGF and AP have a financial interest in the company MD.USE. Cyclarity Therapeutics commissioned this work from all authors., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The development of polymeric fabrics with photoinduced antibacterial activity is important for different emerging applications, ranging from materials for medical and clinical practices to disinfection of objects for public use. In this work we prepared a series of cellulose acetate membranes, by means of phase inversion technique, introducing different additives in the starting polymeric solution. The loading of 5,10,15,20-tetraphenylporphyrin (TPP), a known photosensitizer, was considered to impart antibacterial photodynamic properties to the produced membranes. Besides, the addition of a surfactant (Pluronic F-127) allowed to modify the morphology of the membranes whereas the use of graphene oxide (GO) enabled further photo-activated antibacterial activity. The three additives were tested in various concentrations and in different combinations in order to carefully explore the effects of their mixing on the final photophysical and photodynamic properties. A complete structural/morphologycal characterization of the produced membranes has been performed, together with a detailed photophysical study of the TPP-containing samples, including absorption and emission features, excited state lifetime, singlet oxygen production, and confocal analysis. Their antibacterial activity has been assessed in vitro against S. aureus and E. coli , and the results demonstrated excellent bacterial inactivation for the membranes containing a combination of the three additives, revealing also a non-innocent role of the membrane porous structure in the final antibacterial capacity., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

In the quest for new therapies targeting hypoxia, aromatic endoperoxides have intriguing potential as oxygen releasing agents (ORAs) able to free O 2 in tissues upon suitable trigger. Four aromatic substrates were synthesized and the formation of their corresponding endoperoxides was optimized in organic solvent upon selective irradiation of Methylene Blue, a low-cost photocatalyst, producing the reactive singlet oxygen species. Complexation of the hydrophobic substrates within a hydrophilic cyclodextrin (CyD) polymer allowed their photooxygenation in homogeneous aqueous environment using the same optimized protocol upon dissolution in water of the three readily accessible reagents. Notably, reaction rates were comparable in buffered D 2 O and organic solvent and, for the first time, the photooxygenation of highly hydrophobic substrates was achieved for millimolar solutions in non-deuterated water. Quantitative conversion of the substrates, straightforward isolation of the endoperoxides and recovery of the polymeric matrix were achieved. Cycloreversion of one ORA to the original aromatic substrate was observed upon thermolysis. These results hold great potential for the launch of CyD polymers both as reaction vessels for green, homogeneous photocatalysis and as carrier for the delivery of ORAs in tissues., (© 2023 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH.)

We explored a series of cyclodextrin (CyD) polymers composed either of a single CyD type or a mixture of two CyD types to encapsulate simultaneously different compounds with potential therapeutic interest for multimodal prostate cancer treatment. New mixed CyD polymers were prepared in alkaline water starting from the naturally occurring monomers and a low-cost crosslinking agent. Batches of 200 g of polymer were easily obtained. By means of optical spectroscopy we proved the co-encapsulation of 3 compounds in the polymers: the drugs cabazitaxel (CBX) and bicalutamide (BIC), and the photosensitizer chlorin e6 (Ce6). pβCyD and mixed pαβCyD polymers performed best for single drug solubilization. In the co-encapsulation of BIC and CBX by pβCyD and pαβCyD, pβCyD stands out in drug solubilization ability. Avoiding the use of organic solvents, it was possible to dissolve up to 0.1 mM CBX with 10 mg ml -1 pβCyD polymer and, with 100 mg ml -1 , even 1.7 mM BIC, a 100-fold improvement compared to water. Spectroscopic studies afforded the binding constants of CBX and BIC with pβCyD forming complexes of 1 : 2 stoichiometry (drug : CyD) and CBX displayed significantly higher affinity. Also DFT calculations suggested that the drugs are more stable when complexed by two CyD units. Ce6 could be encapsulated simultaneously with the other two drugs in pβCyD and, most importantly, is able to produce singlet oxygen efficiently. Thanks to a single inexpensive CyD-based polymer we were able to produce a three-in-one platform for future implementation of combined chemotherapy and photodynamic therapy. These achievements are most relevant as nanomedicines are continuously proposed but their potential for translation to the pharma industry is compromised by their limited potential for industrial upscale., Competing Interests: The authors declare no conflicts of interest., (This journal is © The Royal Society of Chemistry.)

We herein address the problem of polymorph selection by introducing a general and straightforward concept based on their ordering. We demonstrated the concept by the ordered patterning of four compounds capable of forming different polymorphs when deposited on technologically relevant surfaces. Our approach exploits the fact that, when the growth of a crystalline material is confined within sufficiently small cavities, only one of the possible polymorphs is generated. We verify our method by utilizing several model compounds to fabricate micrometric "logic patterns" in which each of the printed pixels is easily identifiable as comprising only one polymorph and can be individually accessed for further operations.

Cyclodextrin-based polymers can be prepared starting from the naturally occurring monomers following green and low-cost procedures. They can be selectively derivatized pre- or post-polymerization allowing to fine-tune functionalities of ad hoc customized polymers. Preparation nowadays has reached the 100 g scale thanks also to the interest of industries in these extremely versatile compounds. During the last 15 years, these macromolecules have been the object of intense investigations in view of possible biomedical applications as the ultimate goal and large amounts of scientific data are now available. Compared to their monomeric models, already used in the formulation of various therapeutic agents, they display superior behavior in terms of their solubility in water and solubilizing power toward drugs incompatible with biological fluids. Moreover, they allow the combination of more than one type of therapeutic agent in the polymeric system. In this review, a complete state of the art on the knowledge and potentialities of water-soluble cyclodextrin-based polymers as therapeutic agents as well as carrier systems for different types of therapeutics to implement combination therapy is provided. Finally, a perspective on their assets for innovation in disease treatment as well as their limits that still need to be addressed is given., (© 2022 The Authors. Macromolecular Bioscience published by Wiley-VCH GmbH.)

Osteosarcoma treatment is moving towards more effective combination therapies. Nevertheless, these approaches present distinctive challenges that can complicate the clinical translation, such as increased toxicity and multi-drug resistance. Drug co-encapsulation within a nanoparticle formulation can overcome these challenges and improve the therapeutic index. We previously synthetized keratin nanoparticles functionalized with Chlorin-e6 (Ce6) and paclitaxel (PTX) to combine photo (PDT) and chemotherapy (PTX) regimens, and the inhibition of osteosarcoma cells growth in vitro was demonstrated. In the current study, we generated an orthotopic osteosarcoma murine model for the preclinical evaluation of our combination therapy. To achieve maximum reproducibility, we systematically established key parameters, such as the number of cells to generate the tumor, the nanoparticles dose, the design of the light-delivery device, the treatment schedule, and the irradiation settings. A 60% engrafting rate was obtained using 10 million OS cells inoculated intratibial, with the tumor model recapitulating the histological hallmarks of the human counterpart. By scheduling the treatment as two cycles of injections, a 32% tumor reduction was obtained with PTX mono-therapy and a 78% reduction with the combined PTX-PDT therapy. Our findings provide the in vivo proof of concept for the subsequent clinical development of a combination therapy to fight osteosarcoma.

Candida albicans and Staphylococcus aureus are common human pathogens, frequently isolated independently or co-isolated from bloodstream infections, and able to form dense polymicrobial biofilms on various medical devices resulting in strong resistance to conventionally used antimicrobials. New and innovative approaches are therefore needed to ensure the successful management of biofilm related infections. In this study, a chalcone-based derivative and a polycyclic anthracene-maleimide adduct, previously ascertained by us as inhibitors of C. albicans and S. aureus growths, respectively, were reconsidered in a new perspective by evaluating the efficacy of a combined treatment against a polymicrobial biofilm. Both quantitative and qualitative analyses were carried out to delve into their inhibitory potential on the polymicrobial population. Our results indicate that these newly identified antimicrobials are effective in reducing the biomass of the mixed C. albicans-S. aureus biofilm and the viability of fungal-bacterial cells within the polymicrobial community; in addition, confocal laser scanning microscopy demonstrates that the combined treatment thoroughly modifies the architecture of the dual-species biofilm., Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interest., (Copyright © 2021 Institut Pasteur. Published by Elsevier Masson SAS. All rights reserved.)

Human telomeric DNA with hundreds of repeats of the 5'-TTAGGG-3' motif plays a crucial role in several biological processes. It folds into G-quadruplex (G4) structures and features a pocket at the interface of two contiguous G4 blocks. Up to now no structural NMR and crystallographic data are available for ligands interacting with contiguous G4s. Naphthalene diimide monomers and dyads were investigated as ligands of a dimeric G4 of human telomeric DNA comparing the results with those of the model monomeric G4. Time-resolved fluorescence, circular dichroism, isothermal titration calorimetry and molecular modeling were used to elucidate binding features. Ligand fluorescence lifetime and induced circular dichroism unveiled occupancy of the binding site at the interface. Thermodynamic parameters confirmed the hypothesis as they remarkably change for the dyad complexes of the monomeric and dimeric telomeric G4. The bi-functional ligand structure of the dyads is a fundamental requisite for binding at the G4 interface as only the dyads engage in complexes with 1 : 1 stoichiometry, lodging in the pocket at the interface and establishing multiple interactions with the DNA skeleton. In the absence of NMR and crystallographic data, our study affords important proofs of binding at the interface pocket and clues on the role played by the ligand structure., (© 2021 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH.)

When applied to skin, particulate matter has been shown to accumulate in hair follicles. In addition to follicles, the skin topography also incorporates trench-like furrows where particles potentially can accumulate; however, the furrows have not been as thoroughly investigated in a drug delivery perspective. Depending on body site, the combined follicle orifices cover up to 10% of the skin surface, while furrows can easily cover 20%, reaching depths exceeding 25 µm. Hence, porous particles of appropriate size and porosity could serve as carriers for drugs to be released in the follicles prior to local or systemic absorption. In this paper, we combine multiphoton microscopy, scanning electron microscopy, and Franz cell diffusion technology to investigate ex-vivo skin accumulation of mesoporous silica particles (average size of 400-600 nm, 2, and 7 µm, respectively), and the potential of which as vehicles for topical delivery of the broad-spectrum antibiotic metronidazole. We detected smaller particles (400-600 nm) in furrows at depths of about 25 µm, also after rinsing, while larger particles (7 µm) where located more superficially on the skin. This implies that appropriately sized porous particles may serve as valuable excipients in optimizing bioavailability of topical formulations. This work highlights the potential of skin furrows for topical drug delivery., (Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)

In this work, different materials were fabricated from cellulose acetate, loaded with rhodamine B hydrazide and tested as Cu(II) optical sensor. We prepared membranes displaying a sub-micron porous structure using the phase inversion technique, clusters of fibers with varying diameter depending on the preparation procedure using electrospinning, and casted films presenting a smooth non porous structure. Loading of rhodamine B hydrazide on the fabrics after their production was found to be the best procedure to ensure the stability of the dye in the polymeric materials. Absorption and emission analysis of the solid substrates revealed the presence of the dye on the porous fabrics and allowed to choose the most suited materials and loading conditions to test their response towards Cu(II) ions. Reaction of the loaded rhodamine B hydrazide with Cu(II) was confirmed by absorption and emission spectroscopies and by confocal fluorescence imaging, through detection of the product rhodamine B. The results point to promising sensing applications of the prepared composite materials.

Here we applied a novel concept of "sublimation-aided nanostructuring" to control the polymorphism of a model material. The process exploits fractional precipitation as a tool for crystallisation in confinement using a templating agent that sublimes away from the system at the end of the process.

Herein, we propose an easy and practical method for the fabrication of highly ordered supramolecular structures. The proposed approach combines fractional precipitation and wet lithography, to obtain a spatially-defined pattern of submicrometric structures with a high molecular order of poly(3-hexylthiophene). The process is demonstrated by XRD, confocal and time-resolved spectroscopy and by the performance of an effective field effect transistor.

In this paper, a small series of anthracene-maleimide-based compounds was prepared and evaluated to assess the antimicrobial potential of this polycyclic core, a scaffold previously unexplored for new antibiotic development. Some of the new compounds showed appreciable anti- Staphylococcus aureus activity, together with good safety profiles. In particular, compound 13 proved to be the most promising of the series, showing remarkable antimicrobial activity toward planktonic and sessile bacterial cells within a mature preformed biofilm. The mechanism of action seems to be related to the ability of this compound to interfere with bacterial membrane functionality, probably through the targeting of key enzymes responsible for membrane redox homeostasis and energy production. The data reported confirm the ability of this polycyclic nucleus to behave as a new "privileged structure", suitable to be further exploited in the antimicrobial field.

The fluorescent dye perylene-3,4,9,10-tetracarboxylic dianhydride (PBA) was immobilized onto polysulfone hollow fibers by means of a wet coating procedure. After immobilization, PBA was able to react with primary amines through a double anhydride ring opening reaction. The in situ amine coupling was further revealed by fluorescence analysis. Both emission (534 nm →538 nm) and fluorescence lifetime changes (2.7 ns →3.3 ns) of the dye are a useful tool to detect and visualize the occurrence of the reaction. The successful implementation of amine coupling with a reporting function on polysulfone fibers holds great interest for biomedical applications., (© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Naphthalene diimide (NDI) dyads exhibiting a different substitution pattern and linker length have been synthesised and evaluated as G-quadruplex (G4) ligands, by investigating their cytotoxicity in selected cell lines. The dyads with the long C 7 linker exhibit extremely low IC 50 values, below 10 nm, on different cancer cell lines. Contrary, the dyads with the shorter C 4 linker were much less effective, with IC values increasing up to 1 μm. Among the three dyads with the longest linker, small differences in the IC 50 values emerge, suggesting that the linker length plays a more important role than the substitution pattern. We have further shown that the dyads are able to induce cellular DNA damage response, which is not limited to the telomeric regions and is likely the origin of their cytotoxicity. Both absorption titration and dynamic light scattering of the most cytotoxic dyads in the presence of hTel22 highlight their ability to induce effective G4 aggregation, acting as non-covalent cross-linking agents., (© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Background: Altered energy metabolism is a biochemical fingerprint of cancer cells, widely recognized as one of the "hallmarks of cancer". Cancer cells show highly increased rates of glucose uptake and glycolysis, after which the resulting pyruvate is converted to lactate. The maintenance of this metabolic asset is warranted by lactate dehydrogenase A (LDH-A) and for this reason the development of novel LDH-targeted anticancer therapeutics is underway. However, possible interference in cancer cell metabolism could also arise from cAMP signaling pathway, which could be activated by either oncogenic induction or exogenously, as a result of microenvironment-derived stimuli, increasing cellular cAMP levels. This study aimed at evaluating the impact of activated cAMP signaling pathway on the efficacy of an LDH-targeted anticancer approach., Methods: We exogenously activated cAMP signaling in MCF-7 human breast cancer cells and explored the metabolic interplay between LDH-A and cAMP pathway., Results: In cAMP-activated cells, we evidenced changes in energy metabolism which reduced their response to LDH inhibition. Interestingly, these experiments also highlighted a potential vulnerability state of treated cells., Conclusions: cAMP-induced metabolic changes made MCF-7 cells a preferential target of a drug combination treatment which should not affect normal cell viability., General Significance: cAMP is a well-recognized second messenger of the pro-inflammatory cascade. The obtained results are relevant in consideration of the crucial role played by inflammation in normal breast cell transformation and in cancer progression. Furthermore, they corroborate the idea of exploiting the metabolic changes observed in cancer cells to obtain a therapeutic advantage., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Clofazimine (CLZ) is an antibiotic with a promising behavior against Gram-positive bacteria; however, the drug is completely insoluble in water and accumulates in fat tissues. We explored nanocarriers, labeled and not labeled with rhodamine, consisting of negatively charged sulfobutylether-β-cyclodextrins for CLZ loading. A new oligomeric carrier was obtained cross-linking βCyD with epichlorohydrin followed by sulfonation in a strongly alkaline aqueous medium. The oligomeric carrier has a MW of 53 kDa and forms small nanoparticles of a few tens of nm. With aqueous solutions containing a 25 mg/mL oligomeric carrier, we loaded up to 0.5 mg/mL of drug. The oligomers exhibited a 10-fold better loading capacity compared to monomers and formed nanoparticles with a size in the 20-60 nm range after drug loading. Circular dichroism confirmed encapsulation of the CLZ in the nanocarriers. All carriers with or without CLZ are not cytotoxic up to 1 μM, while CLZ alone is highly cytotoxic at the same concentration. The drug has IC 50 values below 100 nM against S. epidermidis. The same holds true also for clinical isolates of S. epidermidis, some displaying MDR. So, the selectivity index significantly increased for CLZ/carrier systems compared to the drug alone. Taken all together, our results open new avenues for the clinical application of this antibiotic.

The new octacations [(2-Mepy) 8 PzM] 8+ [M = Mg II (H 2 O), Zn II ], isolated as iodide salts, were obtained from the corresponding neutral complexes [Py 8 PzM] (Py = 2-pyridyl; Pz = porphyrazinato dianion) upon quaternization with CH 3 I of the N atoms of the 2-pyridyl rings under mild experimental conditions. The absorption spectra registered in organic solvents as well as in water (H 2 O) confirm the presence of the complexes in their monomeric form in all cases. The two octacations behave as photosensitizers in a H 2 O/sodium dodecyl sulfate solution for the production of singlet oxygen, 1 O 2 , and exhibit quantum yield values (Φ Δ ) 2.2-2.5 higher than those measured for the standard PcAlS mix , a promising feature of interest for photodynamic therapy. The interaction of the Zn II octacation [(2-Mepy) 8 PzZn] 8+ with different types of DNA has been studied by means of optical spectroscopic techniques, clearly suggesting that binding of the charged macrocycle to the DNA effectively takes place. In order to assess the effect of the aromatic ring size, the same binding study was performed for the octapyridinated zinc(II) tetraquinoxalinoporphyrazine complex having a much more expanded macrocyclic framework and compared with the behavior of the parent octapyridinated zinc(II) tetrapyrazinoporphyrazine complex having an intermediate macrocycle. The achieved information confirms the relationship between the binding of the charged macrocycle to the DNA and the dimension of the porphyrazine macrocycle.