Andrea Cesari

Ultrasmall cyclodextrin‐based nanogels (CDngs) crosslinked with ethylene glycol diglycidyl ether (EGDE) were tested as drug delivery systems for poorly water‐soluble anticancer agents for the first time. Two compounds with well‐established pharmacological activity but critical solubility limitations, i.e., Osthole and Combretastatin A‐4 (CA‐4), were selected to evaluate the encapsulation capacity and performance of the nanogel platform. After preliminary screening through experimental and docking investigation, CA‐4 was chosen as the reference compound. Among the formulations developed, the CA‐4/loaded nanogel displayed the highest encapsulation efficiency (EE%). Despite a less‐than‐ideal host–guest fit, the large cavity of γ‐CD allows for efficient drug encapsulation and higher loading capacity. The optimized formulation was tested in vitro to assess both the biocompatibility of γ‐CDngs, as well as the anticancer efficacy of CA‐4 loaded γ‐CD and γ‐CDngs. We demonstrate that empty systems exhibit intrinsic biocompatibility, showing no cytotoxicity toward the A2780 cancer cell line under experimental conditions. Furthermore, the CA‐4 loaded γ‐CDngs retained and enhanced the cytotoxic properties of the free drug against this cell line, compared to the corresponding native γ‐CD. Collectively, these findings validate CDngs as a promising and innovative platform for the delivery of hydrophobic anticancer molecules and support their potential for further therapeutic development.

Cyclodextrins (CDs) are cyclic oligosaccharides extensively utilized in pharmaceutical sciences owing to their ability to form inclusion complexes with a wide variety of hydrophobic guest molecules. This has made them invaluable carriers in drug delivery, enabling improvements in solubility, stability, and bioavailability of therapeutic agents. Beyond these intrinsic advantages, the chemical derivatization of CDs with amino acids (AAs) represents an emerging strategy to further expand their functional landscape. Such modifications not only enhance aqueous solubility and finely tune the binding selectivity but also introduce opportunities for designing stimuli‐responsive systems. The scope of this review is to provide a comprehensive overview of the current synthetic methodologies for both mono‐ and per‐substituted amino‐acid cyclodextrin derivatives. Coupling can be achieved through the amino, carboxyl, or specific side‐chain functionalities of AAs, thereby offering a versatile toolbox for tailoring structural and functional features. By consolidating knowledge on these synthetic strategies and highlighting representative applications, this work emphasizes the broad potential of AA‐CDs as adaptable platforms for biomedical use. Integrating these functionalized CDs into next generation nanocarriers and multifunctional therapeutic systems may pave the way toward innovative solutions for complex clinical challenges.

Background The precision delivery of active pharmaceutical ingredients remains a major challenge in modern pharmacology, where conventional therapies often lack selectivity and cause severe side effects. Stimuli-responsive drug delivery systems (SRDDS) represent a promising strategy to achieve controlled release in response to pathological microenvironments or external triggers. While various organic and inorganic carriers have been investigated, cyclodextrins (CDs) occupy a unique position due to their biocompatibility, safety record, and distinctive molecular architecture. Beyond their established role as solubilizing excipients, CDs can act as a fundamental component capable of driving responsiveness within drug delivery systems. Objective This review highlights cyclodextrin-based stimuli-responsive systems (SRCDS) in which CDs themselves mediate responsiveness, rather than serving as simple structural elements. Scope and Focus A comparative discussion of different responsive mechanisms is provided, offering insights into the design principles that may accelerate the clinical translation of CD-based SRDDS. A particular focus will be provided to chemical structure components exerting stimuli responsiveness. In addition, recent publications on SRCDS with pharmacological or biological experimental investigations and relevance are reviewed, with particular attention to applications in cancer therapy. Graphical Abstract

The determination of the biodistribution of cyclodextrin‐based (nano)materials represents a critical point for their development and in vivo use as drug carriers and gene‐delivery systems. In this work, we report the design and preparation of a Eu(III)‐based emissive probe based on a new adamantyl‐appended β ‐diketone. This probe has favorable emission and structural features, as it is endowed with a long lifetime (280 µs). Also, it is able to form a stable supramolecular inclusion complex with virtually any cyclodextrin‐based systems. With such an emissive probe, time‐resolved fluorescence imaging techniques could be exploited to obtain images with higher contrast and hence enhanced quality, allowing one to follow the fate of cyclodextrin‐based delivery systems in complex biological media, such as cells and tissues.

Computational screening of a 100-tripeptide nanoparticle library ranked the nanoparticles according to their affinity for the neuroblastoma biomarker 3-methoxytyramine (3-MT). Synthesis and testing confirmed their ability to detect 3-MT at 25 μM.

Background/Objectives: Curcumin (CUR) is a natural compound with notable antitumor properties but faces limitations in topical applications due to poor aqueous solubility, instability, and insufficient skin penetration. To overcome these challenges, a nanomicellar formulation (TPGS30ELP15) was developed to enhance CUR solubility, stability, and skin penetration. This study aimed at evaluating the skin permeation and retention of CUR when delivered through nanomicelles alone or combined with a thermosensitive hydrogel for potential melanoma therapy. Methods: A CUR-loaded nanomicellar formulation containing CUR 5 mM was developed, characterized by particle sizes of 12–25 nm. Skin permeation studies utilized pig ear skin to assess CUR localization using both HPLC quantitative analysis and confocal microscopy. To improve patient comfort and application efficiency, the nanomicellar dispersion was incorporated into a thermosensitive hydrogel based on 16% Kolliphor^® P407 and was able to undergo a sol–gel transition at skin temperature (32–36 °C). Formulations were evaluated for physicochemical properties, stability, and CUR distribution within skin layers using in vitro permeation assays. Results: CUR-loaded nanomicelles demonstrated selective localization in the viable epidermis (100–150 µm depth), bypassing the stratum corneum. The addition of the thermosensitive hydrogel enhanced CUR retention and distribution, prolonging contact at the application site and providing a gradual release profile. The hydrogel’s sol–gel transition properties can facilitate ease of use and patient compliance. The combined system effectively delivered CUR to the basal epidermis, a target site for melanoma treatment, achieving therapeutically relevant drug concentrations. Conclusions: The incorporation of CUR-loaded nanomicelles into a thermosensitive hydrogel enhanced the solubility, stability, and targeted delivery of CUR to skin layers. This dual system represents a promising strategy for improving topical drug delivery for melanoma therapy, addressing limitations associated with CUR’s physicochemical properties while ensuring patient-friendly application and gradual drug release.

Background/Objectives: Melanoma is a pathology that affects a large part of the population, and the currently available therapies have many limitations, including the selective targeting of the site of action. This study explores the development of curcumin (CUR)-loaded nanostructured delivery systems for topical melanoma treatment, addressing CUR’s limitations in bioavailability, solubility, and stability. Methods: Binary surfactant mixtures of Vitamin E-TPGS (TPGS) and Kolliphor ELP (ELP) were selected to form stable micelles for curcumin encapsulation. A Design of Experiments (DoE) approach was applied to optimize the surfactant ratios for enhanced drug solubilization and improved cytotoxic effects on melanoma cells. The final formulation was characterized using Fourier Transform Infrared Spectroscopy (FTIR), Differential Scanning Calorimetry (DSC), and Nuclear Magnetic Resonance (NMR) spectroscopy to confirm its properties. Results: The final formulation, TPGS30ELP15, contained 30 mM TPGS and 15 mM ELP and led to formation of nanostructures of the expected size (hydrodinamic diameter, Dh: 13.11 ± 0.01 nm; polydispersivity index, PDI = 0.371 ± 0.05), able to solubilize 5.51 ± 1.09 mM CUR. The formulation was stable for a 120-day period stored at 4 °C and room temperature in the dark. Cytotoxicity testing in A375 melanoma cells demonstrated that curcumin-loaded micelles significantly reduced cell viability compared to free curcumin. Long-term exposure (24 h) revealed that free curcumin caused an 85% reduction in cell viability, while TPGS30ELP15 resulted in a 70% reduction. Additionally, free curcumin induced a 30% increase in cytoplasmic area, indicating necrosis, whereas TPGS30ELP15 decreased the cytoplasmic area by 20%, suggesting apoptosis. Conclusions: This study demonstrates that TPGS30ELP15 nanomicelles enhance curcumin’s anticancer effects while promoting apoptosis and minimizing necrosis, which is associated with lower inflammation and tissue damage. These findings suggest that TPGS30ELP15 offers a more favorable therapeutic profile for melanoma treatment, paving the way for safer and more effective topical therapies.

This study presents the preparation and electrochemical testing of sulfonated styrene‐grafted poly(vinylidene fluoride) (pVDF) copolymers as proton exchange membranes (PEMs) for semi‐organic redox flow batteries (RFBs) based on 9,10‐anthraquinone‐2,7‐disulfonic acid (AQDS)/bromine. The copolymers are synthesized via a two‐step procedure, involving i) atom transfer radical polymerization of styrene (Sty) for the grafting to the pVDF backbone and ii) the sulfonation of the polystyrene grafted side chains. Copolymers with different amounts of sulfonated styrene (SSty) in the side chains (i.e., degree of sulfonation (DS)) are obtained and used for the preparation of PEMs by solution casting. The PEMs are characterized to assess their thermal, mechanical, water absorption, and ion exchange properties, to evaluate the effect of DS on membrane properties, and to select the membrane with the best overall performance for application in single cell tests. Electrochemical testing reveals that the pVDF‐g‐(Sty26‐co‐SSty14) membrane exhibits low crossover of redox species, favorable ohmic resistance, and energy efficiency. Results from single cell tests, as compared with commercial benchmarks such as Nafion 115 and Aquivion E87‐12s, highlight the potential of such copolymers as alternative membranes for RFBs.