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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.)

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.)

Cyclodextrin-based metal-organic frameworks (CD-MOFs) represent an environment-friendly and biocompatible class of MOFs drawing increasing attention in drug delivery. Lansoprazole (LPZ) is a proton-pump inhibitor used to reduce the production of acid in the stomach and recently identified as an antitubercular prodrug. Herein, LPZ loaded CD-MOFs were successfully synthesized upon the assembly with γ-CD in the presence of K + ions using an optimized co-crystallization method. They were characterized in terms of morphology, size and crystallinity, showing almost perfect cubic morphologies with monodispersed size distributions. The crystalline particles, loaded or not with LPZ, have mean diameters of around 6μm. The payloads reached 23.2±2.1% (wt) which corresponds to a molar ratio of 1:1 between LPZ and γ-CD. It was demonstrated that even after two years storage, the incorporated drug inside the CD-MOFs maintained its spectroscopic characteristics. Molecular modelling provided a deeper insight into the interaction between the LPZ and CD-MOFs. Raman spectra of individual particles were recorded, confirming the formation of inclusion complexes within the tridimensional CD-MOF structures. Of note, it was found that each individual particle had the same chemical composition. The LPZ-loaded particles had remarkable homogeneity in terms of both drug loading and size. These results pave the way towards the use of CD-MOFs for drug delivery purposes., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Low aqueous solubility of porphyrin-based photosensitizers hampers their clinical use in photodynamic therapy because of complex delivery. In this study, we explore meso-tetra(m-hydroxyphenyl)-21,23H-porphyrin (mTHPP), a potent photosensitizer, covalently attached to β-cyclodextrin (CD-mTHPP) with a focus on topical delivery and cellular uptake. The photophysical properties of CD-mTHPP were examined using steady-state fluorescence and lifetime measurements verifying increased aqueous solubility. Confocal and fluorescence lifetime imaging microscopy on human squamous carcinoma cells (A431) evidenced a cytoplasmic uptake of CD-mTHPP in predominantly monomeric form. CD-mTHPP was also delivered to human skin ex vivo and the skin penetration was assessed using two-photon fluorescence microscopy. The results indicated that CD-mTHPP exhibits improved skin distribution compared to mTHPP alone using aqueous vehicles. Thus the CD-mTHPP conjugate demonstrates improved biodistribution ex vivo compared to mTHPP and is a promising multimodal system for photodynamic therapy. [ABSTRACT FROM AUTHOR]