Click Chemistry with Polymers, Dendrimers, and Hydrogels for Drug Delivery

This is a post-peer-review, pre-copyedit version of an article published in Pharmaceutical Research. The final authenticated version is available online at: https://doi.org/10.1007/s11095-012-0683-yDuring the last decades, great efforts have been devoted to design polymers for reducing the toxicity, increasing the absorption, and improving the release profile of drugs. Advantage has been also taken from the inherent multivalency of polymers and dendrimers for the incorporation of diverse functional molecules of interest in targeting and diagnosis. In addition, polymeric hydrogels with the ability to encapsulate drugs and cells have been developed for drug delivery and tissue engineering applications. In the long road to this successful story, pharmaceutical sciences have been accompanied by parallel advances in synthetic methodologies allowing the preparation of precise polymeric materials with enhanced properties. In this context, the introduction of the click concept by Sharpless and coworkers in 2001 focusing the attention on modularity and orthogonality has greatly benefited polymer synthesis, an area where reaction efficiency and product purity are significantly challenged. The purpose of this Expert Review is to discuss the impact of click chemistry in the preparation and functionalization of polymers, dendrimers, and hydrogels of interest in drug deliveryThis work was financially supported by the Spanish Ministry of Science and Innovation (CTQ2009-10963 and CTQ2009-14146-C02-02) and the Xunta de Galicia (10CSA209021PR and CN2011/037)S

Interplay between Structure and Dynamics in Chitosan Films Investigated with Solid-State NMR, Dynamic Mechanical Analysis, and X-ray Diffraction

Modern solid-state NMR techniques, combined with X-ray diffraction, revealed the molecular origin of the difference in mechanical properties of self-associated chitosan films. Films cast from acidic aqueous solutions were compared before and after neutralization, and the role of the counterion (acetate vs Cl⁻) was investigated. There is a competition between local structure and long-range order. Hydrogen bonding gives good mechanical strength to neutralized films, which lack long-range organization. The long-range structure is better defined in films cast from acidic solutions in which strong electrostatic interactions cause rotational distortion around the chitosan chains. Plasticization by acetate counterions enhances long-range molecular organization and film flexibility. In contrast, Cl⁻ counterions act as a defect and impair the long-range organization by immobilizing hydration water. Molecular motion and proton exchange are restricted, resulting in brittle films despite the high moisture content

Optical Detection of Distal Lung Enzyme Activity in Human Inflammatory Lung Disease.

Objective and Impact Statement. There is a need to develop platforms delineating inflammatory biology of the distal human lung. We describe a platform technology approach to detect in situ enzyme activity and observe drug inhibition in the distal human lung using a combination of matrix metalloproteinase (MMP) optical reporters, fibered confocal fluorescence microscopy (FCFM), and a bespoke delivery device. Introduction. The development of new therapeutic agents is hindered by the lack of in vivo in situ experimental methodologies that can rapidly evaluate the biological activity or drug-target engagement in patients. Methods. We optimised a novel highly quenched optical molecular reporter of enzyme activity (FIB One) and developed a translational pathway for in-human assessment. Results. We demonstrate the specificity for matrix metalloproteases (MMPs) 2, 9, and 13 and probe dequenching within physiological levels of MMPs and feasibility of imaging within whole lung models in preclinical settings. Subsequently, in a first-in-human exploratory experimental medicine study of patients with fibroproliferative lung disease, we demonstrate, through FCFM, the MMP activity in the alveolar space measured through FIB One fluorescence increase (with pharmacological inhibition). Conclusion. This translational in situ approach enables a new methodology to demonstrate active drug target effects of the distal lung and consequently may inform therapeutic drug development pathways