Compartmentalized Polymeric Nanoparticles Deliver Vancomycin in a pH-Responsive Manner.

Vancomycin (VCM) is a last resort antibiotic in the treatment of severe Gram-positive infections. However, its administration is limited by several drawbacks such as: strong pH-dependent charge, tendency to aggregate, low bioavailability, and poor cellular uptake. These drawbacks were circumvented by engineering pH-responsive nanoparticles (NPs) capable to incorporate high VCM payload and deliver it specifically at slightly acidic pH corresponding to infection sites. Taking advantage of peculiar physicochemical properties of VCM, here we show how to incorporate VCM efficiently in biodegradable NPs made of poly(lactic-co-glycolic acid) and polylactic acid (co)polymers. The NPs were prepared by a simple and reproducible method, establishing strong electrostatic interactions between VCM and the (co)polymers' end groups. VCM payloads reached up to 25 wt%. The drug loading mechanism was investigated by solid state nuclear magnetic resonance spectroscopy. The engineered NPs were characterized by a set of advanced physicochemical methods, which allowed examining their morphology, internal structures, and chemical composition on an individual NP basis. The compartmentalized structure of NPs was evidenced by cryogenic transmission electronic microscopy, whereas the chemical composition of the NPs' top layers and core was obtained by electron microscopies associated with energy-dispersive X-ray spectroscopy. Noteworthy, atomic force microscopy coupled to infrared spectroscopy allowed mapping the drug location and gave semiquantitative information about the loadings of individual NPs. In addition, the NPs were stable upon storage and did not release the incorporated drug at neutral pH. Interestingly, a slight acidification of the medium induced a rapid VCM release. The compartmentalized NPs could find potential applications for controlled VCM release at an infected site with local acidic pH.

Solid-State NMR Spectroscopy: A Key Tool to Unravel the Supramolecular Structure of Drug Delivery Systems.

In the past decades, nanosized drug delivery systems (DDS) have been extensively developed and studied as a promising way to improve the performance of a drug and reduce its undesirable side effects. DDSs are usually very complex supramolecular assemblies made of a core that contains the active substance(s) and ensures a controlled release, which is surrounded by a corona that stabilizes the particles and ensures the delivery to the targeted cells. To optimize the design of engineered DDSs, it is essential to gain a comprehensive understanding of these core-shell assemblies at the atomic level. In this review, we illustrate how solid-state nuclear magnetic resonance (ssNMR) spectroscopy has become an essential tool in DDS design.

Doxorubicin-Loaded Metal-Organic Frameworks Nanoparticles with Engineered Cyclodextrin Coatings: Insights on Drug Location by Solid State NMR Spectroscopy.

Recently developed, nanoscale metal-organic frameworks (nanoMOFs) functionalized with versatile coatings are drawing special attention in the nanomedicine field. Here we show the preparation of core-shell MIL-100(Al) nanoMOFs for the delivery of the anticancer drug doxorubicin (DOX). DOX was efficiently incorporated in the MOFs and was released in a progressive manner, depending on the initial loading. Besides, the coatings were made of biodegradable γ-cyclodextrin-citrate oligomers (CD-CO) with affinity for both DOX and the MOF cores. DOX was incorporated and released faster due to its affinity for the coating material. A set of complementary solid state nuclear magnetic resonance (ssNMR) experiments including 1H-1H and 13C-27Al two-dimensional NMR, was used to gain a deep understanding on the multiple interactions involved in the MIL-100(Al) core-shell system. To do so, 13C-labelled shells were synthesized. This study paves the way towards a methodology to assess the nanoMOF component localization at a molecular scale and to investigate the nanoMOF physicochemical properties, which play a main role on their biological applications.

Solid-state NMR spectroscopy as a powerful tool to investigate the location of fluorinated lipids in highly porous hybrid organic-inorganic nanoparticles.

Nanosized metal-organic frameworks (nanoMOFs) have emerged as a new class of biodegradable and nontoxic nanomaterials of high interest for biomedical applications thanks to the possibility to load large amounts of a wide variety of therapeutic molecules in their porous structure. The surface of the highly porous nanoMOFs is usually engineered to increase their colloidal stability, to tune their interactions with the biological environment, and to allow targeting specific cells or organs. However, the atomic-scale analysis of these complex core-shell materials is highly challenging. In this study, we report the investigation of aluminum-based nanoMOFs containing two fluorinated lipids by solid-state NMR spectroscopy, including 27 Al, 1 H and 19 F MAS NMR. The ensemble of NMR data provides a better understanding of the localization and conformation of the fluorinated lipids inside the pores or on the nanoMOF surface.

Efficient incorporation and protection of lansoprazole in cyclodextrin metal-organic frameworks.

Lansoprazole (LPZ) is an acid pump inhibitor, which readily degrades upon acidic or basic conditions and under heating. We investigated here LPZ stability upon incorporation in particles made of cyclodextrin metal-organic frameworks (CD-MOFs). LPZ loaded CD-MOFs were successfully synthesized, reaching high LPZ payloads of 23.2 ± 2.1 wt%, which correspond to a molar ratio of 1:1 between LPZ and γ-CD. The homogeneity of LPZ loaded CD-MOFs in terms of component distribution was confirmed by elemental mapping by STEM-EDX. Both CTAB, the surfactant used in the CD-MOFs synthesis, and LPZ compete for their inclusion in the CD cavities. CTAB allowed obtaining regular cubic particles of around 5 µm with 15 wt% residual CTAB amounts. When LPZ was incorporated, the residual CTAB amount was less than 0.1 wt%, suggesting a higher affinity of LPZ for the CDs than CTAB. These findings were confirmed by molecular simulations. Vibrational circular dichroism studies confirmed the LPZ incorporation inside the CDs. Solid-state NMR showed that LPZ was located in the CDs and that it remained intact even after three years storage. Remarkably, the CD-MOFs matrix protected the drug upon thermal decomposition. This study highlights the interest of CD-MOFs for the incorporation and protection of LPZ.

New insights on the supramolecular structure of highly porous core-shell drug nanocarriers using solid-state NMR spectroscopy.

Nano-sized metal-organic frameworks (nanoMOFs), with engineered surfaces to enhance the targeting of the drug delivery, have proven efficient as drug nanocarriers. To improve their performances a step further, it is essential to understand at the molecular level the interactions between the nanoMOF interfaces and both the surface covering groups and the drug loaded inside the micropores. Here we show how solid-state NMR spectroscopy allows us to address these issues in an aluminum-based nanoMOF coated and loaded with phosphorus-containing species.

Discovery and development of novel salicylate synthase (MbtI) furanic inhibitors as antitubercular agents.

We report on the virtual screening, synthesis, and biological evaluation of new furan derivatives targeting Mycobacterium tuberculosis salicylate synthase (MbtI). A receptor-based virtual screening procedure was applied to screen the Enamine database, identifying two compounds, I and III, endowed with a good enzyme inhibitory activity. Considering the most active compound I as starting point for the development of novel MbtI inhibitors, we obtained new derivatives based on the furan scaffold. Among the SAR performed on this class, compound 1a emerged as the most potent MbtI inhibitor reported to date (Ki = 5.3 µM). Moreover, compound 1a showed a promising antimycobacterial activity (MIC99 = 156 µM), which is conceivably related to mycobactin biosynthesis inhibition.