Polymeric and Metal-Organic Frameworks for drug delivery

An important issue in therapeutic treatment of diseases is represented by the drug toxicity at high doses (adverse side effects) when, at the same time, it must be present in the systemic circulation for a time sufficient to achieve the desired therapeutic effects. Another critical aspect in drugs administration is that some of them have a very narrow therapeutic window and most of them are poorly soluble in aqueous media (physiological environments) showing a very low bioavailability. Targeted drug-delivery technology represents a valid solution to the problems connected with disease treatments, increasing the circulation stability of drugs (by protecting them within suitable vectors) and allowing them to reach and be active at the target cellular compartment at a suitable concentration, avoiding, at the same time, adverse side effects. Suitable systems for drug-controlled delivery may be obtained, for example, by chemical modification of the drug by soluble polymers to increase the residence time in the diseased system, or to convey more favorable properties to this, such as the reduction of antigenicity or increased stability toward enzymes. In the polymer-drug conjugate the drug and the polymer are linked together by chemical bonds that can be either cleavable into the body to release the starting drug or stable to keep the drug-polymer conjugate as a new therapeutic product. For the latter, the polymer-drug binding must be designed to maintain the drug active moiety free for receptor binding. In such a way, not only desirable and constant drug levels are achieved, but also a delivery that may last longer. In developing drug delivery systems, by specific carriers, the drug is usually loaded during the process by which the matrix is produced or shaped, or it is absorbed into the preformed matrix from a concentrated drug solution. These systems require special designs, homogeneity of the components and purity. Designing drug delivery systems is one of the most challenging issues in polymer science field. POLYSACCHARIDES Despite the huge number of natural and synthetic polymers or lipidic vehicles used to realize drug carriers, polysaccharidic complexes remain as the simplest and the most economical way to realize an efficient drug delivery system. Polyelectrolyte complexes (PECs), formed by the electrostatic attractions between two oppositely charged polymers, have been used for the realization of controlled release formulations. Chitosan and xanthan gum are two of the most utilized and studied natural polysaccharides for the realization of PECs. Xanthan gum is an exopolysaccharide with a cellulosic backbone along which mannose and glucuronic acid moieties are found, and thanks to their presence, it can be considered an anionic polysaccharide able to form PEC with cationic polymers, such as chitosan, the only natural cationic polysaccharide. The large use of chitosan–xanthan gum PECs for the realization of controlled release systems for oral administration can be explained based on several aspects. Firstly, nontoxic metabolites are produced during their degradation; secondly, chitosan–xanthan gum PEC shows a high enzymatic resistance; and finally, its swelling behavior is pH dependent. Moreover, the combination between a hydrophilic polymer (i.e., xanthan gum) and a structural polymer (i.e., chitosan) guarantees a balance between swelling ratio and elasticity and, therefore, a regulated drug release can be observed. Besides chitosan and xanthan gum, the most utilized polysaccharide in biomedical field is Hyaluronic acid. Hyaluronic acid (HA) is a linear polysaccharide consisting of the repetition of a disaccharide composed of D-glucuronic acid (GLCA) and N-acetyl D-glucosamine (GlcNAc). HA belongs to the so called connective tissue polysaccharides, mucopolysaccharides or glycosaminoglycans. HA is ubiquitous among vertebrates and abundantly expressed in the extracellular matrix of all tissues, as well as on the cell surface. Despite its simple chemical structure, HA plays numerous molecular functions that contribute to the structure and physiology of the tissues, modulating cell behavior during morphogenesis, tissue remodeling and inflammation. The inherent biocompatibility and biodegradability together with the susceptibility to chemical modifications have made HA particularly attractive for the development of biomaterials with a broad clinical potential from ophthalmology to dermatology. Nevertheless, viscosupplementation still represents the main field of application for hyaluronic acid and its derivatives. HA with molecular weight ranging from 500 kDa to 6000 kDa has been used for the development of viscosupplements. Despite the presence of several different HA-based commercial viscosupplements, the development of products with enhanced injectability and yet reasonable viscoelastic behavior for OA treatment is necessary. Indeed, if linear HA solutions have a lower viscosity, making injection easier, they are not as effective as crosslinked HA preparations because of their lower viscoelastic properties. Nevertheless, the higher the viscoelastic properties, the higher the force required to be injected. Moreover, if crosslinking HA significantly improves its viscoelastic properties and residence time, it only slows down HA physiological degradation by hyaluronidases with production of low molecular weight fragments, whose pro-inflammatory action is well known. This has directed research to find adequate hyaluronan substitutes for viscosupplementation, even if Hyaluronan still remains the gold standard. Very few studies on Gellan Gum, a linear, anionic extracellular polysaccharide with repeating tetrasaccharide units of d-glucose, d-glucuronic acid, d-glucose, and l-rhamnose, have been done for this application despite its wide use in biomedical engineering. So, an integration between those two polysaccharides could represent a good solution. SYNTHETIC POLYMERS Recently, a great deal of effort has focused on the design of optimal delivery systems for drugs and bioactive factors, such as magnetic nanoparticles, gold nanoparticles, liposomes, dendrimers, and aptamers. However, polymeric vehicles remain the most convenient and versatile way to deliver substances and, among polymers, one of the most utilized is polyvinyl alcohol (PVA). PVA is one of the largest produced polymers worldwide. It shows optimal properties such as high water affinity, wear resistance, biocompatibility and processability. For these characteristics, it has been used as tissue substitute, heavy metal ions absorbent, carrier for antimicrobial substances. Depending on its end use, PVA based material characteristics must be controlled and tailored to better respond. The main concern is about its stability and resistance. Nevertheless, it can be significantly improved by crosslinking it. For those reasons the PVA theta-gel formation will be performed and explored to evaluate the properties of those frameworks for the use as supplement and drug delivery system in osteoarthrosis. METAL-ORGANIC FRAMEWORKS (MOFs) Many carriers have been reported, but in the past decade MOFs have become a hotspot in the field of drug delivery devices for delivering loaded drug to desired sites. Metal-organic frameworks have the potential to be used as drug delivery systems, thanks to their specific characteristics, especially their exceptionally high surface area, large cavity size for drug encapsulation, and a controlled drug-release profile. Furthermore, the MOFs possess an intrinsic biodegradability due to the relative labile metal-ligand bonds and the tunable functionality for post-synthetic grafting of active molecules. A lot of active molecules of different nature (i.e. hydrophilic, hydrophobic, and amphiphilic) can be encapsulated in the MOFs’ cavity and/or tethered with the framework structure. The active molecules loading can be performed either by covalent interaction or through noncovalent interactions. In this work different frameworks for the release of active molecules and extracts were explored. Polymeric drug delivery systems based on polyelectrolyte complexes, polysaccharide blends and synthetic polymeric theta-gels were synthesized and characterized as vehicles for bioactive substances. Xanthan gum and chitosan based delivery systems were prepared and tested as vehicles to deliver vegetable extracts based on red rice and Annurca apple analyzing their effects on the antioxidant power, cholesterol synthesis and bioavailability, and lipoprotein oxidation. The combination of phytochemical nutraceuticals with lipid lowering activity was demonstrated to be a valid alternative to the use of high doses of active molecules (monacolina K, lovastatine, etc.) to reduce cholesterol levels. A Hyaluronan – gellan gum-based system was tested for the delivery of olive leaves extract in the osteoarthritic knee. The GG-HA blend allows the fast release of the bioactive matrix based on oleuropein extract, thus providing a system able to guarantee at the same time an adequate viscosupplementation and anti-inflammatory action thanks to the presence of oleuropein. For the same bioactive substance, a different vehicle was prepared starting from two of the most used biocompatible synthetic polymers, PVA and PEG. PVA in the form of theta-gel can be prepared in a basic environment, without any influence on the properties of the gels. Different molecular weights for both polymers were tested. Contrarily to what was found for hyaluronan - gellan gum system, the obtained PVA-PEG matrices guaranteed a slow release of oleuropein. The slow release of the oleuropein-based extract may suggest a use of these matrices for the prolonged deliverance therapies for active extracts. A metal-organic framework based on vanadium and gallic acid was synthesized and characterized. The synthetic parameters as active time and amplitude of sonication were tested and varied to optimize the MOF structure and properties in terms of particle size, system colloidal stability, surface charge, specific surface area and porosity to develop suitable drug delivery systems for active molecules and natural extracts. Commercial products for oral iron supplementation containing different iron (II or III) chelating agents were studied, focusing on the active iron complex, and evaluating the effect of iron oxidation state, complexing agent, and particle dimensions on the iron bioavailability. The study allowed to discriminate the formulation (MB) with the highest colloidal stability, which was reflected in an enhanced iron bioavailability, as compared to the others, as highlighted by the in vitro tests used to quantify the iron release.