SUPRAMOLECULAR SELF-ASSEMBLED NANOSTRUCTURES BASED ON STAR POLYMERS FOR DRUG AND GENE DELIVERY

Ph.DDOCTOR OF PHILOSOPHY (FOE

SYNTHESIS, CHARACTERIZATION, IN VITRO EVALUTION, AND PRECLINICAL PROFILING OF β-CYCLODEXTRIN POLYROTAXANE FAMILIES FOR USE AS POTENTIAL NIEMANN-PICK TYPE C THERAPEUTICS

Niemann-Pick Disease Type C (NPC) is a rare, autosomal recessive genetic disorder featuring a loss of proteins responsible for unesterified cholesterol (UC) trafficking through the late endosomes/lysosomes (LE/LY) of every cell of the body. Disruption of this pathway leads to abnormal accumulation and storage of UC and other lipids. A broad range of visceral and neurological symptoms result from this accumulation exhibiting a variable age of onset and a disease progression that is ultimately fatal. The disease has an incidence of approximately 1 in 120,000 live births and has no known effective treatment

Cyclodextrin-Based Contrast Agents for Medical Imaging

Cyclodextrins (CDs) are naturally occurring cyclic oligosaccharides consisting of multiple glucose subunits. CDs are widely used in host–guest chemistry and biochemistry due to their structural advantages, biocompatibility, and ability to form inclusion complexes. Recently, CDs have become of high interest in the field of medical imaging as a potential scaffold for the development of a large variety of the contrast agents suitable for magnetic resonance imaging, ultrasound imaging, photoacoustic imaging, positron emission tomography, single photon emission computed tomography, and computed tomography. The aim of this review is to summarize and highlight the achievements in the field of cyclodextrin-based contrast agents for medical imaging

Cyclodextrins as Bricks for Tuning Polymer Properties

Cyclodextrins are natural cyclic oligosaccharides with a cone shape delimiting a hydrophobic cavity. The rims of cyclodextrins can be functionalized in order to improve their properties. Based on this, cyclodextrins can be linked to polymer chains, which further allows the tuning of the polymer properties. This review describes the methods of polymer functionalization with cyclodextrins and highlights the changes in the physicochemical properties of these materials. This chapter is focused on polymers in solution and in gel states. Cyclodextrin-based polymers are evaluated by various physicochemical methods, such as rheology, calorimetry, and spectroscopy (electron paramagnetic resonance, fluorescence, nuclear magnetic resonance (NMR), Fourier transform infrared (FT-IR), etc.). Both natural and synthetic polymers are considered in this chapter

Remission of lymphoblastic leukaemia in an intravascular fluidic environment by pliable drug carrier with a sliding target ligand

A polyrotaxane-based nanoconstruct with pliable structure carrying a chemotherapeutic drug was developed for targeting circulating lymphoblastic leukaemia cells in a fluidic environment of blood vessels in vivo. By introducing lymphoblast targeting aptamer DNA through cyclodextrin, threaded in poly(ethylene glycol) as polyrotaxane, target aptamer slides along the long polymeric chain and actively search for target ligand, leading to active targeting in dynamic fluidic system which is enhanced by up to 6-fold compared with that of control carriers with non-sliding targeting ligands. Moreover, the drug carrier was made stimuli-responsive by employing i-motif DNA to selective releases of its payload at intracellular acidic condition. These combined features resulted in the effective remission of lymphoblastic leukaemia both in vitro and in dynamic blood vessels in vivo.1142Ysciescopu

FUNCTIONALIZATION OF POLYCAPROLACTONE THROUGH NOVEL BLOCK COPOLYMER DESIGN FOR CELL ENGINEERING AND GENE DELIVERY

Ph.DDOCTOR OF PHILOSOPH

Experimental Characterization and Theoretical Calculations of Responsive Polymeric Systems

Due to their controllable size, low cytotoxicity, and unique architecture, cyclodextrin based pseudopolyrotaxanes have been developed to encompass a broad range of diverse medical and chemical engineering applications. The study of complexation between α-cyclodextrin (alfa-CD) grafted PEG segments on the surface of PAMAM dendrimers was carried out to investigate the physical properties and driving force of this so called host guest interaction. At pH of 10, complexation between alfa-CD and PEGylated-PAMAM occurred once alfa-CD was titrated to the PAMAM solution. However, at pH of 2 no binding took place until a critical alfa-CD concentration (C*) of ~ 8.0 mM was exceeded. The size of the nanostructures increased with alfa-CD concentration ranging from 0.5 to 25 mM at pH value of 2. From zeta potential measurements it was found that the PEGylated-PAMAM possessed positive charges, attributed to the protonation of primary amine groups on PAMAM chains that impart electrostatic repulsive forces to the system. As observed from DLS and SLS study at increasing alfa-CD concentration and pH values, the morphology of the complex changed from a start shaped to a Gaussian like structure. The dynamics and dimensions (length, diameter, translation and diffusion coefficients) of rod-like cellulose micro crystallites (whisker) were also investigated using simulated parameter estimation technique. For rod with L/d ratio equal to 17 (ROD 17), experimental D and Θ values produced length and diameter values showing close resemblance to experimental results with a significant reduction in the percentage error approaching 0.22 and 0.27% after 1000 iterations, respectively. The proposed approach provides a suitable and simple method to determine the length and diameter of rod-like nanoparticles, such as nanocrystalline cellulose

Biomasses for the obtainment of new functional polymer materials

This thesis collects three years of work dedicated to the development of new polymeric systems based on the use of raw materials derived from biomasses. Biomasses are a very versatile renewable energy source with low environmental impact and are less expensive than the resources deriving from petroleum. Furthermore, the use of biomasses leads to environmental advantages. This PhD work is divided into two parts: the first one describes the works (someone already published by me and my group) in which cyclodextrins are chosen for the synthesis and characterization of crosslinked or non-crosslinked hydrogels, and polypseudorotaxane hydrogels. Moreover, they were also used for the synthesis of a new class of on cork-based materials, and for the synthesis of cyclodextrin-based lactic acid oligomers. While in the second one, methyl cellulose was chosen as starting material for the obtainment of semi-interpenetrating polymer network hydrogel systems

Advanced hydrogels based on natural macromolecules: chemical routes to achieve mechanical versatility

Advances in synthetic routes to chemically modify natural macromolecules such as polysaccharides and proteins have allowed designing functional hydrogels able to tackle current challenges in the biomedical field. Hydrogels are hydrophilic three-dimensional systems able to absorb or retain a large volume of water, prepared from a low percentage of precursor macromolecules. The typical fragile elastic structure of common hydrogel formulations often limits their usage. Three main fabrication strategies involving several compounds or multimodified materials known as double networks, dual-crosslinked networks, and interpenetrating networks have been explored to impart mechanical strength to hydrogels. Widely investigated for synthetic polymers, these approaches allow obtaining added-value hydrogels with a large spectrum of mechanical properties. Advances in the development of such hydrogels with biomacromolecules as main constituent materials have enabled the fabrication of hydrogels with improved key properties for medical use, including biocompatibility, controlled release of active substances and tailored biodegradability, while exploring sustainable sources. This review describes recent advances in the use of proteins, as well as natural and semi-synthetic polymers for the fabrication of hydrogels for biomedical applications. Structures processed via double network, dual-crosslinked, or interpenetrating network strategies are reviewed, and emphasis is given to the type of chemical modifications and reactions, as well as the covalent and non-covalent interactions/bonds involved in those mechanisms.publishe

SUPRAMOLECULAR BIOMATERIALS BASED ON CYCLODEXTRIN-OLIGOETHYLENIMINE STAR POLYMERS FOR DRUG AND GENE DELIVERY

Ph.DDOCTOR OF PHILOSOPH