Αμφίφιλα Συμπολυμερή κατά Συστάδες P(MMA-co-HPMA)-b-POEGMA: Σύνθεση, Χαρακτηρισμός, Αυτο-οργάνωση σε Υδατικά Διαλύματα και Εγκλωβισμός Φαρμάκων

Σκοπός της παρούσας ερευνητικής εργασίας είναι η σύνθεση καινοτόμων πολυμερικών συστημάτων με εφαρμογές στον τομέα μεταφοράς φαρμάκων. Τα αμφίφιλα συμπολυμερή κατά συστάδες λόγω της ικανότητάς τους να αυτο-οργανώνονται σε νανοσωματίδια όταν εισέρχονται σε υδατικά διαλύματα καθίστανται ιδιαίτερα χρήσιμα ως νανοφορείς υδρόφοβων φαρμάκων. Μελετήθηκε η σύνθεση αμφίφιλων δισυσταδικών συμπολυμερών πολυ (μεθακρυλικού μεθυλεστέρα - co – μεθακρυλικού υδροξυπροπυλεστέρα) -b- πολυ(μεθακρυλικού εστέρα της ολιγοαιθυνελογλυκόλης) ([poly(methyl methacrylate) - co - hydroxy propyl methacrylate) - b – poly[ oligo(ethylene glycol) methyl ether methacrylate)] με τη μέθοδο RAFT. Στη συνέχεια ακολούθησε ο μοριακός χαρακτηρισμός των συμπολυμερών με χρωματογραφία αποκλεισμού μεγεθών (size exclusion chromatography, SEC) για τον προσδιορισμό των μοριακών βαρών και των κατανομών μοριακών βαρών καθώς και με φασματοσκοπικές μεθόδους όπως πυρηνικό μαγνητικό συντονισμό πρωτονίου (1H-NMR) για τον προσδιορισμό της σύστασης του συμπολυμερούς και τέλος με φασματοσκοπία υπέρυθρης ακτινοβολίας (FT-IR) προκειμένου να γίνει η ταυτοποίηση χαρακτηριστικών ομάδων του συμπολυμερούς. Μελετήθηκαν οι ιδιότητες αυτο-οργάνωσής τους σε υδατικά διαλύματα με χρήση των μεθόδων σκέδασης φωτός (DLS, SLS, ELS) και φασματοσκοπιάς φθορισμού (FS). Τέλος, έγινε η παρασκευή υδατικών διαλυμάτων των συμπολυμερών και έγινε εγκλωβισμός των φαρμάκων κουρκουμίνης και ινδομεθακίνης στα μικκύλια που σχηματίζονται και τα κολλοειδή συστήματα μελετήθηκαν διεξοδικά ως προς τη δομή και τη σταθερότητά τους.The purpose of this research work is to synthesize innovative polymer systems with applications in the field of drug delivery. Amphiphilic block copolymers due to their capability to self-assemble into nanoparticles when inserted in aqueous media are particularly useful as drug vectors. We studied the synthesis of amphiphilic block copolymers ([poly (methyl methacrylate) - co - hydroxy propyl methacrylate) - b – poly [ oligo (ethylene glycol) methyl ether methacrylate)] by the RAFT method. The molecular characterization was carried out using size exclusion chromatography (SEC) for the determination of molecular weights and molecular weight distributions and by proton nuclear magnetic resonance (1H-NMR) for the determination of the composition percentage for each block, and finally by infrared spectroscopy (FT-IR) to identify the copolymer functional groups. Their self-assembly properties in aqueous solutions were studied using light scattering methods (DLS, SLS, ELS) and fluorescence spectroscopy. Finally, aqueous solutions of the copolymers were prepared and two drugs was encapsulated in the micelles formed and the colloidal systems were studied in detail. The polymer nanostructures and drug-loaded nanocarriers were studied by a gamut of physicochemical techniques, including static, dynamic light scattering (SLS, DLS), UV-Vis and FTIR spectroscopy, which gave information on the size and structure of the nanocarriers, and the interactions between the drug and the components of the block copolymers

Dual-Responsive Amphiphilic P(DMAEMA-co-LMA-co-OEGMA) Terpolymer Nano-Assemblies in Aqueous Media

This work reports on the synthesis and self-assembly of a novel series of dual-responsive poly[2-(dimethylamino)ethylmethacrylate-co-laurylmethacrylate-co-(oligoethyleneglycol)methacrylate], P(DMAEMA-co-LMA-co-OEGMA)statistical terpolymers in aqueous solutions. Five P(DMAEMA-co-LMA-co-OEGMA) amphiphilic terpolymers, having different content of the three monomers, were synthesized via reversible addition-fragmentation chain transfer (RAFT) polymerization. The success of the synthesis was confirmed by the molecular characterization of the terpolymers via size exclusion chromatography (SEC) for the determination of molecular weights and the molecular weight distributions. By using nuclear magnetic resonance (1H-NMR) and Fourier-transform infrared (FTIR) spectroscopy, it was possible to determine the exact composition of the terpolymers. Dynamic light scattering (DLS) and fluorescence spectroscopy (FS) indicated the formation of P(DMAEMA-co-LMA-co-OEGMA) unimolecular or multichain aggregates in aqueous solutions, as a response to pH, temperature and ionic strength changes, with their dimensions being largely affected. The amphiphilic terpolymers were able to encapsulate the hydrophobic drug curcumin (CUR) and demonstrate stability to fetal bovine serum (FBS) solutions. These terpolymer aggregates were studied by DLS, FS and UV-Vis, and it was found that they may have been used as potential nanocarriers for drug delivery and bio-imaging applications

Amphiphilic P(OEGMA-co-DIPAEMA) Hyperbranched Copolymer/Magnetic Nanoparticle Hybrid Nanostructures by Co-Assembly

This work presents the utilization of amphiphilic poly(oligo(ethylene glycol) methyl methacrylate)-co-poly(2-(diisopropylamino)ethyl methacrylate), P(OEGMA-co-DIPAEMA), hyperbranched (HB) copolymers, forming polymeric aggregates in aqueous media, as building nanocomponents and nanocarriers for the entrapment of magnetic cobalt ferrite nanoparticles (CoFe2O4, MNPs), and the hydrophobic drug curcumin (CUR) in their hydrophobic domains. Dynamic light scattering (DLS) and cryogenic transmission electron microscopy (cryo-TEM) techniques were used to evaluate the multifunctional hybrid nanostructures formed in aqueous media by co-assembly of the components and their solution properties. Magnetic nanoparticles (MNPs) or MNPs/CUR were co-assembled effectively with pre-existing polymer aggregates, leading to well-defined hybrid nanostructures. Magnetophoresis experiments revealed that the hybrid nanostructures retain the magnetic properties of MNPs after their co-assembly with the hyperbranched copolymers. The hybrid nanostructures demonstrate a significant colloidal stability under physiological conditions. Furthermore, MNPs/CUR-loaded aggregates displayed considerable fluorescence as demonstrated by fluorescence spectroscopy. These hybrid nanostructures could be promising candidates for drug delivery and bio-imaging applications

Surfactant and Block Copolymer Nanostructures: From Design and Development to Nanomedicine Preclinical Studies

The medical application of nanotechnology in the field of drug delivery has so far exhibited many efforts in treating simple to extremely complicated and life-threatening human conditions, with multiple products already existing in the market. A plethora of innovative drug delivery carriers, using polymers, surfactants and the combination of the above, have been developed and tested pre-clinically, offering great advantages in terms of targeted drug delivery, low toxicity and immune system activation, cellular biomimicry and enhanced pharmacokinetic properties. Furthermore, such artificial systems can be tailor-made with respect to each therapeutic protocol and disease type falling under the scope of personalized medicine. The simultaneous delivery of multiple therapeutic entities of different nature, such as genes and drugs, can be achieved, while novel technologies can offer systems with multiple modalities often combining therapy with diagnosis. In this review, we present prominent, innovative and state-of-the-art scientific efforts on the applications of surfactant-based, polymer-based, and mixed surfactant-polymer nanoparticle drug formulations intended for use in the medical field and in drug delivery. The materials used, formulation steps, nature, properties, physicochemical characteristics, characterization techniques and pharmacokinetic behavior of those systems, are presented extensively in the length of this work. The material presented is focused on research projects that are currently in the developmental, pre-clinical stage

Non-Ionic Surfactant Effects on Innate Pluronic 188 Behavior: Interactions, and Physicochemical and Biocompatibility Studies

The aim of this research was to prepare novel block copolymer-surfactant hybrid nanosystems using the triblock copolymer Pluronic 188, along with surfactants of different hydrophilic to lipophilic balance (HLB ratio—which indicates the degree to which a surfactant is hydrophilic or hydrophobic) and thermotropic behavior. The surfactants used were of non-ionic nature, of which Tween 80® and Brij 58® were more hydrophilic, while Span 40® and Span 60® were more hydrophobic. Each surfactant has unique innate thermal properties and an affinity towards Pluronic 188. The nanosystems were formulated through mixing the pluronic with the surfactants at three different ratios, namely 90:10, 80:20, and 50:50, using the thin-film hydration technique and keeping the pluronic concentration constant. The physicochemical characteristics of the prepared nanosystems were evaluated using various light scattering techniques, while their thermotropic behavior was characterized via microDSC and high-resolution ultrasound spectroscopy. Microenvironmental parameters were attained through the use of fluorescence spectroscopy, while the cytotoxicity of the nanocarriers was studied in vitro. The results indicate that the combination of Pluronic 188 with the above surfactants was able to produce hybrid homogeneous nanoparticle populations of adequately small diameters. The different surfactants had a clear effect on physicochemical parameters such as the size, hydrodynamic diameter, and polydispersity index of the final formulation. The mixing of surfactants with the pluronic clearly changed its thermotropic behavior and thermal transition temperature (Tm) and highlighted the specific interactions that occurred between the different materials, as well as the effect of increasing the surfactant concentration on inherent polymer characteristics and behavior. The formulated nanosystems were found to be mostly of minimal toxicity. The obtained results demonstrate that the thin-film hydration method can be used for the formulation of pluronic-surfactant hybrid nanoparticles, which in turn exhibit favorable characteristics in terms of their possible use in drug delivery applications. This investigation can be used as a road map for the selection of an appropriate nanosystem as a novel vehicle for drug delivery