Claudia Forte

Influence of Amide versus Ester Linkages on the Properties of Eight-Armed PEG-PLA Star Block Copolymer Hydrogels

Water-soluble eight-armed poly(ethylene glycol)-poly(l-lactide) star block copolymers linked by an amide or ester group between the PEG core and the PLA blocks (PEG-(NHCO)-(PLA)(8) and PEG-(OCO)-(PLA)(8)) were synthesized by the stannous octoate catalyzed ring-opening polymerization of l-lactide using an amine- or hydroxyl-terminated eight-armed star PEG. At concentrations above the critical gel concentration, thermosensitive hydrogels were obtained, showing a reversible single gel-to-sol transition. At similar composition PEG-(NHCO)-(PLA)(8) hydrogels were formed at significantly lower polymer concentrations and had higher storage moduli. Whereas the hydrolytic degradation/dissolution of the PEG-(OCO)-(PLA)(8) takes place by preferential hydrolysis of the ester bond between the PEG and PLA block, the PEG-(NHCO)-(PLA)(8) hydrogels degrade through hydrolysis of ester bonds in the PLA main chain. Because of their relatively good mechanical properties and slow degradation in vitro, PEG-(NHCO)-(PLA)(8) hydrogels are interesting materials for biomedical applications such as controlled drug delivery systems and matrices for tissue engineering.

PREPARATION, CHARACTERISATION AND PHOTOSENSITIVITY STUDIES OF SOLID DISPERSIONS OF DIFLUNISAL AND EUDRAGIT RS100 AND RL100

Solid dispersions of diflunisal (DIF) with Eudragit RS100 (RS) and RL100 (RL) with different drug-to-polymer ratios were prepared by a solvent method (coevaporates) and were characterised in the solid state in comparison with the corresponding physical mixtures. The work was aimed at characterising the interactions occurring between DIF and RS or RL polymers, along with their influence on the in-vitro drug-dissolution pattern. The findings suggest that the drug did not change its crystalline form within the polymer network. Drug dispersion in the polymer matrix strongly influences its dissolution rate, which appears slower and more gradual while increasing the polymer ratios. Moreover, DIF is known to be a photosensitive compound, and its photoproduct has been found to be a toxic agent. This can be evidenced by testing red blood cell membranes for their resistance to the osmotic shock induced by UVA irradiation in the presence of DIF. The presence of some DIF/RS coevaporates was shown to reduce significantly the drug photosensitization process towards cell membranes. This suggests the possibility of combining the design of a drug delivery system with a photoprotective strategy.

Self-Aggregation of Gel Forming PEG-PLA Star Block Copolymers in Water

The aggregation behavior and dynamics of poly(ethylene glycol) (PEG) and poly(lactide) (PLA) chains in a homologous series of eight-armed PEG-PLA star block copolymers ((PEG(65)-NHCO-PLA(n))(8) with n = 11, 13, and 15) in water at different concentrations and temperatures were studied by means of (1)H and (13)C NMR spectroscopy and (1)H longitudinal relaxation time analysis. The state of water in these systems was also investigated through the combined use of (1)H and (2)H longitudinal relaxation time measurement. On the basis of the NMR experimental findings and of dynamic light scattering measurements, (PEG(65)-NHCO-PLA(n))(8) in water can be described as self-aggregated systems with quite rigid hydrophobic domains made of PLA chains and aqueous domains where both PEG chains and water molecules undergo fast dynamics. A smaller number of rigid domains was found for (PEG(65)-NHCO-PLA(11))(8) with respect to the homologous copolymers with longer PLA chains. At low concentrations, the PLA domains are mainly formed by chains belonging to the same molecule, thus giving rise to unimolecular micelles. At intermediate concentrations, that is, above the critical association concentration (CAC) but below the critical gel concentration (CGC), nanogels are formed by interconnection of several PLA domains through shared unimers. Above the CGC, the network is extended to the entire system, giving rise to macroscopic gels. In all cases, a fraction of PLA chains remains quite mobile and exposed to water due to topological constraints of the star architecture.

Structure determination of clay/methyl methacrylate copolymer interlayer complexes by means of 13C solid state n.m.r.

Abstract The interlayer complexes of several methyl methacrylate (MMA)/2-( N -methyl- N,N -diethylammonium iodide) ethyl acrylate (MDEA) copolymers with two smectite clays (bentonite and hectorite), synthesized in two different ways, were studied by means of solid state 13 C n.m.r. techniques. Given the relatively high content of paramagnetic centres in bentonite, which is approximately 50 times more paramagnetic than hectorite, the s.p.e./m.a.s. and c.p./m.a.s. spectra of the different complexes with bentonite show differences according to the proximity of the different copolymer moieties to the clay surface. The dynamics of the organic macromolecules in the inorganic interlayers has been investigated by measuring various relaxation times ( 13 C T 1 , 13 C T 1 ρ and 1 H T 1 ρ ). The paramagnetism of the clay, where relevant, strongly influences the relaxation times measured, whereas in the other cases the different relaxation times allow one to discern differences in the structural organization and mobility of the organic macromolecules dependinding on the complex preparation. Useful indications on the structure of the different complexes have been obtained by combining the above results with X-ray measurements of the interlayer distance for all the samples investigated.

Boron nitride nanotubes for boron neutron capture therapy as contrast agents in magnetic resonance imaging at 3 T.

The applicability of boron nitride nanotubes (BNNTs) containing Fe paramagnetic impurities as contrast agents in magnetic resonance imaging (MRI) was investigated. The measurement of longitudinal and transverse relaxation times of water protons in homogeneous aqueous dispersions of BNNTs wrapped with poly(L-lysine) at different concentrations allowed longitudinal (r(1)) and transverse (r(2)) relaxivities to be determined at 3T. The r(2) value was comparable to those of commercial superparamagnetic iron oxide nanoparticles, indicating that Fe-containing BNNTs have the potential to be used as T(2) contrast-enhancement agents in MRI at 3T.

Solute-Solvent Interactions in the Nematic and Smectic A Phases of 4 4-di-n-Heptylazoxybenzene Studied by Deuteron NMR

Abstract The orientational order parameters have been measured by deuteron N.M.R. of both solute (at low dilution) and solvent in various binary mixtures involving the liquid crystal 4,4′-di-n-heptylazoxybenzene (HAB). The solutes studied were azoxybenzene-d10 and n-heptylbenzene-d7 which are fragments of HAB, azobenzene-d 10 because of its similarity to azoxybenzene, and anthracene-d10 because of its known structure and symmetric shape. The major and biaxial order parameters of the solutes are analysed in terms of a molecular field model for the potential of mean torque for biaxial particles. The behaviour of the solute order parameters on approaching and entering the smectic A phase is interpreted in terms of a temperature and phase dependent partitioning of the solute between aromatic and aliphatic regions of the solvent.

Active Targeting of Sorafenib: Preparation, Characterization, and In Vitro Testing of Drug-Loaded Magnetic Solid Lipid Nanoparticles.

Sorafenib is an anticancer drug approved by the Food and Drug Administration for the treatment of hepatocellular and advanced renal carcinoma. The clinical application of sorafenib is promising, yet limited by its severe toxic side effects. The aim of this study is to develop sorafenib-loaded magnetic nanovectors able to enhance the drug delivery to the disease site with the help of a remote magnetic field, thus enabling cancer treatment while limiting negative effects on healthy tissues. Sorafenib and superparamagnetic iron oxide nanoparticles are encapsulated in solid lipid nanoparticles by a hot homogenization technique using cetyl palmitate as lipid matrix. The obtained nanoparticles (Sor-Mag-SLNs) have a sorafenib loading efficiency of about 90% and are found to be very stable in an aqueous environment. Plain Mag-SLNs exhibit good cytocompatibility, whereas an antiproliferative effect against tumor cells (human hepatocarcinoma HepG2) is observed for drug-loaded Sor-Mag-SLNs. The obtained results show that it is possible to prepare stable Sor-Mag-SLNs able to inhibit cancer cell proliferation through the sorafenib cytotoxic action, and to enhance/localize this effect in a desired area thanks to a magnetically driven accumulation of the drug. Moreover, the relaxivity properties observed in water suspensions hold promise for Sor-Mag-SLN tracking through clinical magnetic resonance imaging.

Self-Assembly and Photo-Cross-Linking of Eight-Armed PEG-PTMC Star Block Copolymers

Eight-armed poly(ethylene glycol)-poly(trimethylene carbonate) star block copolymers (PEG-(PTMC)(8)) linked by a carbamate group between the PEG core and the PTMC blocks were synthesized by the metal-free, HCl-catalyzed ring-opening polymerization of trimethylene carbonate using an amine-terminated eight-armed star PEG in dichloromethane. Although dye solubilization experiments, nuclear magnetic resonance spectroscopy, and dynamic light scattering clearly indicated the presence of aggregates in aqueous dispersions of the copolymers, no physical gelation was observed up to high concentrations. PEG-(PTMC(9))(8) was end-group-functionalized using acryloyl chloride and photopolymerized in the presence of Irgacure 2959. When dilute aqueous dispersions of PEG-(PTMC(9))(8)-Acr were UV irradiated, chemically cross-linked PEG-PTMC nanoparticles were obtained, whereas irradiation of more concentrated PEG-(PTMC(9))(8)-Acr dispersions resulted in the formation of photo-cross-linked hydrogels. Their good mechanical properties and high stability against hydrolytic degradation make photo-cross-linked PEG-PTMC hydrogels interesting for biomedical applications such as matrices for tissue engineering and controlled drug delivery systems.

Dynamics and morphology of polyolefinic elastomers by means of 13C and1H solid-state n.m.r.

Abstract An extensive study of both 1H and 13C Tl (spin-lattice) and Tlρ (spin-lattice in the rotating frame) relaxation times as well as TCH (proton—carbon cross-polarisation times) was undertaken in order to investigate the morphology and dynamics of an ethylene/propylene/ethylidene-norbornene terpolymer and two ethylene/propylene random copolymers obtained using different catalytic systems. Several selective n.m.r. techniques were first used in order to obtain information on the structure and phase composition of the three copolymers. Two of the samples were found to consist of a single phase, whereas the copolymer obtained with a Ti-based catalyst clearly showed three phases: rubbery ethylene/propylene random copolymer, crystalline polyethylene, and isotactic crystalline polypropylene. Moreover, a fourth phase, made of ‘rigid’ amorphous polyethylene, bordering the crystalline polyethylenic regions, was singled out by means of1H Tl, 13C T1ρ and TCH measurements. In the same sample the dimensions of the crystalline domains dispersed in the rubber matrix were roughly estimated on the basis of the proton relaxation times. Qualitative and semi-quantitative information on motions in the kHz and MHz ranges was derived from carbon relaxation times.

Conformations of phenylalanine in the tripeptides AFA and GFG probed by combining MD simulations with NMR, FTIR, polarized Raman, and VCD spectroscopy.

Conformational properties of small, flexible peptides are a matter of ongoing interest since they can be considered as models for unfolded proteins. However, the investigation of the conformations of small peptides is challenging as they are ensembles of rapidly interconverting conformers; moreover, the different methods used are prone to different approximations and errors. In order to obtain more reliable results, it is prudent to combine different techniques; here, molecular dynamics (MD) simulations together with nuclear magnetic resonance (NMR), Fourier transform IR (FTIR), polarized Raman, and vibrational circular dichroism (VCD) measurements were used to study the conformational propensity of phenylalanine in the tripeptides AFA and GFG, motivated by the relevance of phenylalanine for the self-aggregation of peptides. The results of this analysis indicate that the F residue predominantly populates the beta-strand (beta) and polyproline II (PPII) conformations in both AFA and GFG. However, while phenylalanine exhibits a propensity for beta-strand conformations in GFG (0.40 < or = beta population < or = 0.69 and 0.29 < or = PPII population < or = 0.42), the substitution of terminal glycines with alanine residues induces a higher population of PPII (0.31 < or = beta population < or = 0.50 and 0.37 < or = PPII population < or = 0.57).