PHOTODYNAMIC THERAPY OF MALIGNANT PRIMARY BRAIN TUMOURS: CLINICAL EFFECTS, POSTOPERATIVE ICP, and LIGHT PENETRATION OF THE BRAIN

Abstract We are reporting our experience with intraoperative PDT in 32 patients with malignant supratentorial gliomas; in 19 cases the tumour was recurrent. There were 20 males and 12 females with an age range of 17-73 (mean = 45) yr. The first 8 patients in this series received HpD (Photofrin I) and the next 24 received DHE (Photofrin II). A photo-illuminating device, of the author's design, was coupled to an argon dye pump laser in order to deliver light at 630 nm to a tumour cavity created by radical tumour resection and/or tumour cyst drainage. The total light energy delivered ranged from 440 to 3888 J and the light energy density ranged from 8 to 68 J cm^?2. There were two post-operative deaths as the consequence of hematoma accumulation in an extensive tumour resection cavity. In two patients neurological function was worse post-operatively and did not recover. Post-operative cerebral edema was pronounced in eight cases and required emergency craniotomy in two patients (the histology from both showed hemorrhagic necrosis of residual tumour). We have fashioned continuous post-operative ICP measurements in the last 15 patients treated with PDT and compared the values to those obtained from cases with malignant gliomas who did not have PDT; the mean ICP was significantly greater in the PDT group. Four patients developed wound infections; two of these required surgical treatment. Four patients, two of whom were hemiparetic, developed deep vein thrombosis and required anticoagulant therapy. There were no adverse systemic reactions to the administration of either photosensitizer and only 3 skin photosensitivity reactions. Follow up has ranged from 1 to 26 months at the time of writing; 38% were still alive; in the interval between PDT and death, the deaths per observation year was 1.11 for the whole group and 1.00 when the two post-operative deaths are excluded. In the interval between first diagnosis and death the rate was 0.45 deaths per observation year. Photodynamic therapy of malignant brain tumours using surface or cavitary photo-illumination can be carried out with acceptable risk. In eight patients we determined the penetration depth of light in brain tissue in vivo by reading the detected light flux from a fiber passed radially into the brain towards the centre of the irradiation volume. The optical fiber consisted of a single 400 μ.m, cleaved fiber fixed in a 17-gauge biopsy needle coupled to a photometer. The light penetration depth ranged from 0.8 to 4.9. The mean PD values in the‘tumour’group and the‘brain’group was 2.9 ± 1.5 and 1.5 ± 0.43, respectively. We attribute this significant difference to the differences in the absorption and scattering properties of brain and tumour.     

Investigation of non-covalent interactions between paramagnetic complexes and human serum albumin by electrospray mass spectrometry

Stable gadolinium(III) chelates are nowadays routinely used as contrast agents for magnetic resonance imaging (MRI). Their non-covalent binding to human serum albumin (HSA) has shown to improve their efficacy. Non-covalent interactions lead to complex formation that can be quantified by several techniques that are mostly tedious and time-consuming. In this study, electrospray ionization mass spectrometry (ESI-MS) was used to investigate the interaction between HSA and several gadolinium(III) complexes. The results were compared with those obtained in the liquid phase. Four gadolinium complexes were investigated: Gd-DTPA 1, Gd-C(4)Me-DTPA 2, Gd-EOB-DTPA 3, and MP-2269 4. Relaxometry studies show that complexes 1 and 2 have no significant affinity for HSA, while complexes 3 and 4 have increasing affinities for the protein. 1:1 and 1:2 complexes between HSA and MP-2269 were detected by ESI-MS for a twofold excess of the contrast agent, whereas a ligand/protein molar ratio of 4:1 was necessary to observe a 1:1 stoichiometry for Gd-EOB-DTPA, an observation that is in good agreement with the known weaker affinity of the contrast agent for the protein. At a fourfold molar excess, no supramolecular complex was observed for Gd-DTPA 1 and Gd-C(4)Me-DTPA 2; a tenfold molar excess was necessary to detect a 1:1 complex, confirming the very weak affinity of these contrast agents for HSA.     

On the structure of tetracoordinated organocobalt complexes of the type [CoR2L2]

A series of square-planar organocobalt complexes of the type [CoR₂L₂] (R = 2,3,4,6-C₆,HCl₄ and 2,3,6-C₆H₂Cl₃, L = PEtPh₂, PEt₂Ph, and PEt₃; R = 2,3,5,6-C₆HCl₄, and 2,6-C₆H₃Cl₂, L = PEt₂Ph, PEt₃, and $\text{1}\text{2}$dpe) have been prepared in which the electronegativities of the ligand R vary progressively. The reaction of o-C₆H₄ClMgBr with [CoCl₂L₂] (L = PEtPh₂ PEt₂Ph, γ-pic or $\text{1}\text{2}$bipy) did not give air stable compounds at room temperature, but the solutions obtained at ?78°C appear to contain square-planar species for L = PEtPh₂, PEt₂Ph, and γ-pic, and tetrahedral for L₂ = bipy. The tendency towards square-planar or tetrahedral structures for the compounds [CoR₂L₂] depends on the following factors in order of importance: (i) when the neutral ligand is a phosphine a square-planar structure is adopted; (ii) when L is an aromatic amine, bulky ortho substituents on R favour a square-planar structure; and (iii) a tetrahedral geometry is favoured by bidentate amine ligands. The electronegativity of the organic group R seems to be less important.     

Characterization of photoproducts of m-THPP in aqueous solution

This study examined the nature of photoproducts after pulse laser irradiation (647.5 nm) of 5,10,15,20-tetrakis(meso-hydroxyphenyl)porphyrin (m-THPP) (10 micromol/L) in ethanol-water (1/99, vol/vol) solution. Spectroscopic measurements (UV-visible absorption and fluorescence) and mass spectrometry techniques (matrix-assisted laser desorption-ionization [MALDI] coupled with time-of-flight mass spectrometer [TOF-MS] or tandem time of flight mass spectrometer [TOF/TOF-MS]) were used to follow photomodifications. Spectroscopic measurements evidenced photomodification as the main process after m-THPP irradiation. Three oxidized photoproducts at m/z 693.25, 695.24 and 713.25 were characterized by MS. After prolonged irradiation new isotopic distributions were registered at m/z 1355.41, 2031.57, 2707.80 and 3383.98 with MALDI-TOF-MS and TOF/TOF-MS. These new photoproducts were attributed to covalent oligomeric structures as dimer, trimer, tetramer and pentamer of m-THPP.     

Effect of nonelectrostatic interactions on the macromolecular behavior of polyelectrolytes. III. Optical rotatory dispersion of PLL in water and aqueous-organic mixtures

We have investigated the optical rotatory dispersion of a stereo-irregular polyelectrolyte when neutralized with alkaline and N-tetraalkylammonium hydroxides, both in water and aqueousacetone mixtures. The variations of the optical activity properties during the neutralization can be well related to potentiometric and viscosity measurements. They are interpreted by assuming two kinds of solvation of the chiral centers located on the main chain, to which two partial optical rotary dispersions (ORD) of opposite signs are associated. The observed optical activity changes and specifically the discontinuity occurring in the neutralization range where a conformational transition between a compact structure and a more extended one is initiated, are thus accounted for in terms of the corresponding changes in the state of solvation of chains.     

Circularly polarized luminescence from bridged triarylamine helicenes

The first examples of circularly polarized luminescence from chiral bridged triarylamine-based heterohelicene molecules are reported. The luminescence dissymmetry factors are approximately |0.001|.     

Adsorption of Poly(ethylene oxide)-Poly(lactide) Copolymers. Effects of Composition and Degradation

The effect of chemical degradation of two diblock copolymers of poly(ethylene oxide) (E) and poly(lactide) (L), E(39)L(5) and E(39)L(20), on their adsorption at silica and methylated silica was investigated with in situ ellipsometry. Steric stablization of polystyrene dispersions was investigated in relation to degradation. Hydrolysis of the poly(lactide) block of the copolymers was followed at different temperatures and pH by using HPLC to measure the occurrence of lactic acid in solution. The block copolymers were quite stable in pH-unadjusted solution at low temperature, whereas degradation was facilitated by increasing temperature or lowering of the pH. Lower degradation rates of E(39)L(20) where observed at low temperature in comparison with those of E(39)L(5), whereas the degradation rates of the copolymers were quantitatively similar at high temperature. The adsorption of the copolymers at methylated silica substrates decreased with increasing degree of degradation due to the reduction in the ability of hydrophobic block to anchor the copolymer layer at the surface. At silica the adsorption initially increased with increasing degradation, particularly for E(39)L(20) due to deposition of aggregates onto the surface. After extensive degradation the adsorption of the copolymers at both silica and methylated silica resembled that of the corresponding poly(ethylene oxide) homopolymer. Overall, it was found that the eventual reduction in adsorption occurred at a lower degree of degradation for E(39)L(5) than for E(39)L(20). Mean-field calculations showed a reduced anchoring for the block copolymers with decreasing poly(lactide) block length at hydrophobic surfaces. In accordance with this finding, it was observed that polystyrene dispersions were stabilized by E(39)L(20) or E(39)L(5) in a way that depended on both the lactide block length and the degree of degradation. Upon degradation of the hydrophobic block, stabilization of the polystyrene dispersions was maintained initially, but eventually degradation resulted in destabilization. The average residual copolymer concentration required for stabilization of the polystyrene dispersions was much higher than the corresponding concentration of intact copolymer required for stabilization. Copyright 2001 Academic Press.     

Synthesis, characterization, and pharmacokinetic evaluation of a potential MRI contrast agent containing two paramagnetic centers with albumin binding affinity

A dinuclear gadolinium(III) complex of an amphiphilic chelating ligand, containing two diethylenetriamine-N,N,N',N',N'-pentaacetate (DTPA) moieties bridged by a bisindole derivative with three methoxy groups, has been synthesized and evaluated as a potential magnetic resonance imaging (MRI) contrast agent. Nuclear magnetic relaxation dispersion (NMRD) measurements indicate that at 20 MHz and 37 degrees C the dinuclear gadolinium(III) complex has a much higher relaxivity than [Gd(DTPA)] (6.8 vs 3.9 s(-1) mmol(-1)). The higher relaxivity of the dinuclear gadolinium(III) complex can be related to its reduced motion and larger rotational correlation time relative to [Gd(DTPA)]. In the presence of human serum albumin (HSA) the relaxivity value of the noncovalently bound dinuclear complex increases to 15.2 s(-1) per mmol of Gd3+, due to its relatively strong interaction with this protein. The fitted value of the binding constant to HSA (Ka) was found to be 10(4) M(-1). Because of its interaction with HSA, the dinuclear complex exhibits a longer elimination half-life from the plasma, and a better confinement to the vascular space compared to the commercially available [Gd(DTPA)] contrast agent. Transmetalation of the dinuclear gadolinium(III) complex by zinc(II) has been investigated. Biodistribution studies suggest that the complex is excreted by the renal pathway, and possibly by the hepatobiliary route. In vivo studies indicated that half of the normal dose of the gadolinium(III) complex enhanced the contrast in hepatic tissues around 40 % more effectively than [Gd(DTPA)]. The dinuclear gadolinium(III) complex was tested as a potential necrosis avid contrast agent (NACA), but despite the binding to HSA, it did not exhibit necrosis avidity, implying that binding to albumin is not a key parameter for necrosis-targeting properties.     

Intramolecular allyl transfer reaction from allyl ether to aldehyde groups: experimental and theoretical studies

The intramolecular transfer of the allyl group of functionalized allyl aryl ethers to an aldehyde group in the presence of Ni0 complexes was studied from chemical, electrochemical and theoretical points of view. The chemical reaction involves the addition of Ni0 to the allyl ether followed by stoichiometric allylation. The electrochemical process is catalytic in nickel and involves the reduction of intermediate eta3-allylnickel(II) complexes.     

Occurrence, shape, and dimensions of large surface hemimicelles made of semifluorinated alkanes. Elongated versus circular Hemimicelles. Pit- and tip-centered hemimicelles

The formation of large (approximately 20-35 nm) surface hemimicelles in monolayers of semifluorinated alkanes, C(n)F(2)(n)(+1)C(m)H(2)(m)(+1) (FnHm), observed after transfer onto silicon wafers, is a general phenomenon. F6H16 and F8H14 exclusively form highly monodisperse circular hemimicelles, organized in a hexagonal array. The other FnHm investigated form both circular and elongated hemimicelles. The longer FnHm is, the larger the area fraction of elongated micelles; both the hydrocarbon block (H-block) and the fluorocarbon block (F-block) affect this area fraction. The length of the elongated micelles increases with the total length of the diblocks. The diameter of the circular micelles increases with the length of the H-block but, unexpectedly, not with that of the F-block. Model calculations account for these observations. Close examination of the circular micelles showed that they generally present a pit or a tip at their center. The width of the elongated micelles is comparable to the radius of the circular micelles, suggesting that the latter arise from a partition of elongated micelles, followed by coalescence of the edges of the resulting fragments. The elongated micelles become shorter and fewer when surface pressure increases, further suggesting a conversion of elongated into circular micelles. This conversion is reversible. The surface pressure-molecular area isotherms do not present any feature that forebears the existence of hemimicelles. The obtaining of stable surface patterns from simple, "nonpolar" molecular fluorocarbon/hydrocarbon diblocks opens a new approach for producing featured nanostructures from organic templates.