Christian Braud

Optically active poly (\-malic-acid)

SummaryA simple and reproducible method of synthesizing enantiomers of benzyl malolactonate is described starting from optically active aspartic acid. Chiral benzyl malolactonate is a β-substituted β-lactone monomer which can be readily polymerized anionically using triethylamine as the initiator to yield poly(benzyl β-malate) which is an optically active, semicrystalline polymer. Cleavage of protecting benzyl ester groups yields optically active poly(β-malic acid). The properties of the racemic and optically active monomers and polymers are compared. Optically active (−)poly(β-malic acid) shows one accessible positive CD band in the far UV.

Poly(β-malic acid) : a new polymeric drug-carrier

SummaryPoly(β-malic acid) is a new synthetic functional polyester of the poly(β-hydroxy-acid)-type whose properties are investigated in regard to possible uses as bioresorbable polyvalent drug-carrier. Degradation of polymer chains in 0.15 N phosphate buffer at pH=7.5 is monitored by aqueous GPC on SEPHADEX gels and by enzymatic titration of ultimate degradation products. It is shown that the rate of degradation obeys first order kinetics at the begining and that poly(β-malic acid) degrades to malic acid at last.

In vivo Fate of Repeat-Unit-Radiolabelled Poly(β-malic acid), a Potential Drug Carrier

In order to compare the fates of end-chain-radiolabelled and repeat-unit-radiolabelled poly(β-malic acid)s after intravenous injection in mice, repeat-unit 14C-radiolabelling of this biodegradable water-soluble poly carboxylic acid polymer was achieved starting from 14C-aspartic acid. The ac tivity of the resulting radioactive poly(β-malic acid) (sodium salt) (Mw ∼ 20,000 as determined by aqueous SEC) was 4.5 μCi·g -1. Aliquots of a neutral 0.3 monoM (4.14% w/v) solution of poly(β-malic acid) (sodium salt) were given intravenously to mice through a lateral tail vein. Intravenous and intra peritoneal toxicity was checked in order to show whether injection of this polymer can affect significantly the normal behavior of experimental animals. Radioactivity was counted in liver, kidney, intestine, lung, brain, spleen, heart, muscle, urine and blood for various post-injection times up to 24 h. Data con firmed the occurrence of predominant and fast urinary excretion (70% after 1 h) already observed with the end-chain-radiolabelled homologue. Although the polymer is basically metabolizable, the fast elimination of radioactivity via urinary tract is most likely to be due to the excretion of polymeric molecules and not of metabolic by-products because end-chain- and repeat-unit-labellings led to similar excretion patterns.

Blocky structure of copolymers obtained by Pd/C-catalysed hydrogenolysis of benzyl protecting groups as shown by sequence-selective hydrolytic degradation in poly(β-malic acid) derivatives

Abstract The pendant benzyl groups of benzyl-protected poly(carboxylic acid) can be cleaved totally or partially by Pd/C-catalysed hydrogenolysis. Partial hydrogenolysis has been suspected to yield copolymers in which acid and acid benzyl ester units are not distributed at random. In order to demonstrate the blocky structure of such copolymers, five samples of poly(benzyl malolactonate), a degradable functional polyester, have been hydrogenolysed under different conditions. It has been found that hydrogenolysis is more complex than suspected, and yields mixtures of homopolymers and/or copolymers depending on the progress of the reaction and on parameters such as the nature of the solvent and catalyst and the macromolecular characteristics of the starting polyester. The ability of these hydrogenolysates to form aggregates has been studied by aqueous size exclusion chromatography. Ageing of aqueous solutions of aggregate-forming copolymers in two different aqueous media yielded non-degradable benzyl ester-rich oligomers, whose degree of polymerization was too large to correspond to the sequences normally present in random copolymers of similar composition. Therefore, it is concluded that malic acid sequences degrade much faster than do malic acid benzyl ester sequences, and that Pd/C-catalysed hydrogenolysates that form aggregates are blocky copolymers.

In Vivo Fate of End-Chain Radiolabelled Poly(β-malic acid), a Water-Soluble Biodegradable Drug Carrier

In a first attempt to determine the fate of poly(β-malic acid) after intravenous injection in mice, polymer end-chain 14C-radiolabelling was achieved using 14C-triethylamine as the initiator for the ring-opening polymer ization of benzyl malolactonate. The corresponding poly(β-malic acid) sodium salt (Mw ∼ 30,000) exhibited an activity of 4.2 μCi :g-1. Aliquots of a neutral isoosmotic solution of the latter were given intravenously to mice through a lateral tail vein. Radioactivity was counted in the liver, kidney, intestine, lung, brain, spleen, heart, muscle, urine and blood for various post-injection times up to 24 hours. Fast urinary excretion (70% after 1 hour and 90% after 6 hours) was observed. For all the sites investigated, radioactivity decreased exponen tially except in the liver and kidneys where a small peak was detected after 2 hours. Further investigations with poly(β-malic acid) radiolabelled in repeat ing units will be necessary to overcome the shortcomings of the end-chain radiolabelling method applied to degradable polymers.

Monomeric unit distribution and optical activity of copolymers: random copolymers of acrylic acid and N-(s-butyl)-N-methyl acrylamide antipodes

For copolymers of acrylic acid and N-(s-butyl)-N-methyl acrylamide antipodes as for most copolymers, the dependence of the optical rotatory power was found to be non-linear with regard to their composition. This non-linearity has been discussed generally in terms of conformation or second-ary structure. It is proposed that this effect is due to the presence of more than two independent optically active species. The different species were found in terms of triads as the effect of neighbours on the partial specific contribution of a monomeric unit to the total optical activity. A relation was developed for a random copolymer with ideal distribution using eight triads. This relation was applied to acrylic acid/(+) and (−) N-(s-butyl)-N-methyl acrylamide copolymers which can be considered as ideally random; good independent agreement of the optical purity was obtained. The results are discussed in terms of induced optical activity at the level of the electronic transitions of achiral acid unit chromophores.

Comportement hydrophile-hydrophobe de copolymeres d'acide acrylique et de N-(sec-butyl)-N-methyl-acrylamide en solution aqueuse

Resume Lhydrolyse partielle du poly N- (sec-butyl) -N- m e thyl-acrylamide (PAAm) fournit une serie de copolymeres amide-acide dont le caractere hydrophobe en solution aqueuse diminue quand la fraction en groupes acide augmente. Lhydrolyse totale de PAAm conduit au poly(acide acrylique) (PAA). Le caractere hydrophobe etudie par potentiometrie en absence de sel est analyse en termes de “transition conformationnelle” de facon analogue au poly(acide methacrylique) (PMA). On met en evidence la contribution de la chaine principale et la contribution des groupes lateraux a lenergie libre globale de la transition. La contribution partielle du groupe amide N-N- disubstitu e est celle dun compose hydrophobe par analogie avec la solubilite des hydrocarbures dans leau. Les titrages viscosimetriques du copolymere a 55,1 pour cent de groupes acide et de PMA en presence de Ca2 sont compares. La relation entre le comportement hydrophile hydrophobe de ces polyelectrolytes et la distribution des parties hydrophile et hydrophobe est discutee.

Pd/charcoal-catalysed cleavage of benzyl ester protecting groups in poly(benzyl acrylate) and poly(benzyl methacrylate)

Abstract The cleavage of benzyl protecting groups of poly(benzyl acrylate), poly(benzyl malolactonate) and poly(benzyl methacrylate) by Pd/charcoal-catalysed hydrogenolysis was investigated in order to show the consequences of chemical modification on the molecular structures of the resulting polymeric compounds. It is shown that such catalytic cleavage is a general reaction that depends very much on the structure of the porous charcoal and on the location of the Pd-metal catalyst, which can be either at the surface or well inside the pores, or both. The rate of cleavage depends on many factors, namely nature of the parent polyacid backbone, stirring rate, solvent, relative amounts of poly(benzyl ester) and of catalytic system, etc. However, molecular weights, molecular-weight distribution and the origin of the catalytic system seem to be the main factors. Data confirm that partial catalytic hydrogenolysis can lead to the formation of blocky acid/ester copolymers or to mixtures of homopolymers depending on the structure of the Pd/charcoal catalytic system.

The interaction of auramine o with some synthetic polycarboxylic acids

Abstract The interaction of Auramine O (AuO), a cationic dye, with copolymers of acrylic acid with N-(sec-butyl)-N-methyl-acrylamide, poly(acrylic acid) and poly(methacrylic acid) has been studied during neutralization using spectrofluorimetric and absorption spectroscopic data for the dye. A very large polymer-to-dye ratio (200) has been used to avoid any significant influence of the dye on the conformational behaviour of the polyacids. It has been shown that the binding of AuO is mainly governed by electrostatic attraction from ue5f8COO−. The enhancement of the fluorescence of AuO in the presence of polyacids with hydrophobic character is attributed to decrease of the freedom of the dye due (i) to its insertion into the polyion compact conformations (this appears as the main factor) and (ii) to the presence of apolar groups in the neighbourhood of the dye for open solvated polyions.

Poly(β-Malic Acid) as a Source of Polyvalent Drug Carriers: Possible Effects of Hydrophobic Substituents in Aqueous Media

According to literature, the interest in investigating synthetic macromolecular compounds for uses in biology and medicine is rapidely increasing. On one hand, attention has been focussed on polymer based implants for prostheses, tissue restauration and drug-delivery devices. In these cases, macromolecular compounds act, and sometimes react, as solids in the biological milieu. However, attention has been also payed to uses of synthetic polymers molecularly dispersed in body fluids and, more generally, in the living medium. Two types of compounds have been considered: macromolecules that are pharmacologically active by themselves (polymeric drugs), and drug-polymeric carrier systems which bear drugs temporarily attached to the polymer backbone either covalently (macromolecular prodrugs) or because of physical interactions. It is of value to note that distinction between polymeric drugs and macromolecular prodrugs is based on expected uses. Indeed, it is likely that no macromolecule is inert in the living medium.