Temporary Therapeutic Applications Research Articles

Polyester-based nanoparticles for the controlled release of bioactive coumarinic derivatives

Event Abstract Back to Event Polyester-based nanoparticles for the controlled release of bioactive coumarinic derivatives Ines Msolli1, 2, Frederic Chaubet1, Raoui Mounir Maaroufi2 and Christel Barbaud1 1 Galilee institute, LVTS, France 2 ISBM, LGBBV, Tunisia Introduction: Advancement in polymer science and engineering led to new polymers for controlled delivery of therapeutic drugs [1]. Poly([R,S]-3,3-dimethylmalic acid) (PDMMLA) and its hydrophobic derivatives can be considered as a family of promising polymers. PDMMLA is polyester synthesized for temporary therapeutic applications. Bioactive coumarinic derivatives, such as warfarin, present biological activities related to the cardiovascular field [2]. The encapsulation of a coumarinic derivative and its controlled delivery would be a relevant application of PDMMLA. Thus we first tried to encapsulate warfarin as a coumarinic model drug to optimize the controlled release settings. Experimental Part: A series of amphiphilic statistical and block copolyesters with different carboxylic acid/hexylic ester proportion: 70/30, 50/50 and 30/70 (mol/mol) belonging to the poly([R,S]-3,3-dimethylmalic acid) (PDMMLA) family have been synthesized [2],[3]. Polymer nanoparticles were further prepared by a nanoprecipitation solvent-evaporation method, and characterized by Transmission Electronic Microscopy (TEM) for nanoparticles morphology and dynamic light scattering for size and zeta potential studies.Controlled release of warfarin as a coumarinic drug model was followed by reversed-phase HPLC. Results: Statistical polymer with 30% of carboxylic acid and 70% of hexylic ester was choosen to investigate warfarin encapsulation by nanoprecipitation method and controlled release efficiency. TEM analysis evidenced spherical nanoparticles (Figure 2), which present an average size in physiological medium of about 80 nm (with a slight evolution of the size distribution over the study (28 days). The release of warfarin in a phosphate buffer saline at pH 7.4 and 37°C was monitored with reversed-phase HPLC over 28 days. The release followed a zero-order kinetics. Conclusion: We prepared a copolyester PDMMLAH30-co-Hex70 able to steadily release warfarin under simulated physiological conditions over 28 days. First results evidenced this polymer as a promising candidate for the delivery of bioactive coumarinic derivatives.

Not Any New Functional Polymer Can Be for Medicine: What About Artificial Biopolymers?

Man-made artificial organic polymers are among the more recent sources of materials used by humans. In medicine, they contribute to applications in surgery, dentistry and pharmacology. Nowadays, innovations in the field of therapeutic polymers rely on novel polymers for specific applications such as guided tissue regeneration, tissue engineering, drug delivery systems, gene transfection, etc. Introducing reactive chemical functions within or along polymer backbones is an attractive route to generate functional polymers for medicine. However, any candidate to effective application must fulfil a number of requirements, grouped under the terms biocompatibility and biofunctionality, to be of real interest and have a future for effective application. Whenever the application requires a therapeutic aid for a limited period of time to help natural healing, bioresorbability is to be taken into account on top of biocompatibility and biofunctionality. This contribution presents the case of "artificial biopolymers" and discusses the potential of some members of the family with respect to temporary therapeutic applications that require functional polymers.

Degradation of polymeric systems aimed at temporary therapeutic applications: Structure-related complications

AbstractThe number of degradable or biodegradable polymers that are aimed or claimed as aimed at therapeutic purposes is rapidly increasing in literature. In most cases, contributions deal primarily with synthesis. However it is the matching of degradation characteristics to application requirements that is important. This contribution, based on personal experience, is aimed at discussing some of the structure-related complications that can be expected when a polymeric therapeutic device degrades in an aqueous medium or in an animal organism. It is shown that dramatic changes can be observed because of selective degradation of some parts leading to the formation of undesired degradation by-products or undesired changes of properties.

Synthesis and degradation of PLA–PCL–PLA triblock copolymer prepared by successive polymerization of ε-caprolactone and dl-lactide

A PLA–PCL–PLA triblock copolymer was synthesized by ring-opening polymerization of successively added ε-caprolactone and dl-lactide in the presence of ethylene glycol, using zinc powder as catalyst. The resulting copolymer was compression molded to yield circular films from which 10×10×0.4 mm 3 square samples were cut. These samples were allowed to degrade in isoosmolar 0.13 M, pH 7.4 phosphate buffer at 37 °C. Various analytical techniques such as weighing, SEC, 1H NMR, IR, DSC, X-ray, ESEM and CZE were used to monitor property changes during degradation such as water absorption, weight loss, molecular weight distribution, composition, bulk and surface morphologies, thermal behavior, and release of water-soluble oligomers into the aqueous phase. Comparison is made with a PCL homopolymer under similar ageing conditions. The presence of PLA sequences did not alter the ability of PCL segments to crystallize during degradation, in agreement with the microphase separation between PLA and PCL blocks. Large amounts of lactic acid-rich soluble degradation by-products were released into the solution between 18 and 25 weeks. Copolymer films cracked down under drying beyond 25 weeks' degradation, while the surface remained smooth. The copolymer exhibited faster degradation as compared with PCL homopolymer, a feature which is of great interest for temporary therapeutic applications.

Biosynthetic stereocopolymer of 3-methylmalic acid as hydrolyzable and biocompatible polyester for temporary therapeutic applications

A mixture of (2 S,3 S) and (2 S,3 R)-3-methylaspartic acid, obtained by bioconversion of mesaconic acid in the presence of 3-methylaspartase as enzymatic catalyst, was transformed into the corresponding benzyl 3-methylmalolactonate stereoisomers using a multiple-step synthesis. A mixture of (3 R,4 R) and (3 S,4 R) (80/20 (mol/mol) ratio) benzyl-3-methylmalolactonate was transformed by anionic ring-opening polymerization to an optically active and stereoregular stereocopolymer constituted by 80 mol% of benzyl (3 R,4 S) 3-methylmalate repeating units and 20 mol% of benzyl (3 S,4 S) 3-methylmalate units, as determined by 1H NMR. The corresponding optically active poly( β-3-methylmalic acid) was obtained by catalytic hydrogenolysis of the protecting benzyl ester groups, in N-methylpyrrolidone as solvent. This functionalized hydrosoluble polyester was degraded by simple hydrolysis in a phosphate buffer at pH 7, as shown by SEC measurements. It is worth noting that the kinetic profile was equivalent to the one of poly( β-malic acid). Moreover, at 37°C, the hydrolysis was complete within six weeks, yielding to the corresponding optically active 3-methylmalic acid. In order to use this polymeric material for temporary therapeutic applications, polymers containing both diastereoisomers as repeating units as well as their ultimate products of degradation were evaluated based on harmlessness towards their environment. No toxicity was detected against a human cell line, HepG2.

Natural and Artificial Functionalized Biopolyesters. II. Medium-Chain Length Polyhydroxyoctanoates from Pseudomonas Strains

Sixteen Pseudomonas strains have been tested with a view to developing medium-chain length polyhydroxyalkanoates. Four strains were selected and it is shown that their ability for producing three different polyesters with variable properties was dependent on the strains and substrates. Otherwise, Pseudomonas oleovorans was grown on a mixture of sodium octanoate and undecenoate salts at a 90/10 mol/mol ratio. The corresponding copolymer, bearing lateral double bonds, was chemically modified in the carboxy group. Finally, the ability to tailor-make functional bacterial polyesters aimed at temporary therapeutic applications is demonstrated.

Present and Future of PLA Polymers

Abstract Lactic acid-based aliphatic polyesters (PLAs) are well known biocompatible bioresorbable polymers which are being increasingly used as biomaterials for temporary therapeutic applications. Because of their sensitivity to water and the formation of degradation by-products which can be easily metabolized by microorganisms, this type of polymers also has potential to replace commodity polymers in packagings or as mulch films. From an overview of synthesis routes, structural characteristics, and performances, an attempt is made to evaluate the future of PLA polymers insofar as industrial development is concerned.

Degradation of poly(?-malic acid)-monitoring of oligomers formation by aqueous SEC and HPCE

Poly (β-malic acid) is a functional aliphatic polyester which can serve as parent compound to make systems aimed at temporary therapeutic applications. Degradation of the polyester backbone of poly(β-malic acid) leads to the formation of oligomers which can be hardly separated by conventional Size Exclusion Chromatography. In order to monitor the formation of oligomeric degradation by-products and to quantify their relative amount, the potential of two separation techniques has been investigated, namely Aqueous Size Exclusion Chromatography using a Bio-Gel P2 gel column and High Performance Capillary Electrophoresis. Aqueous SEC allowed separation of oligomers smaller than hexamer whereas HPCE successfully separated oligomers smaller than pentadecamers. These techniques were used to control the efficiency of oligomer fractionation by the dissolution/precipitation method.applied to the sodium salt of poly(β-malic acid).

Bioresorbable polymers for temporary therapeutic applications

AbstractPolymer science is mature enough to allow one to think about tailor‐making macromolecular compounds aimed at interacting purposely with living systems. Reasons for developing bioresorbable polymers for temporary therapeutic applications are discussed with respect to property adjustments and economical factors. The field of the applications is first described and guidelines for tailor‐making multimeric macromolecules with desired properties are presented. The approach led to focuss investigations on poly(α‐hydroxy acids) and functional poly(β‐hydroxy acids) derived from natural hydroxy acids, namely lactic, glycolic and malic acids. Physical, mechanical and biological properties of some corresponding polymers and copolymers are presented. Last but not least, examples of applications currently investigated are recalled.