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PubMed2000

Photopolymers in orthopedics: characterization of novel crosslinked polyanhydrides.

Novel, high modulus, degradable polymers were prepared from methacrylated anhydride monomers of tricarballylic acid (MTCA) and pyromellitylimidoalanine (MPMA-ala). Kinetic studies indicate that the time scale of photopolymerization of MTCA (< 30 s) is suitable for in vivo applications. Additionally, the tensile modulus of copolymers of these novel monomers with methacrylic anhydride (MA) ranged from 0.8 to 2.1 GPa, which lies between the modulus of trabecular and cortical bone. Degradation studies indicate that the copolymers of MTCA and MPMA-ala with MA are initially surface degrading, which is important to maintaining polymer strength through the degradation process. Monomers such as these that can be rapidly polymerized using ultraviolet or blue light into high modulus degradable materials have great potential in orthopedics.

Anhydrides↗
PubMedDate not supplied

Antigenicity of recombinant proteins after regioselective immobilization onto polyanhydride-based copolymers.

We previously demonstrated that the introduction of a tag consisting of several contiguous lysines at the N- or C-terminus of a recombinant protein greatly improved the covalent grafting of the protein onto negatively charged maleic anhydride-alt-methyl vinyl ether (MAMVE) copolymer, under many different experimental conditions (Ladavière, C., et al. (1998) Bioconjugate Chem. 9, 655; Allard, L., et al. (2002) Biotechnol. Bioeng. 80, 341). The grafting efficiency was dependent on the charge and amine density of the tag, characteristics which were determined by the tag composition. The six lysine tag (Lys6) was found to be the most efficient (Allard, L., et al. (2001) Bioconjugate Chem. 12, 972). In the present work, the biological activity of Lys6-proteins covalently bound to polymer was investigated. N- or C-terminal Lys6-tagged HIV-1 p24 recombinant proteins (RK24H and RH24K) were grafted onto MAMVE, and the antigenicity each of the bioconjugates was evaluated using six monoclonal antibodies that recognized different epitopes distributed along the protein. We demonstrate that the position of the tag and the hydrolysis rate of the anhydride moieties of the polymer are the two main parameters involved in the conservation of the biological activity of the immobilized protein. We thus present a process which allows an efficient oriented immobilization of proteins onto copolymers with optimal biological activity that is suitable for the controlled production of active bioconjugates.

Amino Acid Sequence↗
PubMed2001

Nonlinear fatty acid terminated polyanhydrides.

A systemic study on the synthesis, characterization, degradation, drug release, and stability of nonlinear fatty acid terminated poly(sebacic anhydride) (PSA) is reported. Ricinoleic acid was transformed into a nonlinear fatty acid by esterification with fatty acid chlorides of C8-C18 chain length in the presence of pyridine. Pure nonlinear fatty acids were obtained by purification of the reaction product using column chromatography. Poly(sebacic acid)s terminated with 30 wt % of various nonlinear fatty acids were synthesized by melt condensation to yield waxy off-white materials with molecular weights in the range of 5000-9000. The terminated polymers are soluble in common organic solvents and melt at temperatures between 70 and 79 degrees C, which allow their fabrication into microspheres and implants. These polymers degrade into their counterparts during a period of a few weeks while constantly releasing an incorporated drug. The incorporation of nonlinear fatty acid terminals to poly(sebacic anhydride) increased the polymer hydrophobicity and decreased polymer crystallinity when compared to PSA or to linear fatty acid terminated PSA. The hydrophobic nonlinear side chains retard water from penetrating into the polymer mass, which resulted in higher stability and surface erosion front mechanism of polymer degradation and drug release.

Anhydrides↗
PubMed1999

Photopolymerizable degradable polyanhydrides with osteocompatibility.

We have developed a new family of photopolymerizable, methacrylated anhydride monomers and oligomers that combine high strength, controlled degradation, and photoprocessibility in a singular system. Networks with degradation times ranging from 1 week to nearly 1 year and that retain up to 90% of their tensile modulus at 40% mass loss are attainable. In vivo studies in rats have shown that these networks possess excellent osteocompatibility. These combined properties could offer many advantages in medical applications ranging from dentistry to orthopedics.

Anhydrides↗
PubMed1993

Controlled release of polypeptides from polyanhydrides.

The effects of both polymer hydrophobicity and addition of stabilizers on the release and integrity of polymer-encapsulated proteins were studied. By using very hydrophobic poly[1,3-bis(p-carboxyhydroxy)hexane anhydride] with sucrose as an excipient, both recombinant bovine somatotropin and zinc insulin were released intact over 3 weeks. The released proteins appeared to maintain their integrity as judged by acidic reverse-phase HPLC, size-exclusion HPLC, radioimmunoassay, and conformation-sensitive immunoassays. Our results also suggest how polymer hydrophobicity can be used to enhance protein stability.

Animals↗
PubMed2001

The relationship between structures and in vitro properties of a polyanhydride implant containing gentamicin sulfate.

Laboratory scale injection-molding equipment was utilized to fabricate an implant consisting of poly(FAD:SA 1:1) and 20% (w/w) gentamicin sulfate. Characterizations were performed to determine the molecular weight and glass transition temperature of poly(FAD:SA 1:1). A study was carried out to investigate the relationships between the in vitro performance, morphology, and micro-structures of the molded implants. It was found that implants produced with different structures exhibited different physical integrities in water, i.e., cracking or non-cracking. For the non-cracking implants, a skin-core structure formed by an oriented skin layer was observed under a polarized light microscope. The same morphology was not seen in the cracking implants. The crystal orientation in the skin layer of the non-cracking implants was further identified using a wide-angle x-ray diffraction method (WAXD). No crystal orientation could be found in the cracking implants by WAXD. Furthermore, studies were carried out to evaluate the in vitro drug release for implants showing different degrees of integrity in water. The in vitro drug release of the cracking implants was markedly faster than that of the non-cracking implants due to the pronounced initial drug-burst effect as a result of crack formation in the implants.

Absorbable Implants↗
PubMed1998

Effect of fabrication technique on the erosion characteristics of polyanhydride matrices.

The aim of this study was to investigate the effect of device fabrication technique on the erosion characteristics of poly[1,3-bis(p-carboxyphenoxy) propane:sebacic acid] [p(CPP:SA)] 20:80 copolymer. Devices were prepared using melt-molding, solvent-casting, and compression-molding techniques and their erosion was followed by determining changes in device morphology, molecular weight, water uptake, mass loss, and release of monomers, with time of immersion in phosphate buffer pH 7.4 at 37 degrees C. Melt-molded devices had a very dense and uniform structure and displayed characteristics typical of surface eroding systems. Devices produced using a solvent-casting technique had a very porous structure with no detectable erosion zone and the erosion profiles were indicative of bulk rather than pure surface erosion. Compression-molded devices had a dense structure and revealed a faster rate of erosion than melt-molded devices. A comparison of the extent of changes of polymer molecular weight, water uptake, mass loss, and monomer release showed a marked dependence on the method of fabrication.

Chemical Phenomena↗
PubMed1989

Brain biocompatibility of a biodegradable, controlled-release polymer in rats.

We report the biocompatibility in the rat brain of a controlled-release, biodegradable polymer, the polyanhydride poly-[bis(p-carboxyphenoxy)propane-sebacic acid] copolymer (PCPP-SA) in a 20:80 formulation. The biodegradable polyanhydride can be used for drug delivery directly into the brain, circumventing the difficulties posed by the blood-brain barrier and avoiding the consequences of having to administer toxic doses systematically to reach therapeutic doses in the central nervous system. The tissue reaction in the presence of PCPP-SA was compared to that seen with other standard neurosurgical implants. Fifty-six adult Sprague-Dawley rats were assigned to one of seven groups and underwent bilateral frontal lobe implantation of PCPP-SA (42 hemispheres), Surgicel (oxidized regenerated cellulose) (35 hemispheres), or Gelfoam (absorbable gelatin sponge) (35 hemispheres). None of the animals showed any behavioral changes or neurological deficits suggestive of either systemic or localized toxicity from the biodegradable polyanhydride, all surviving to the scheduled data of sacrifice. PCPP-SA evoked a well localized inflammatory reaction, comparable to that of Surgicel, which resolved as the PCPP-SA polymer degraded over five weeks. The biodegradable polyanhydride has been shown in this study to be nontoxic and biocompatible in the rat brain, when compared to standard neurosurgical implants.

Animals↗
PubMed1994

Chemical interactions between drugs containing reactive amines with hydrolyzable insoluble biopolymers in aqueous solutions.

Chemical reactions between drugs containing reactive amines with hydrolyzable polymers in buffer solutions were investigated. Phenylalkylamines with increasing nucleophilic reactivity were used as model drugs. Solutions of phenylalkylamines were reacted heterogeneously with representative biodegradable polyanhydride and polyester powders in various pH solutions, and the recovery of the amines from the solutions was determined. Poly(sebacic acid), a reactive polyanhydride, reacted by amide formation with the tested amines and their respective HCl salts when exposed to physiologic pH (pH 7.4). However, at pH 5.0 no interaction occurred. The aromatic polyanhydride, PCPP, and the polyesters based on lactic acid and caprolactone did react with the amine derivatives at pH 7.4, but at a slower rate. The reaction can be avoided with appropriate salt derivatives of the amines.

Amines↗
PubMed2001

Degradation and drug delivery properties of poly(1,4-cyclohexanedicarboxylic anhydride).

Polyanhydrides for drug-controlled release systems from cis- and trans-1,4-cyclohexanedicarboxylic acid (1,4-CHDA) were synthesized by melt polycondensation. The degradation of polymers was estimated by weight loss in 0.1 mol l(-1), pH 7.4 phosphate buffer at 37 degrees C. The drug delivery was conducted in the same buffer. The results show that the different polymers lost weight over 150-360 h, and fine surface erosion was investigated. The different conformation of CHDA has an obvious influence on the degradation of polyanhydrides due to their different crystallinity, with higher crystallinity samples degrading much more slowly. The incorporation of adipic acids into the poly(CHDA) can obviously accelerate the degradation and the introduction of -CH2- segments increased the flexibility of polyanhydride backbone and accelerated the degradation rate. In vitro delivery experiments show that Bruffen was completely released in about 10 days from a melting mold disk with a fine linear delivery curve.

Anhydrides↗
PubMed1999

Ricinoleic acid-based biopolymers.

Polyanhydrides synthesized from pure ricinoleic acid half-esters with maleic and succinic anhydrides possess desired physicochemical and mechanical properties for use as drug carriers. Ricinoleic acid maleate or succinate diacid half-esters were prepared from the reaction of crude ricinoleic acid (85% content) with succinic or maleic anhydride. The pure diacid monomers were obtained by chromatography purification through silica gel using petroleum ether/ethyl acetate/acetic acid (80/30/1 v/v/v) mixture as eluent. The pure diacid monomers (>99%) were polymerized by melt condensation to yield film-forming polymers with molecular weights exceeding 40,000 with a polydispersity of 2. Extensive biocompatibility study demonstrated their toxicological inertness and biodegradability. Their rate of elimination from rats in the course of about 4-6 weeks was faster than that found for similar fatty acid-based polyanhydrides previously tested. In vitro studies showed that these polymers underwent rapid hydrolytic degradation in 10 days. Methotrexate release from the polymers was not affected by the initial polymer molecular weight in the range of 10,000-35,000. The in vitro drug release correlated with the degradation of the polymers. The fatty acid ester monomers were further degraded to its counterparts, ricinoleic acid and succinic or maleic acid.

Animals↗
PubMed2005

Poly(ester-anhydride):poly(beta-amino ester) micro- and nanospheres: DNA encapsulation and cellular transfection.

Poly(ester-anhydride) delivery devices allow flexibility regarding carrier dimensions (micro- versus nanospheres), degradation rate (anhydride versus ester hydrolysis), and surface labeling (through the anhydride functional unit), and were therefore tested for DNA encapsulation and transfection of a macrophage P388D1 cell line. Poly(l-lactic acid-co-sebacic anhydride) and poly(l-lactic acid-co-adipic anhydride) were synthesized through melt condensation, mixed with 25 wt.% poly(beta-amino ester), and formulated with plasmid DNA (encoding firefly luciferase) into micro- and nanospheres using a double emulsion/solvent evaporation technique. The micro- and nanospheres were then characterized (size, morphology, zeta potential, DNA release) and assayed for DNA encapsulation and cellular transfection over a range of poly(ester-anhydride) copolymer ratios. Poly(ester-anhydride):poly(beta-amino ester) composite microspheres (6-12 microm) and nanospheres (449-1031 nm), generated with copolymers containing between 0 and 25% total polyanhydride content, encapsulated plasmid DNA (>or=20% encapsulation efficiency). Within this polyanhydride range, poly(adipic anhydride) copolymers provided DNA encapsulation at an increased anhydride content (10%, microspheres; 10-25%, nanospheres) compared to poly(sebacic anhydride) copolymers (1%, microspheres and nanospheres) with cellular transfection correlating with the observed DNA encapsulation.

Adipates↗
PubMed2000

Degradable poly(anhydride ester) implants: effects of localized salicylic acid release on bone.

Degradable poly(anhydride ester) implants in which the polymer backbone breaks down into salicylic acid (SA) were investigated. In this preliminary work, local release of SA from the poly(anhydride esters), thus classified as 'active polymers', on healthy bone and tissue was evaluated in vivo using a mouse model. Degradable polyanhydrides that break down into inactive by-products were used as control membranes because of their chemical similarity to the active polymers. Small polymer squares were inserted over the exposed palatal bone adjacent to the maxillary first molars. Active polymer membranes were placed on one side of the mouth, control polymers placed on the contra lateral side. Intraoral clinical examination showed that active polymer sites were less swollen and inflamed than control polymer sites. Histopathological examination at day 1 showed essentially no difference between control and active polymers. After 4 days, active polymer sites showed epithelial proliferation to a greater extent than the polyanhydride controls. After 20 days, active polymer sites showed greater thickness of new palatal bone and no resorptive areas, while control polymer sites showed less bone thickness as well as resorption including lacunae involving cementum and dentine. From these preliminary studies, we conclude that active polymers, namely poly(anhydride esters), stimulated new bone formation.

Animals↗
PubMed1997

Erosion of composite polymer matrices.

The erosion of composite polymer matrices made of slow and fast eroding polymers was investigated. These matrices can be used as implants that release drugs in a preprogrammed way. To understand the mechanism of drug release, the erosion of cylindrical polymer matrices made of several layers of different polymers was investigated. A layer of poly(D,L-lactic acid) was used to separate a core and a mantle consisting of poly(1,3-bis[p-carboxyphenoxy]propane-co-sebacic acid) 20:80. The investigation of the erosion mechanism revealed that erosion is a two-phase process. Wide angle X-ray diffraction and differential scanning calorimetry proved that the crystalline polymer parts of the polyanhydride layers above and below the polylactide erode one after the other. Concomitantly, sebacic acid accumulates periodically inside the matrix and leaves it in two phases. This agrees well with the release of brilliant blue and carboxyfluorescein, two model compounds, from such implants when incorporated into the polyanhydride layers. It can be concluded that the core of the composite implant erodes with a delay of 10-14 days because the polylactide protects it against premature erosion. Theoretical erosion models that were developed to simulate erosion support the proposed mechanism.

Biocompatible Materials↗
PubMed1999

Perivascular delivery of heparin for the reduction of smooth muscle cell proliferation after endothelial injury.

Thin flexible sheets composed of poly(lactic acid) (PLA) laminated polyanhydride, poly(erucic acid dimer-sebacic anhydride) (P(EAD-SA)), loaded with heparin were evaluated in vitro and in vivo. PLA was used for coating the polyanhydride to improve the release profile and improve the strength of the films. Heparin was released constantly for 20 days from PLA-coated 2% loaded P(EAD-SA). The uncoated film of P(EAD-SA) released heparin for only 4 days. The localized delivery of heparin around the carotid artery was investigated by implanting polymer loaded with [3H]heparin around the carotid artery of rats and the heparin release and tissue distribution was monitored. The maximum heparin concentration in the artery exposed to the drug was on day 4 for the P(EAD-SA) uncoated device (fast releasing system) and day 11 for the coated devices. The control artery, the uncovered segments of the artery, and the surrounding tissue contained negligible amounts of radioactivity. These data confirm that heparin was delivered locally without systemic exposure. Two independent animal studies were conducted to evaluate the effectiveness of these heparin-releasing devices. In both studies the balloon catheter injury in a rat model was used. After inflicting an injury to the common carotid, a matrix oriented with its long axis along the artery was placed under the injured portion of the vessel. In both studies the treated rats showed a very thin layer of neointima where the control group showed a significant reduction of the artery internal diameter with SMC neointima ratio greater than 1.

Animals↗
PubMed2001

Design of a core-shelled polymer cylinder for potential programmable drug delivery.

A cylindrical dosage form comprising a laminated composite polymer core and a hydrophobic polycarbonate coating was proposed for programmable drug delivery. In the core, poly[(ethyl glycinate) (benzyl amino acethydroxamate) phosphazene] was synthesized as drug-loaded layers for its strong pH-sensitive degradation (eroded after 1.5 days at pH 7.4 and more than 20 days at pH 5.0 and 6.0). Poly(sebacic anhydride)-b-polyethylene glycol or poly(sebacic anhydride-co-trimellitylimidoglycine)-b-poly(ethylene glycol) was selected as isolating layers for their good processing properties at room temperature and suitable erosion duration. The in vitro drug release studies of these devices were conducted under physiological conditions (pH 7.4). The results revealed that the model drugs (brilliant blue, FITC-dextran, myoglobin) could be released in typical pulsatile manner. Moreover, the duration time of drug release (24-40 h) and the lag time (18-118 h) could be separately regulated by the mass of polyphosphazene and the type or mass of polyanhydride. In this experiment, the cooperative effect of polyanhydrides and pH-sensitive degradable polyphosphazene was specially demonstrated, which offers a new idea to develop a programmable drug delivery system for single dose vaccine and other related applications.

Anhydrides↗