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PubMed1992

Molecular weight changes in polymer erosion.

We report a study of the effects of polymer molecular weight on the erosion of polyanhydride copolymer matrices composed of 1,3-bis(p-carboxyphenoxy)-propane (CPP) and sebacic acid (SA) in aqueous solution. The erosion profile characteristically displays an induction period during which the erosion rate is relatively slow. The length of this period depends on the initial molecular weight of the polymer. The induction period may be characterized as a time during which a rapid decrease in polymer molecular weight occurs, the end of this period correlating with the time required for the polymer molecular weight to decrease to below a value of approximately 5000 (MW).

Decanoic Acids↗

PubMed1993

Sustained local anesthetic release from bioerodible polymer matrices: a potential method for prolonged regional anesthesia.

Polyanhydride polymer matrices have been used successfully for sustained release of a number of drugs in vitro and in vivo. Dibucaine free base, dibucaine HCl, and bupivacaine HCl were incorporated into polymer matrices with copolymer 1,3-bis(p-carboxyphenoxy)propane-sebacic acid anhydride (1:4). Drug release was measured in vitro following incubation of the drug-polymer matrices in phosphate buffered solution, pH 7.4, at 37 degrees C, to approximate in vivo conditions. Local anesthetics were released in a sustained manner yielding 90% cumulative drug release over periods ranging from 3 to 14 days. The kinetics of release varied with both the choice of local anesthetic and the method of drug incorporation into the matrix (hot melt versus compression molding). Polymer local anesthetic matrix devices (PLAM), loaded by hot melt incorporation with 20% bupivacaine, were implanted in vivo adjacent to the sciatic nerve in three rats. Reversible neural blockade was observed for 4 days in all animals. Polymer implants without local anesthetic showed no neural blockade. This technology could lead to methods of prolonged blockade of peripheral nerves or of sympathetic ganglia, which may be utilized for the management of postoperative pain, sympathetically maintained pain, or certain forms of chronic pain.

Analysis of Variance↗

PubMed2003

Local delivery of minocycline and systemic BCNU have synergistic activity in the treatment of intracranial glioma.

Minocycline, a tetracycline derivative, has been shown to inhibit tumor angiogenesis through inhibitory effects on matrix metalloproteinases. Previous studies have shown this agent to be effective against a rodent brain tumor model when delivered intracranially and to potentiate the efficacy of standard chemotherapeutic agents. In the present study, the in vivo efficacy of intracranial minocycline delivered by a biodegradable controlled-release polymer against rat intracranial 9L gliosarcoma was investigated to determine whether it potentiates the effects of systemic 1,3-bis (2-chloroethyl)-1-nitrosourea (BCNU). Minocycline was incorporated into the biodegradable polymer polyanhydride poly[bis(p-carboxyphenoxy)propane-sebacic acid] (pCPP:SA) at a ratio of 50:50 by weight. The release kinetics of minocycline from the polymer were assessed. For the efficacy studies, female Fischer 344 rats were implanted with 9L glioma. Treatment with minocycline delivered by the pCPP:SA polymer at the time of tumor implantation resulted in 100% survival in contrast to untreated control animals that died within 21 days. Treatment with the minocycline-polymer 5 days after tumor implantation provided only modest increases in survival. The combination of intracranial minocycline and systemic BCNU extended median survival by 82% compared to BCNU alone (p < 0.0001) and 200% compared to no treatment (p < 0.004). We conclude that local intracranial delivery of minocycline from biodegradable controlled-release polymers inhibits tumor growth and may have clinical utility when combined with a chemotherapeutic agent.

Absorbable Implants↗

PubMed1989

Ultrasound-enhanced polymer degradation and release of incorporated substances.

The effect of ultrasound on the degradation of polymers and the release rate of incorporated molecules within those polymers was examined. Up to 5-fold reversible increases in degradation rate and up to 20-fold reversible increases in release rate of incorporated molecules were observed with biodegradable polyanhydrides, polyglycolides, and polylactides. Up to 10-fold reversible increases in release rate of incorporated molecules within nonerodible ethylene/vinyl acetate copolymer were also observed. The release rate increased in proportion to the intensity of ultrasound. Temperature and mixing were relatively unimportant in effecting enhanced polymer degradation, whereas cavitation appeared to play a significant role. Increased release rates were also observed when ultrasound was applied to biodegradable polymers implanted in rats. Histological examination revealed no differences between normal rat skin and rat skin that had been exposed to ultrasonic radiation for 1 hr. With further study, ultrasound may prove useful as a way of externally regulating release rates from polymers in a variety of situations where on-demand release is required.

Animals↗

PubMedDate not supplied

Bioadhesive fluorescent microspheres as visible carriers for local delivery of drugs. I: preparation and characterization of insulin-loaded PCEFB/PLGA microspheres.

Inherently fluorescent microspheres composed of a fluorescent polyanhydride, poly(p-(carboxyethylformamido) benzoic anhydride) (PCEFB), and poly(lactide-co-glycolide) (PLGA) were prepared using the water-in-oil-in-water (w/o/w) emulsion solvent evaporation technique. The effect of the PCEFB/PLGA feed ratio and composition of the oil phase on insulin entrapment and microsphere diameter was evaluated. It was found that the insulin entrapment efficiency increased with PCEFB content and acetone per cent in the oil phase. Microsphere diameter decreased as acetone was added into the oil phase. The blend of microspheres were further characterized by GPC, IR, fluorometry and SEM. Although slight degradation of PCEFB during the fabrication process was revealed by GPC and IR, PCEFB/PLGA microspheres could still be clearly visualized by either CLSM or fluorescent microscopy, which makes it possible to directly detect the microspheres by fluorometry in vivo without the need of labelling with fluorescent dyes. The surface of PCEFB/PLGA (1:2) microspheres was smooth, while PCEFB/PLGA (2:1) microspheres were observed with rough and uneven surfaces. Sustained release of insulin from the microspheres could be achieved for approximately 4 days.

Adhesiveness↗

PubMedDate not supplied

Bioadhesive fluorescent microspheres as visible carriers for local delivery of drugs. II: Uptake of insulin-loaded PCEFB/PLGA microspheres by the gastrointestinal tract.

Uptake of novel inherently fluorescent microspheres composed of a luminescent polyanhydride, poly[p-(carboxyethylformamido)-benzoic anhydride] (PCEFB), and poly(lactide-co-glycolide) (PLGA) (2:1, weight ratio) by the gastrointestinal tract was evaluated by fluorescent microscopy. Oral efficiency of the incorporated insulin also was determined by measuring reduction of plasma glucose levels after feeding diabetic rats with a single dose of the microspheres. We found that PCEFB/PLGA microspheres could adhere to the intestinal epithelium and traverse the absorptive cells. A large number of the spheres were observed in spleen, whereas few were detected in liver within the evaluated period of time. Apparent reduction of the plasma glucose levels was observed over a span of 6 h postfeeding. The unique properties of the delivery system such as biodegradability, bioadhesivity, and inherently luminescent characteristics render it an ideal "visible" tracer for monitoring oral fate of polymeric microspheres.

Adhesives↗

PubMed1992

Drug-polymer conjugates: potential for improved chemotherapy.

Use of polymeric drug delivery systems is rapidly becoming an established approach for improvement of cancer chemotherapy. Zoladex, a poly lactide-co-glycolide subcutaneous implant that delivers a luteinizing hormone releasing hormone analog over 28 days, is now the treatment of choice for prostate cancer, and a polyanhydride matrix containing BCNU is currently in phase III evaluation for treatment of glioma multiforme. Soluble polymers were first proposed as targetable drug carriers in the mid-1970s, and although the first conjugates are still at an early stage of development some, e.g. SMANCS (styrene maleic acid-neocarzinostatin) and monomethoxypolyethyleneglycolasparaginase, are now undergoing clinical evaluation and show considerable promise. Polymeric drug delivery systems are usually designed to produce an improved pharmacokinetic profile of an antitumor agent (controlled release) and in addition soluble carriers can achieve either first-order (organ specific) or second-order (tumor specific) drug targeting by virtue of the fact that they are usually administered intravenously and should theoretically access primary and secondary disease. Soluble polymeric carriers have the potential to improve the activity of conventional antitumor agents, peptide and protein drugs, and have recently been used in constructs for delivery of oligonucleotides. With increased awareness that the successful design of a polymeric drug delivery systems can only be achieved with prior consideration of the pathology and stage of the disease, tumor accessibility, biochemistry and cell biology of the target site, choice of appropriate therapeutic agent(s) and understanding of their fundamental mode of action, we have seen the emergence of a number of exciting and potentially more selective antitumor therapies based on polymer technologies. Here, the basic principles for design of soluble polymeric drug delivery systems are explained and illustrated using examples drawn from our studies on the development of N-(2-hydroxypropyl)methacrylamide copolymer conjugates for use in cancer chemotherapy. Those soluble polymeric carriers that are undergoing clinical evaluation are briefly reviewed.

Animals↗

PubMed1999

Synthetic biodegradable polymers for orthopaedic applications.

Synthetic biodegradable polymers offer an alternative to the use of autografts, allografts, and nondegradable materials for bone replacement. They can be synthesized with tailored mechanical and degradative properties. They also can be processed to porous scaffolds with desired pore morphologic features conducive to tissue ingrowth. Moreover, functionalized polymers can modulate cellular function and induce tissue ingrowth. This review focuses on four classes of polymers that hold promise for orthopaedic applications: poly alpha-hydroxy esters, polyphosphazenes, polyanhydrides, and polypropylene fumarate crosslinked networks.

Animals↗

PubMed2000

Polymer chemotherapy for head and neck cancer.

OBJECTIVES: To study a new method of delivery of chemotherapy for the treatment of squamous cell carcinomas (SCCs) of the head and neck, to evaluate the pharmacokinetics of four anticancer agents (cisplatin, fluorouracil [5-FU], methotrexate [MTX], and paclitaxel) loaded into the biodegradable polymer, polyanhydride polymer poly(FAD:SA), and to evaluate the effectiveness and toxicity of the drug-polymer combination against human SCCs, both in vitro and in vivo. STUDY DESIGN: Poly(FAD:SA) was loaded with different chemotherapeutic drugs and its in vitro and in vivo drug release and tissue penetration characteristics were studied. The biocompatibility and toxicity of the polymer-drug combination were determined. The effectiveness of the drug-polymer was evaluated against three different human SCCs (larynx O11, pharynx FADU, and floor of mouth UM- SCC1) cultured in vitro and in nude mice carrying human SCC xenografts. METHODS: The in vitro drug release pharmacokinetics of the drugs were performed using atomic absorption spectrometry for cisplatin and high-pressure liquid chromatography for the 5-FU, MTX, and paclitaxel studies. In vitro tumor cytotoxicity was assessed by growth assay. In vivo cytotoxicity was assessed by growth rate inhibition in a nude mouse model. RESULTS: All four chemotherapy drugs demonstrated a continuous release that followed first-order kinetics from the polymer. More than 95% of the MTX and 5-FU, 70% of the cisplatin, and 20% of the paclitaxel was released within the 10 days of the assay. Tumor cytotoxicity revealed that the polymer was very effective against the human SCCs O11, FADU, and UM- SCC1 in vitro. When a small amount of polymer (1-2 g) was added to the cell culture and left for 7 days, 96.6% of the UM-SCC1 cells, 86.9% of the FADU cells, and 94.6% of the O11 cells were killed. When the culture medium was then changed every 2 days to remove the effect of nutrient depletion or chemicals released by the degrading polymer, 74% of the UM-SCC1 cells, 94.5% of the FADU cells, and 66.1% of the O11 cells were killed at 7 days. The tumor animal model was the nude mouse carrying human floor of mouth SCC xenografts. Different amounts of cisplatin were incorporated into the polymers (5% and 7% drug/polymer at a weight/weight [wt/wt] load). Thirty-five days after implantation of the polymer in nude mice, the mean treated tumor size was 65.5% of controls in the 5% group and 31.8% in the 7% group. Seventy days after implantation the mean treated tumor size was 41.4% of controls in the 5% group and 38.1% in the 7% group, indicating a statistically significant delay of tumor growth compared with controls or with intraperitoneally injected cisplatin. The blank polymer was well tolerated by the mouse and had no effect on tumor growth. CONCLUSIONS: The study results indicate that polymer chemotherapy is effective against a variety of SCCs of the head and neck, both in vitro and in vivo, and may become a useful therapeutic option for head and neck cancer.

Animals↗

PubMed2002

Application of a kinetic gelation simulation to the characterization of in situ cross-linking biomaterials.

Multifunctional monomers that are polymerized in situ to form highly cross-linked biomaterials have been an area of recent interest for medical applications. From a biomaterial application standpoint, the relationship between the reaction conditions, polymer structure, and final physical properties is important, particularly for in situ formed materials, as they must have optimum network properties immediately after Formation. However, multifunctional monomer reaction mechanisms are complicated by mobility restrictions on the reacting species, cyclization of pendant groups, unequal reactivity of functional groups, and structural heterogeneities. Also, experimental characterization of these complexities is difficult and limited by the insolubility of the resulting cross-linked structure. Thus, in this contribution, a kinetic gelation simulation was used to understand and characterize the evolution of in situ forming, three-dimensional polymer structures. Specifically, the reaction of tetrafunctional monomers (i.e. divinyl monomers) to form high strength networks with degradable cross-links was modeled. This work focuses on using a lattice-based model to characterize network properties important for biomaterial applications and compare them with an experimental system (i.e. cross-linked polyanhydrides) where appropriate. Simulated results for pendant group reactivity, kinetic chain lengths, and radical concentrations (trapped and free) are presented herein.

Biocompatible Materials↗

PubMed1992

Trends in the development of bioresorbable polymers for medical applications.

The gradual shift from biostable prostheses to degradable, temporary implants represents one of the most significant trends in biomaterials research. In view of this trend, medical applications of degradable implant materials were reviewed with special emphasis on orthopedic polymeric implants. Among the polymeric implant materials derived from natural sources, collagen, various polysaccharides such as cellulose, and microbial polyesters have been intensively investigated. Among the synthetic, degradable polymers, aliphatic polyesters such as poly(glycolic acid), poly(lactic acid), poly(caprolactone) and polydioxanone, are most commonly investigated. Only recently, several new classes of polymers such as poly(ortho esters), polyanhydrides, and degradable polycarbonates have been introduced as potential implant materials. A particularly versatile group of new biomaterials with promising engineering properties are the "pseudo"-poly(amino acids), amino acid derived polymers in which conventional peptide bonds have been replaced by various chemical linkages.

Absorption↗

PubMed2005

Local delivery of a synthetic endostatin fragment for the treatment of experimental gliomas.

OBJECTIVE: Endostatin is an anti-angiogenic agent that blocks matrix-metalloproteinase-2 and inhibits endothelial cell proliferation. Currently, endostatin is available through recombinant technology, which limits its broader use. In this study, a synthetic endostatin fragment (EF) was analyzed to determine its anti-angiogenic properties when locally delivered by controlled-release polymers and to establish its effect as a treatment for experimental gliomas. METHODS: Cytotoxicity of EF against 9L gliosarcoma and F98 glioma was determined in vitro. EF was loaded into polyanhydride-poly-(bis-[carboxyphenoxy-propane]-sebacic-acid) (pCPP:SA) polymers at increasing concentrations. Pharmacokinetics of the EF/polymer formulations were defined in vitro. Anti-angiogenic properties of the EF/polymer formulations were evaluated in the rat-cornea micropocket assay. Toxicity and efficacy of locally delivered EF polymers either alone or combined with systemic bischloroethylnitrosourea (carmustine) were determined in rats intracranially challenged with 9L gliosarcoma. RESULTS: EF showed scarce cytotoxicity against 9L and F98 in vitro. EF/pCPP:SA formulations showed sustained release by day 19. Mean corneal angiogenesis index 20 days after tumor implantation was 4.5 +/- 0.7 for corneas implanted with 40% EF/pCPP:SA compared with controls (8.5 +/- 1.3, P = 0.02). Intracranial efficacy studies showed that EF polymers alone did not prolong animal survival. Combination of 40% EF/pCPP:SA polymers with systemic bischloroethylnitrosourea (carmustine) prolonged survival (median survival of 44 d, P = 0.001) and generated 33% long-term survivors. CONCLUSION: Controlled-release polymers can effectively deliver a biologically active EF in a sustained fashion. EF inhibits angiogenesis in vitro and in vivo, and even though EF does not prolong survival as a single agent, it exhibits a synergistic effect when combined with systemic bischloroethylnitrosourea (carmustine) in the intracranial 9L gliosarcoma model.

Animals↗

PubMed2003

Biodegradable synthetic polymers for tissue engineering.

This paper reviews biodegradable synthetic polymers focusing on their potential in tissue engineering applications. The major classes of polymers are briefly discussed with regard to synthesis, properties and biodegradability, and known degradation modes and products are indicated based on studies reported in the literature. A vast majority of biodegradable polymers studied belongs to the polyester family, which includes polyglycolides and polylactides. Some disadvantages of these polymers in tissue engineering applications are their poor biocompatibility, release of acidic degradation products, poor processability and loss of mechanical properties very early during degradation. Other degradable polymers such as polyorthoesters, polyanhydrides, polyphosphazenes, and polyurethanes are also discussed and their advantages and disadvantages summarised. With advancements in tissue engineering it has become necessary to develop polymers that meet more demanding requirements. Recent work has focused on developing injectable polymer compositions based on poly (propylene fumarate) and poly (anhydrides) to meet these requirements in orthopaedic tissue engineering. Polyurethanes have received recent attention for development of degradable polymers because of their great potential in tailoring polymer structure to achieve mechanical properties and biodegradability to suit a variety of applications.

Biocompatible Materials↗

PubMed1998

Bioabsorbable polymers for implantable therapeutic systems.

For a long time, subcutaneous implantable drug pellets using nondegradable polymers have been used for long-term, continuous drug administration. The procedure requires surgical implantation and removal of the drug-containing devices or polymeric matrices, which has a significant negative impact on the acceptability of the product candidate. In addition, the release profile from such devices is neither constant nor readily controlled in terms of precision of rate of release and duration of action. These facts have led to the research and development of novel, controllable, nonirritating, noncarcinogenic, biocompatible, and bioabsorbable drug delivery systems for overcoming the drawbacks of nondegradable implantable pellets for prolonged continuous release. Biodegradable implantable systems release the drug over a long period of time with simultaneous or subsequent degradation in the tissue of the polymer to harmless constituents, thus avoiding removal once the therapy is complete. This approach has considerably improved patient acceptability and patient compliance. Various bioabsorbable polymers have been evaluated for controlled implantable drug delivery, including hydrogels, copolymers of polylactic and polyglycolic acids, polylactic acid, poly(orthoesters), polyanhydrides, poly(E-caprolactone), and polyurethanes. Their characteristics have been studied using a variety of drugs, like anticancer agents, hormone agonists and antagonists, nonsteroidal anti-inflammatory agents, neuroleptics, contraceptives, and others. The present paper describes the current research on implantable therapeutic systems, the bioabsorbable polymers, and the biologically active agents being used in this approach.

Absorption↗

PubMed1989

Intracerebral drug delivery in rats with lesion-induced memory deficits.

Pharmacological treatments directed at increasing cortical acetylcholine activity in patients with Alzheimer's disease have largely been disappointing, perhaps because denervated areas of brain may not be exposed to adequate amounts of drug. A new method has been developed to enable localized intracerebral delivery of neurotransmitter substances using a polymeric drug delivery system. Microspheres of a polyanhydride sebacic acid copolymer were impregnated with bethanechol, an acetylcholinesterase-resistant cholinomimetic. Twenty rats received bilateral fimbria-fornix lesions, producing cholinergic denervation of the hippocampus and marked impairment in spatial memory. The animals were trained for 2 weeks to run after which they received bilateral intrahippocampal implants of saline (five rats), blank polymer (five rats), or bethanechol-impregnated polymer (10 rats). Following implantation, spatial memory was assessed by radial-maze performance testing for 40 days. Untreated lesioned rats showed persistently poor spatial memory, entering maze arms with near random frequency. Similarly, animals treated with saline and blank polymer did not improve after implantation. Rats treated with bethanechol-impregnated microspheres, however displayed significant improvement within 10 days after implantation; this improvement persisted for the duration of the experiment (p less than 0.05, Student's t-test). Histological analysis of regional acetylcholinesterase staining showed widespread loss of activity throughout the hippocampus bilaterally in all animals. The microsphere implants were visible within the hippocampus, with minimal reactive changes in surrounding brain. It is concluded that intracerebral polymeric drug delivery successfully reversed lesion-induced memory deficits, and has potential as a neurosurgical treatment method for Alzheimer's disease and other neurodegenerative disorders.

Anhydrides↗

PubMed1991

Interstitial chemotherapy with drug polymer implants for the treatment of recurrent gliomas.

Malignant gliomas have been difficult to treat with chemotherapy. The most effective agent, BCNU (carmustine), has considerable systemic toxicity and a short half-life in serum. To obviate these problems, a method has been developed for the local sustained release of chemotherapeutic agents by their incorporation into biodegradable polymers. Implantation of the drug-impregnated polymer at the tumor site allows prolonged local exposure with minimal systemic exposure. In this Phase I-II study, 21 patients with recurrent malignant glioma were treated with BCNU released interstitially by means of a polyanhydride biodegradable polymer implant. Up to eight polymer wafers were placed in the resection cavity intraoperatively, upon completion of tumor debulking. The polymer releases the therapeutic drug for approximately 3 weeks. Three increasing concentrations of BCNU were studied; the treatment was well tolerated at all three levels. There were no adverse reactions to the BCNU wafer treatment itself. The average survival period after reoperation was 65 weeks for the first dose group, 64 weeks for the second dose group, and 32 weeks for the highest dose group. The overall mean survival time was 48 weeks from reoperation and 94 weeks from the original operation. The overall median survival times were 46 weeks postimplant and 87 weeks from initial surgery. Eighteen (86%) of 21 patients lived more than 1 year from the time of their initial diagnosis and eight (38%) of 21 patients lived more than 1 year after intracranial implantation of the polymer. Frequent hematology, blood chemistry, and urinalysis tests did not reveal any systemic effect from this interstitial chemotherapy. Since the therapy is well tolerated and safe, a placebo-controlled clinical trial has been started. The trial will measure the effect of the second treatment dose on survival of patients with recurrent malignant glioma.

Brain Neoplasms↗

PubMed2001

[Use of synthetic biodegradable polymers in medicine].

Synthetic biodegradable polymers, such as polyesters, polyanhydrides, polyorthoesters, polycarbonates, polyphosphoesters, polyphosphazenes, polyesteramides, polyalkylenoxalates, polyalkylcyanoacrylates, etc., are represented as materials which are being tested for use, or which have been already used in surgery, orthopaedics, and pharmacy. A particular attention is devoted to their use in the preparation of systems with prolonged release or with targeted biodistribution of active ingredients.

Biodegradation, Environmental↗

PubMed2002

[In vivo degradation and tissue compatibility of polyphosphazene blend films].

The degradation performance and tissue compatibility of polyphosphazene/polyester or polyanhydride (PGP/PLGA or PGP/PSTP) blend films were investigated in mice. The results showed that the blend degradation rate could be regulated by adjusting PLGA or PSTP content in the blends. For example, the weight loss of PGP/PLGA (70:30 by wt) film was 68.4% after 55 days, whereas that of PGP/PSTP (70:30 by wt) was 88.5% only after 12 days. Also the mechanisms for in vivo degradation of blends of PGP/PLGA and PGP/PSTP were hydrolysed enzymatically and non-enzymatically, respectively. The tissue compatibility of PGP/PLGA was better than that of PGP/PSTP, and an increase of the percentage of PGP in PGP/PSTP blends would help improve the tissue compatibility. These findings suggested that polyphosphazene blends be potential materials applied in medical field.

Animals↗