Biomedical subjects

E Mathiowitz

Publications and source records attributed to E Mathiowitz.

At least 19 recordsLinked to original sources

PubMed2000

Nanosphere based oral insulin delivery.

Zinc insulin is successfully encapsulated in various polyester and polyanhydride nanosphere formulations using Phase Inversion Nanoencapsulation (PIN). The encapsulated insulin maintains its biological activity and is released from the nanospheres over a span of approximately 6 h. A specific formulation, 1.6% zinc insulin in poly(lactide-co-glycolide) (PLGA) with fumaric anhydride oligimer and iron oxide additives has been shown to be active orally. This formulation is shown to have 11.4% of the efficacy of intraperitoneally delivered zinc insulin and is able to control plasma glucose levels when faced with a simultaneously administered glucose challenge. A number of properties of this formulation, including size, release kinetics, bioadhesiveness and ability to traverse the gastrointestinal epithelium, are likely to contribute to its oral efficacy.

Administration, Oral↗

PubMed2000

Interleukin-12 delivered by biodegradable microspheres promotes the antitumor activity of human peripheral blood lymphocytes in a human head and neck tumor xenograft/SCID mouse model.

BACKGROUND: The role of cytokines in tumor regression is now well established. The major limitation for the clinical use of cytokines is the lack of a simple and effective protocol for the local and sustained delivery of cytokines to the tumor milieu. This study reports suppression of human head and neck squamous cell carcinoma (HNSCC) by human peripheral blood lymphocytes (HuPBL) following local, sustained delivery of interleukin-12 (IL-12) to tumors with biodegradable microspheres in a human/SCID mouse chimeric model. Materials and Methods Nondisrupted biopsy pieces (120 mg) of primary HNSCC were implanted s.c. into severe combined immunodeficient (SCID) mice and were expanded by serial passage in mice. Tumors were then titrated with different doses of allogeneic HuPBL by coengraftment of tumor pieces and HuPBL into the subcutis of SCID mice to determine whether the HuPBL possessed antitumor activity (the SCID/Winn model). The lymphocyte subsets that were responsible for the suppression of tumor engraftment were identified by selective depletion of the CD4+, CD8+, and CD56+ cells from the HuPBL prior to engraftment into mice. Attempts were then made to augment the antitumor activity of the HuPBL either by repeated intralesional bolus injections of recombinant human IL-12 (0.5 microg x 10 doses) or with a single dose of IL-12-loaded microspheres ( approximately 1.65 microg IL-12/mg microspheres, 2 mg microspheres/mouse). RESULTS: Successful engraftment of HNSCC was observed in 12 of 19 different patient samples. Normal histological architecture of tumor was maintained up to four serial passages in the SCID mice. After the first tumor engraftment, but not in subsequent passages, human immunoglobulin produced by plasma cells present in the tumor infiltrating lymphocyte population was detected in the mouse sera. Allogeneic human PBL displayed antitumor cytotoxic activity in a cell dose-dependent fashion when coengrafted with the tumors passaged in SCID mice. Lymphocyte subset depletion studies established that tumor suppression was dependent on both the CD8+ T lymphocytes and the CD56+ natural killer cells. Treatment of tumors with a single intralesional injection of IL-12-loaded microspheres was highly effective, resulting in the complete suppression of tumor engraftment in 50% of the mice. In contrast, treatment of tumors with repeated bolus IL-12 injections suppressed tumor engraftment only transiently and did not result in complete tumor rejection in any of the mice. CONCLUSION: The coengraftment of HNSCC and allogeneic lymphocytes into SCID mice provides a viable model with which to evaluate immunotherapeutic strategies for human cancer. The use of biodegradable microspheres for local sustained delivery of cytokines to augment lymphocyte mediated antitumor immunity within the tumor microenvironment provides a safer and simpler alternative to current cytokine immunotherapy protocols.

Animals↗

PubMed1999

Correlation of two bioadhesion assays: the everted sac technique and the CAHN microbalance.

This contribution correlates two in vitro methods utilized to determine bioadhesion. One method, the everted intestinal sac technique, is a passive test for bioadhesion involving several polymer microspheres and a section of everted intestinal tissue. The other method, the CAHN microbalance, employs a CAHN dynamic contact angle analyzer with modified software to record the tensile forces measured as a single polymer microsphere is pulled from intestinal tissue. This study demonstrates that CAHN and everted sac experiments yield similar results when used to quantify the bioadhesive nature of polymer microsphere systems. A polymer showing high adhesion in one method also demonstrates high bioadhesion in the other method; polymers that exhibit high fracture strength and tensile work measurements with the CAHN microbalance also yield high binding percentages with the everted sac method. The polymers tested and reported here are poly(caprolactone) and different copolymer ratios of poly(fumaric-co-sebacic anhydride). The results of this correlation demonstrate that each method alone is a valuable indicator of bioadhesion.

Adhesiveness↗

PubMed1999

Poly(fumaric-co-sebacic anhydride). A degradation study as evaluated by FTIR, DSC, GPC and X-ray diffraction.

The degradation of three poly(fumaric-co-sebacic anhydride) [P(FA:SA)] copolymers is examined in a composition of microspheres made by the hot melt encapsulation process. The emergence of low molecular weight oligomers occurs during degradation of the copolymer microspheres, as evidenced by a variety of characterization methods. Characterization was conducted to determine the extent of degradation of the polyanhydride microspheres using Fourier-transform infrared spectroscopy (FTIR), gel permeation chromatography (GPC), differential scanning calorimetry (DSC) and X-ray diffraction. It is demonstrated that degradation of P(FA:SA) is greatly accelerated at basic pH, yet there is little difference between degradation in neutral and acidic buffers. A good correlation exists between the results of each characterization method, which allows a better understanding of the degradation process and the resulting formation of low molecular weight oligomers in poly(fumaric-co-sebacic anhydride).

Anhydrides↗

PubMed1999

Oral insulin delivery.

An oral form of insulin has been the elusive goal for many investigators since the protein's initial discovery by Banting and Best in 1922. This paper will attempt to answer why this is the case by describing the substantial barriers to the development of oral insulin formulations. Following this description, specific strategies to overcome the barriers to oral insulin administration will be discussed. Most notably, the use of permeation enhancers, protease inhibitors, enteric coatings and polymer microsphere formulations will be covered, including commentary on which methods hold more promise towards the successful development of oral insulin.

Journal Article↗

PubMed1998

Characterization of soluble, salt-loaded, degradable PLGA films and their release of tetracycline.

A local drug delivery system has been designed to release tetracycline over a period of 30 days from poly (lactide-co-glycolide) films. Incorporation of either soluble salt excipients or low molecular weight polymeric species has been found to modulate the release kinetics of the system. The following research describes the fabrication of the delivery system, monitors tetracycline release from the system, and fully characterizes the degradation of the polymer films via scanning electron microscopy, gel permeation chromatography, differential scanning calorimetry, Fourier-transform infrared spectroscopy, and X-ray diffraction techniques. Results show that the modulation via use of salts occurs without changing the inherent degradation rate of the system. We suggest that this phenomenon may be due to the increased amount of swelling and uptake of buffer by the films loaded with soluble salt. Uptake, therefore, may be creating microscopic pores that permit further diffusion of tetracycline from the polymer matrix as well as allow the free monomers to leave the system, thereby preventing autocatalysis within the system.

Biodegradation, Environmental↗

PubMed1998

Cytokine immunotherapy of cancer with controlled release biodegradable microspheres in a human tumor xenograft/SCID mouse model.

A novel biodegradable poly(lactic acid) microsphere formulation was evaluated for in vivo cytokine immunotherapy of cancer in a human tumor xenograft/ severe combined immunodeficiency (SCID) mouse model. Co-injection of interleukin-2 (IL-2)-loaded microspheres with tumor cells into a subcutaneous site resulted in the complete suppression of tumor engraftment in 80% of animals. In contrast, bovine-serum-albumin(BSA)-loaded particles or bolus injections of poly(ethylene glycol)/IL-2 were ineffective in preventing tumor growth. The antitumor effect of IL-2 released by the microspheres was shown to be mediated by the mouse natural killer cells. This is the first evidence that the rejection of human tumor xenografts can be provoked by the sustained in vivo delivery of IL-2 from biodegradable microspheres. The use of poly(lactic acid) microspheres to deliver cytokines to the tumor environment could provide a safer and simpler alternative to gene therapy protocols in the treatment of cancer.

Animals↗

PubMed1998

Degradation of double-walled polymer microspheres of PLLA and P(CPP:SA)20:80. I. In vitro degradation.

Double-walled (DW) polymer microspheres with a core of poly(1,3-bis-(p-carboxyphenoxy propane)-co-(sebacic anhydride)20:80 (P(CPP:SA)20:80) and an external coat of poly(L-lactic acid) (PLLA) were degraded for up to 6 months in vitro. The effects of hydrolytic degradation on the polymers were studied by Fourier-transform infrared (FTIR) spectroscopy, differential scanning calorimetry (DSC), gel permeation chromatography (GPC) and scanning electron microscopy (SEM). The inner core of the polyanhydride copolymer (P(CPP:SA)20:80) degraded first, breaking down into oligomers during the first week and then into monomers which were trapped by the outer shell of PLLA, crystallized, and remained in the core for the duration of the study. As expected, the PLLA coat degraded at a slower rate due to the ester bonds between lactic acid monomers being more hydrolytically resistant than the anhydride bonds. The PLLA in the DW microspheres decreased from its original molecular weight (Mw) of 24,000 g mol(-1) to approximately 5,000 g mol(-1) over the 6 month study. The melting temperature of the PLLA decreased more than 30 degrees C during the study, but no changes were observed in the FTIR spectra. The 6 month samples were very brittle, showing the concomitant drop in mechanical strength with the decrease in Mw.

Biocompatible Materials↗

PubMed1998

Degradation of double-walled polymer microspheres of PLLA and P(CPP:SA)20:80. II. In vivo degradation.

Double-walled (DW) polymer microspheres with a core of poly(1,3-bis-(p-carboxyphenoxy propane)-co-(sebacic anhydride)20:80 (P(CPP:SA)20:80) and an external coat of poly(L-lactic acid) (PLLA) were implanted subcutaneously and intramuscularly and were allowed to degrade for up to 6 months. The tissue surrounding the implant was fixed and sectioned for histological evaluation by light and scanning electron microscopy. The remaining polymer was extracted with chloroform and analyzed by gel permeation chromatography (G PC), Fourier-transform infrared (FTIR) spectroscopy, and differential scanning calorimetry (DSC). The inner core of the more hydrolytically labile P(CPP:SA)20:80 degraded first, becoming more granular over time. The PLLA coating showed no changes morphologically. The DW microspheres induced a stronger inflammatory response during the first week than did the SW PLLA microspheres, but this resolved by the second week. The SW PLLA microspheres showed no changes by SEM or optical microscopy. No differences in degradation were seen between samples implanted subcutaneously and those implanted intramuscularly. In vivo degradation was correlated to the results of an in vitro degradation study published as the first paper in this two paper series.

Animals↗

PubMed1997

Biologically erodable microspheres as potential oral drug delivery systems.

Biologically adhesive delivery systems offer important advantages over conventional drug delivery systems. Here we show that engineered polymer microspheres made of biologically erodable polymers, which display strong adhesive interactions with gastrointestinal mucus and cellular linings, can traverse both the mucosal absorptive epithelium and the follicle-associated epithelium covering the lymphoid tissue of Peyer's patches. The polymers maintain contact with intestinal epithelium for extended periods of time and actually penetrate it, through and between cells. Thus, once loaded with compounds of pharmacological interest, the microspheres could be developed as delivery systems to transfer biologically active molecules to the circulation. We show that these microspheres increase the absorption of three model substances of widely different molecular size: dicumarol, insulin and plasmid DNA.

Adhesiveness↗

PubMed1997

Controlled delivery of therapeutics from microporous membranes. I. Fabrication and characterization of microporous polyurethane membranes containing polymeric microspheres.

This paper describes a process for the inclusion of polymer microspheres in microporous polyurethane tubes and membranes. These composites were fabricated via a spray, phase-inversion technique using Cardiothane 51, a medical grade polyurethane, and either spray-dried poly(D,L-lactide-co-glycolide 50:50) microspheres or commercially available fluorescent polystyrene-latex microspheres. Characterization of the polyurethane membranes was performed using Fouriertransform infrared spectroscopy, differential scanning calorimetry, dynamic mechanical analysis, hydraulic permeability testing, scanning electron microscopy, and visible and fluorescence light microscopy. The results indicated the feasibility of layering microspheres throughout the microporous membrane or wall of the microporous tube, and the potential of such composite structures for local delivery of bioactive substances.

Blood Vessel Prosthesis↗

PubMed1997

Controlled delivery of therapeutics from microporous membranes. II. In vitro degradation and release of heparin-loaded poly(D,L-lactide-co-glycolide).

In vitro degradation and release of five types of heparin/surfactant-loaded poly(D,L-lactide-co-glycolide 50:50) (PLG) microspheres alone and also incorporated within microporous polyurethane tubes were studied over a 3-month period. Degradation was studied with scanning electron microscopy (SEM), Fourier-transform infrared spectroscopy (FTIR), gel permeation chromatography (GPC) and differential scanning calorimetry (DSC). Heparin release was characterized using a modified Azure A assay. SEM suggests that microspheres may be entrapped within polyurethane fibrils of the polyurethane tubes, thereby reducing contact with their hydrated environment. FTIR transmittance spectra confirm microsphere incorporation within the polyurethane tubes and PLG ester hydrolysis occurring over the 3-month period. A correlation was observed between decreasing molecular weights and glass transition temperatures (Tg). The microspheres alone exhibited a change in Tg but not when incorporated within the microporous tubes. Release profiles revealed a burst effect occurring during the first 4h and total release of the heparin from the microspheres by 12 weeks.

Anticoagulants↗

PubMed1994

Double-walled polymer microspheres for controlled drug release.

One approach to the controlled release of drugs involves incorporation of the drug molecules into the matrix of microscopic polymer spheres or capsules. Existing methods for preparing such microparticles do not, however, always guarantee a constant release rate, for example because drug molecules may be trapped preferentially at the surface, because they have to diffuse through an increasing thickness of polymer when the particles are non-eroding or because the surface area changes for eroding particles. In other situations pulsed release may be required--an application to which simple polymer microspheres do not readily lend themselves. Multi-walled microspheres might solve some of these problems. Here we describe a one-step process for preparing double-walled polymer microspheres with diameters ranging from about 20 to 1,000 micrometers. Our technique involves the phase separation of a polymer mixture owing to solvent evaporation: with an appropriate choice of interfacial tensions and evaporation rate, a spherical droplet of one polymer becomes coated with a highly uniform layer of the other. This process, which might be adapted to yield multi-walled microspheres, should make possible the engineering of highly specific drug-release properties.

Drug Delivery Systems↗

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↗

PubMed1991

Controlled and modulated release of basic fibroblast growth factor.

Basic fibroblast growth factor has multivariate effects in stimulating cell growth and the processes that surround tissue repair. Pathophysiologic studies have been hampered by the stability of the compound. Though very potent, basic fibroblast growth factor is rapidly degraded when injected or ingested. Controlled release of basic fibroblast growth factor would allow for examination of the chronic effects of this compound. Conventional matrix polymer-based release devices were fabricated and basic fibroblast growth factor released in a sustained fashion, but 99% of basic fibroblast growth factor mitogenic activity was lost. The source of these losses was identified and preventative measures examined. Preservation and stabilization of basic fibroblast growth factor was accomplished by binding the factor to heparin-Sepharose beads. This permitted prolonged storage, repeated handling, and the encapsulation of basic fibroblast growth factor within a microspherical controlled-release device using a naturally occurring polymer material, alginate. Encapsulation was accomplished with 77% efficiency and 87.5 +/- 12% of the basic fibroblast growth factor was released in a biologically active form. Release activation and regulation was achieved when cleavage of the basic fibroblast growth factor-heparin bonds was enhanced (e.g. by enzymatic bond cleavage with heparinase). Kinetic profiles were identified for a variety of experimental conditions and the effects of the controlled release of basic fibroblast growth factor on BALBc/3T3 fibroblasts examined.

Alginates↗

PubMed1991

A novel, self-correcting membrane coating technique.

A novel coating process, leading to formation of uniform, defect-free coating on solid dosage forms, is proposed. The coating process, termed "diffusion-controlled interfacial complexation," involves a chemical reaction between a reactant incorporated in the solid unit to be coated and a polymer solution, forming the coating medium. The reaction results in the formation of an insoluble reactant-polymer film around the solid. The rate of film/membrane formation is controlled by the rate of diffusion of reactant through the reactant-polymer film. In the model system, calcium acetate was selected as the reactant and algin as the polymer. The coating process was mathematically characterized in terms of rate of increase in film thickness, film weight, and depletion of reactant. Compressed tablets coated using the above process provided zero-order release in distilled water.

Dosage Forms↗

PubMed1990

Morphology of polyanhydride microsphere delivery systems.

Scanning electron microscopy (SEM) was used to elucidate the mechanism of polymer degradation and drug release in polyanhydride microspheres. Three different fabrication methods--solvent removal, solvent evaporation, and hot melt microencapsulation--were used to prepare polyanhydride microspheres containing a variety of drugs. The morphology of these microspheres releasing drug in vitro and in vivo was studied by SEM and compared with degradation and release data measured by conventional methods. Microspheres prepared by the three techniques were shown to have distinctive morphological characteristics induced by the nature of the fabrication method. In addition, SEM analysis could be used to explain the drug release profiles and polymer degradation behavior seen in vitro as well as the in vivo effects of insulin-loaded microspheres on diabetic rats. This study has shown SEM to be an important and powerful tool for analyzing the effects of microsphere fabrication method on drug release.

Anhydrides↗

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↗