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PubMed1990

Drug delivery systems: 3A. Role of polymers in drug delivery.

At present, polymers represent a class of ubiquitous materials. They are being used for a multitude of purposes and the almost inexhaustible varieties of molecular architecture that macromolecular materials can possess provides the possibility for a myriad of applications. Because of the increased interest being shown in the macromolecules by the pharmaceutical industry for the fabrication of drug delivery systems, numerous polymers have been synthesized and successfully used in drug delivery devices. The necessary conditions for developing the concept of pharmaceutically applicable polymers depend upon delineating a detailed knowledge of the relationship between the structure and properties of polymer networks. A number of polymers have been studied systematically from this point of view and there is every indication that the systems described have the potential to become clinically valuable and therefore marketable drug delivery systems. The potential of these promising polymers is still far from being exhausted and there is a strong possibility that many important developments will be forthcoming in this field in the future. In the current review article, polymers for controlled release have been divided into four major categories: diffusion-controlled systems; chemically controlled systems; solvent-activated systems; and magnetically controlled systems. Polymers as drug carriers also have been divided into various subgroups: soluble, biodegradable, mucoadhesive and other polymeric systems. The latter group includes polymers containing pendant bioactive substituents, matrix systems, heparin-releasing polymers, ionic polymers, oligomers and miscellaneous. At an introductory and fundamental level, an overview of these polymers and the materials science for the design of drug delivery systems will be discussed.

Animals↗

PubMed1995

Fate of water-soluble polymers administered via different routes.

The biological fate of synthetic water-soluble polymers administered to mice by injection at different sites is described. After intraperitoneal (ip), subcutaneous (sc), and intramuscular (im) injections of 125I-labeled poly(vinyl alcohol) (PVA) and poly(ethylene glycol) (PEG) with various molecular weights, the time-course of polymer concentration in the blood was measured and analyzed pharmacokinetically. The location of PVA in the body was similar to that of PEG; that is, the elimination from the injection sites and the translocation from the injection sites into the blood circulation were similar for both polymers. The elimination rate of both polymers from the injection sites increased in the order ip > sc > im. After sc and im injections of polymers, the elimination rate decreased with an increase in the molecular weight, whereas the elimination rate of polymers injected showed no molecular weight dependence over the range studied, regardless of the type of polymers used. The time-course of polymer concentration in the blood depended largely on the injection route of the polymers, and the polymer elimination from the blood circulation was enhanced with the decreasing molecular weight of polymers injected. It was concluded that the molecular weight and the injection site are the important factors that affect the concentration profile of polymers in the blood circulation.

Alcohols↗

PubMedDate not supplied

Temperature-induced switching of enzyme activity with smart polymer-enzyme conjugates.

A method for thermally induced switching of enzyme activity has been developed, based on the site-directed conjugation of end-reactive temperature-responsive polymers to a unique cysteine (Cys) residue positioned near the enzyme active site. The reversible temperature-induced collapse of N,N-dimethylacrylamide (DMA)/N-4-phenylazo-phenylacrylamide (AZAAm) copolymers (DMAAm) has been used as a molecular switch to control the catalytic activity of endoglucanase 12A (EG 12A). The polymer was conjugated to the EG 12A site-directed mutant N55C, directly adjacent to the cellulose binding cleft, and to the S25C mutant, where the conjugation site is more distant. The N55C conjugate displayed a larger activity shutoff efficiency in the collapsed polymer state than the S25C conjugate. Increasing the polymer molecular weight was also shown to increase the shutoff efficiency of the switch. Related to these effects of conjugation site and polymer size, the switching efficiency was found to be strongly dependent on substrate size. With a small substrate, o-nitrophenyl-beta-d-cellobioside (ONPC), there was minimal blocking of enzyme activity when the polymer was in the expanded state. With a large substrate, hydroxyethyl cellulose (HEC), there was a large reduction of enzyme activity in the polymer expanded state, even with relatively small polymer chains, and a further reduction when the polymer was collapsed. Similar general trends for the interactive effects of conjugation site, polymer size, and substrate size were observed for immobilized conjugates. Kinetic studies demonstrated that the switching activity was due to the blocking of substrate association by the collapsed polymers. These investigations provide mechanistic insight that can be utilized to design molecular switches for a variety of stimuli-responsive polymer-protein conjugates.

Catalysis↗

PubMedDate not supplied

Protective effects of polymer additives on animal cells exposed to rapidly falling liquid films.

The protective effects of polymer additives on insect cells against fluid mechanical damage was investigated in a falling film-flow device. The falling liquid film creates rapidly moving air-liquid interfaces and high fluid shear stress, mimicking the characteristics of a bursting bubble in aerated cell culture. The additives tested included a group of surface-active polymers, (i.e., Pluronic F68, poly(ethylene glycol)s, and Tween 80) and a group of viscosity-enhancing polymers (i.e., dextrans, methyl-cellulose, and (carboxymethyl)cellulose). We found that methylcellulose, which was previously considered a viscosity-enhancing polymer, actually had significant surface-active properties. All of the surface-active polymers exhibited significant protective effects, with Pluronic F68 and the higher molecular weight poly(ethylene glycol), PEG 20M, providing the best protection. In contrast, the viscosity-enhancing polymers, with the exception of methylcellulose, showed little or no protection for insect cells in the film flow. All of the protective polymers had surface-active properties, even though some of them did not change the surface tension in the actual insect cell medium. There was no correlation between the protective effect and the changes in liquid viscosity and surface tension due to the polymer additives. The level of protection was shown to be dependent upon the type of polymer, its concentration in the culture medium, and the polymer molecular weight. We concluded that the mechanism of protection of these surface-active polymers was through interaction of the polymer molecules with the cell plasma membranes: a fast-acting biological mechanism.

Animals↗

PubMed2005

Structure and thermodynamics of protein-polymer solutions: effects of spatially distributed hydrophobic surface residues.

Protein-polymer association in solution driven by a short-range attraction has been investigated using a simple coarse-grain model solved by Monte Carlo simulations. The effect of the spatial distribution of the hydrophobic surface residues of the protein on the adsorption of weakly hydrophobic polymers at variable polymer concentration, polymer length, and polymer stiffness has been considered. Structural data on the adsorbed polymer layer and thermodynamic properties, such as the free energy, energy, and entropy, related to the protein-polymer interaction were calculated. It was found that a more heterogeneous distribution of the surface residues promotes adsorption and that this also applies for different polymer concentrations, polymer chain lengths, and polymer flexibilities. Furthermore, the polymer adsorption onto proteins with more homogeneous surface distributions displayed larger sensitivity to polymer properties such as chain length and flexibility. Finally, a simple relation between the adsorption probability and the change in the free energy was found and rationalized by a simple two-state adsorption model.

Adsorption↗

PubMed2005

Fragmentation of the lamellae and fractionation of polymer coils upon mixing poly(dimethylacrylamide) with the lamellar phase of aerosol OT in water.

The lamellar mesophase formed by surfactant 1,4-bis(2-ethylhexyl) sodium sulfosuccinate (AOT) in deuterated water is mixed with poly(dimethylacrylamide) (PDMAA) polymers of low molecular weight (Mn= (2-20) x 10(3)). The mixtures separate into microphases (lamellar plus isotropic polymer solution). Their microstructures are studied by microscopy, small-angle X-ray scattering (SAXS), and deuterium NMR (2H NMR). According to SAXS, the lamellar phase fractionates the molecular weight distribution of the polymer, by dissolving only chains with coil sizes smaller than the thickness of the water layers between lamellae, and keeping larger chains segregated from the lamellar phase. The fraction of polymer that is segregated from the lamellar phase grows with Mn of the polymer. In 2H NMR, there are two signals, a quadrupolar doublet (water molecules hydrating the anisotropic lamellar phase contribute to this doublet) and a singlet (water molecules in the isotropic polymer solution contribute to this singlet). These two signals are deconvoluted to analyze the phases. Mixing with the polymer produces the partial dispersion of the lamellar phase into small fragments (microcrystallites). The structure of these microcrystallites is such that they conserve the regular long period spacing of the macrophase, and are thus identified in SAXS, but they are smaller than the minimum size required to produce quadrupolar splitting (about 4 microm), and therefore, in 2H NMR, they contribute to the singlet. 2H NMR can thus not distinguish between small microcrystallites and an isotropic polymer solution segregated from the lamellar phase; instead small microcrystallites are detected as an apparent increase of the isotropic solution. The degree of dispersion produced by the polymer in the lamellar phase is correlated with the degree of segregation that the polymer suffers. Thus, much greater dispersion into microcrystallites is produced by the higher Mn polymers than by the lower Mn polymers (in the range covered by the present samples, although with a much higher molecular weight sample (3 x 10(6)) that is totally segregated no such microcrystallites were detected).

Acrylamides↗

PubMed2007

Designing polymer conjugates as lysosomotropic nanomedicines.

Marriage of cell biology (the concept of 'lysosomotropic drug delivery') and the realization that water-soluble synthetic polymers might provide an ideal platform for targeted drug delivery led to the first synthetic polymer-drug conjugates that entered clinical trials as anticancer agents. Conceptually, polymer conjugates share many features with other macromolecular drugs, but they have the added advantage of the versatility of synthetic chemistry that allows tailoring of molecular mass and addition of biomimetic features. Conjugate characteristics must be optimized carefully to ensure that the polymeric carrier is biocompatible and that the polymer molecular mass enables tumour-selective targeting followed by endocytic internalization. The polymer-drug linker must be stable in transit, but be degraded at an optimal rate intracellularly to liberate active drug. Our early studies designed two HPMA [N-(2-hydroxypropyl)methacrylamide] copolymer conjugates containing doxorubicin that became the first synthetic polymer-drug conjugates to be tested in phase I/II clinical trials. Since, a further four HPMA copolymer-anticancer drug conjugates (most recently polymer platinates) and the first polymer-based gamma-camera imaging agents followed. Polymer-drug linkers cleaved by lysosomal thiol-dependent proteases and the reduced pH of endosomes and lysosomes have been used widely to facilitate drug liberation. It is becoming clear that inappropriate trafficking and/or malfunction of enzymatic activation can lead to new mechanisms of clinical resistance. Recent studies have described HPMA copolymer conjugates carrying a combination of both endocrine and chemotherapy that are markedly more active than individual conjugates carrying a single drug. Moreover, current research is investigating novel dendritic polymer architectures and novel biodegradable polymers as drug carriers that will provide improved drug delivery and imaging probes in the future. The present paper reviews the clinical status of polymeric anticancer agents, the rationale for the design of polymer therapeutics and discusses the benefits and challenges of lysosomotropic delivery.

Antineoplastic Agents↗

PubMed2006

Molecular-dynamics simulations with explicit hydrodynamics II: on the collision of polymers with molecular obstacles.

We present a study of the dynamics of single polymers colliding with molecular obstacles using Molecular-dynamics simulations. In concert with these simulations we present a generalized polymer-obstacle collision model which is applicable to a number of collision scenarios. The work focusses on three specific problems: i) a polymer driven by an external force colliding with a fixed microscopic post; ii) a polymer driven by a (plug-like) fluid flow colliding with a fixed microscopic post; and iii) a polymer driven by an external force colliding with a free polymer. In all three cases, we present a study of the length-dependent dynamics of the polymers involved. The simulation results are compared with calculations based on our generalized collision model. The generalized model yields analytical results in the first two instances (cases i) and ii)), while in the polymer-polymer collision example (case iii)) we obtain a series solution for the system dynamics. For the case of a polymer-polymer collision we find that a distinct V-shaped state exists as seen in experimental systems, though normally associated with collisions with multiple polymers. We suggest that this V-shaped state occurs due to an effective hydrodynamic counter flow generated by a net translational motion of the two-chain system.

Adsorption↗

PubMed1982

[Hydrosoluble polymers of NAD+ and ADP. Study of their coenzymatic properties as a function of their size].

Hydrosoluble polymers of NAD+ and ADP were synthesized according to a described method with some modifications. The cofactor was bound to the matrix by a spacer group of five atoms at the exocyclic adenine C-6 amino group. Cofactor incorporations were very high. The loading of NAD+ polymers were: 420 mumol NAD+/g polymer and 330 mumol ADP ribose/g polymer arising from degradation of NAD+; the loading of ADP polymers were: 1.40 and 1.43 mmol ADP/g polymer. Each polymer obtained in a same polymerization step was fractionated in two parts by gel filtration in such a manner that these two parts had the same framework but different molecular weights. The biological properties of the fractionated polymers were compared. The small sized polymers of NAD+, assayed with four dehydrogenases, were more reduced enzymatically than the larger ones and had the higher reduction rates relative to free NAD+. In a coupled system (L-lactate dehydrogenase, formate dehydrogenase) with coenzyme regeneration, the rate of production of L-lactate at the steady state of the system using NAD+ polymers of small size was 80% that of the system using free NAD+. The small-sized polymers of ADP were more phosphorylated by pyruvate kinase and creatine kinase than the larger ones. But the relative rates of transformation by pyruvate kinase of large sized polymers were higher than those of smaller ones.

Adenosine Diphosphate↗

PubMed1999

Implantable polymers for tirapazamine treatments of experimental intracranial malignant glioma.

Malignant gliomas remain refractory to intensive radiotherapy and cellular hypoxia enhances clinical radioresistance. Under hypoxic conditions, the benzotriazine di-N-oxide (3-amino-1,2,4-benzotriazine 1,4-dioxide) (tirapazamine) is reduced to yield a free-radical intermediate that results in DNA damage and cellular death. For extracranial xenografts, tirapazamine treatments have shown promise. We therefore incorporated tirapazamine into the synthetic, biodegradable polymer, measured the release, and tested the efficacy both alone and in combination with external beam radiotherapy in the treatment of experimental intracranial human malignant glioma xenografts. The [(poly(bis(p-carboxyphenoxy)-propane) (PCPP):sebacic acid (SA) (PCPP:SA ratio 20:80)] polymer was synthesized. The PCPP:SA polymer and solid tirapazamine were combined to yield proportions of 20% or 30% (wt/wt). Polymer discs (3 x 2 mm) (10 mg) were incubated (PBS, 37 degrees C), and the proportion of the drug released vs. time was recorded. Male nu/nu nude mice were anesthetized and received intracranial injections of 2 x 10(5) U251 human malignant glioma cells. For single intraperitoneal (i.p.) drug and/or external radiation treatments, groups of mice had i.p. 0.3 mmol/kg tirapazamine, 5 Gy cranial irradiation, or combined treatments on day 8 after inoculation. For fractionated drug and radiation treatments, mice had i.p. 0.15 mmol/kg tirapazamine, 5 Gy radiation, or combined treatments on days 8 and 9 after inoculation. For intracranial (i.c.) polymer treatments, mice had craniectomies and intracranial placement of polymer discs at the site of cellular inoculation. The maximally tolerated percentage loading of tirapazamine in the polymer.disc was determined. On day 7 after inoculation, groups of mice had i.c. empty or 3% tirapazamine alone or combined with radiation (5 Gy x 2 doses) or combined with i.p. drug (0.15 mmol/kg x 2 doses on days 8 and 9). Survival was recorded. Polymers showed controlled, protracted in vitro release for over 100 days. The 5 Gy x 1 treatment resulted in improved survival; 28.5 +/- 3.7 days (P = 0.01 vs. controls), while the single i.p. 0.3 mmol/kg tirapazamine treatment, 17.5 +/- 1.9 days (P = NS) and combined treatments; 21.5 +/- 5.0 days (P = NS) were not different. The fractionated treatments: 5 Gy x 2, i.p. 0.15 mmol/kg tirapazamine x 2 and the combined treatments resulted in improved survival: 44.5 +/- 3.9 (P < 0.001), 24.5 +/- 2.3 (P = 0.05) and 50.0 +/- 6.0 (P < 0.001), respectively. Survival after intracranial empty polymer was 16.5 +/- 3.0 days and increased to 31.0 +/- 3.0 (P = 0.003) days when combined with the 5 Gy x 2 treatment. The survival after the polymer bearing 3% tirapazamine alone vs. combined with radiation was not different. The combined 3% tirapazamine polymer, i.p. tirapazamine, and radiation treatments resulted in both early deaths and the highest long-term survivorship. The basis for potential toxicity is discussed. We conclude that implantable biodegradable polymers provide controlled intracranial release for treatment of experimental glioma. For treatment of malignant gliomas, the combination of continuous polymer-mediated delivery and fractionated systemic delivery of tirapazamine with external beam radiotherapy warrants further exploration.

Absorbable Implants↗

PubMed2001

The use of light scattering for precise characterization of polymers for DNA sequencing by capillary electrophoresis.

The ability of a polymer matrix to separate DNA by capillary electrophoresis (CE) is strongly dependent upon polymer physical properties. In particular, recent results have shown that DNA sequencing performance is very sensitive to both the average molar mass and the average coil radius of the separation matrix polymers, which are affected by both polymer structure and polymer-solvent affinity. Large polymers with high average molar mass provide the best DNA sequencing separations for CE, but are also the most challenging to characterize with accuracy. The methods most commonly used for the characterization of water-soluble polymers with application in microchannel electrophoresis have been gel permeation chromatography (GPC) and intrinsic viscosity measurements, but the limitations and potential inaccuracies of these approaches, particularly for large or novel polymers and copolymers, press the need for a more universally accurate method of polymer molar mass profiling for advanced DNA separation matrices. Here, we show that multi-angle laser light scattering (MALLS) measurements, carried out either alone or in tandem with prior on-line sample fractionation by GPC, can provide accurate molar mass and coil radius information for polymer samples that are useful for DNA sequencing by CE. Wider employment of MALLS for characterization of novel polymers designed as DNA separation matrices for microchannel electrophoresis should enable more rapid optimization of matrix properties and formulation, and assist in the development of novel classes of polymer matrices.

Electrophoresis, Capillary↗

PubMed1990

Hydrolysis and absorption of glucose polymers from rice compared with corn in chronic diarrhea of infancy.

Because rice remains the most available carbohydrate in developing countries, where chronic diarrhea is most prevalent, we compared the in vitro hydrolysis and clinical tolerance of rice glucose polymer with those of corn glucose polymer. Rice glucose polymer hydrolysis to D-glucose and short-chain polymers (polymers with two to four glucose units and those with five or more units) was similar to that for corn glucose polymers during incubation with saliva or duodenal aspirates. However, rice glucose polymers yielded more short-chain products than corn glucose polymers during incubation with pooled mucosal homogenates (p less than 0.01). In vivo tolerance testing of 16 infants with chronic diarrhea confirmed that rice glucose polymers were well tolerated and, compared with corn glucose polymers, achieved a higher maximal increase of serum glucose concentration (36.6 +/- 7.3 vs 27.6 +/- 10.3 mg/dl; p less than 0.02), a shorter time to peak serum glucose concentration (34.0 +/- 10.2 vs 52.5 +/- 25.7 minutes; p less than 0.02), and a greater area under the serum glucose response curve at 30 minutes (538 +/- 131 vs 1035 +/- 501 cm; p less than 0.02). We conclude that rice glucose polymers are rapidly hydrolyzed in vitro and in vivo and are more rapidly absorbed than are corn glucose polymers in children with chronic diarrhea.

Absorption↗

PubMed2004

Monte Carlo simulation of structure and nanoscale interactions in polymer nanocomposites.

Off-lattice Monte Carlo simulations in the canonical ensemble are used to study polymer-particle interactions in nanocomposite materials. Specifically, nanoscale interactions between long polymer chains (N=550) and strongly adsorbing colloidal particles of comparable size to the polymer coils are quantified and their influence on nanocomposite structure and dynamics investigated. In this work, polymer-particle interactions are computed from the integrated force-distance curve on a pair of particles approaching each other in an isotropic polymer medium. Two distinct contributions to the polymer-particle interaction potential are identified: a damped oscillatory component that is due to chain density fluctuations and a steric repulsive component that arises from polymer confinement between the surfaces of approaching particles. Significantly, in systems where particles are in a dense polymer melt, the latter effect is found to be much stronger than the attractive polymer bridging effect. The polymer-particle interaction potential and the van der Waals potential between particles determine the equilibrium particle structure. Under thermodynamic equilibrium, particle aggregation is observed and there exists a fully developed polymer-particle network at a particle volume fraction of 11.3%. Near-surface polymer chain configurations deduced from our simulations are in good agreement with results from previous simulation studies.

Journal Article↗

PubMed2002

Optimal transfection with the HK polymer depends on its degree of branching and the pH of endocytic vesicles.

We have recently reported that liposomes in combination with histidine (HK)-containing polymers enhanced the expression of luciferase in transfected cells. In transformed or malignant cell lines, branched HK polymers (combined with liposome carriers) were significantly more effective than the linear HK polymer in stimulating gene expression. In the current study, we found that the linear HK polymer enhanced gene expression in primary cell lines more effectively than the branched polymers. The differences in the optimal carrier (linear versus branched) were not due to initial cellular uptake, size of the complexes or level of gene expression. There was, however, a strong association between the optimal type of HK polymer and the pH of endocytic vesicles (P = 0.0058). By altering the percentage of histidines carrying a positive charge, the endosomal pH of a cell may determine the amount of DNA released from the linear or branched HK polymer. In the two cell lines in which the linear HK was the optimal polymer, the endocytic vesicles were strongly acidic with a pH of <5.0. Conversely, in the four cell lines in which the branched polymers were optimal transfection agents, the pH of endocytic vesicles was >6.0. Furthermore, binding data support the relationship between DNA release from the optimal HK polymer and endosomal pH. The interplay between optimal HK polymers and the endosomal pH may lead to improved gene-delivery polymers tailored to a particular cell.

Animals↗

PubMed2004

Three-dimensional orientational order in the bulk and on the surface of polymer films and its effect on liquid-crystal alignment.

The correlation between orientation ordering of polymer chains in the bulk of polymer film and at the polymer-liquid-crystal (LC) interface has been studied to determine it's role in LC alignment. The bulk and surface ordering of polymer were investigated by null ellipsometry and x-ray reflectivity, respectively. Two kinds of liquid-crystalline polymers were used; side-chain azopolymers with azochromophores containing hydrophobic OC4H9 alkyl chain (P1) and strongly polar NO2 group (P2) as the end substituents. The uniaxial tilt orientation of azochromophores in the films of both polymers was induced by the oblique irradiation with unpolarized UV light. The two polymers exhibit similar chain orientation but different ordering of azochromophores on the surface of the films of P1 and P2. Surface ordering of P1 films correlates very well with the order in the bulk of the film, which are essentially determined by the UV exposure. However, orientational order of polymer chains at the surface of P2 films is different from that in its bulk and is not determined by UV exposure. This is explained by strong aggregation of azochromophores during its self-assembling at the polymer-air interface. The LC alignment is determined by the surface ordering of azochromophores. The results imply that ordering tendency can be effectively transferred from polymer bulk to polymer surface and then to LC if it is not lost at the polymer-LC interface.

Journal Article↗

PubMed1999

Competitive adsorption between phospholipid and plasma protein on a phospholipid polymer surface.

The competitive adsorption of proteins and phospholipids on omega-methacryloyloxyalkyl phosphorylcholine (MAPC) polymer was evaluated in this study. Albumin, fibrinogen, and dimyrstoyl phosphatidylcholine (DMPC) were used as model components. The amount of DMPC adsorbed on the MAPC polymers increased with an increase in the MAPC unit composition of the polymer. The methylene chain length of the MAPC unit was another factor influencing the DMPC adsorption when the MAPC unit composition of the MAPC polymer was low. The state of albumin and DMPC liposome adsorbed on the 2-methacryloyloxyethyl phosphorylcholine (MPC) polymer was determined by dynamic contact angle (DCA) measurement. The adsorption strength of albumin on the MPC polymer was weaker than that on the poly[n-butyl methacrylate (BMA)], that is, the albumin was detached from the MPC polymer during the rinsing process. On the poly(BMA) surface, no difference in the shape of the DCA loops before and after contact with the DMPC liposomal suspension was observed. Fibrinogen adsorption on the MAPC polymer was detected by gold-colloid labeled immunoassay. The amount of fibrinogen adsorbed on every MAPC polymer surface was reduced by addition of the DMPC liposome in the fibrinogen solution. The number of platelets adhered on the MAPC polymer was also decreased when the DMPC liposome was present in the fibrinogen solution during pretreatment. We concluded that phospholipids were preferentially adsorbed on the MAPC polymer surface compared with plasma protein and that the adsorbed phospholipids played an important role in showing an excellent blood compatibility on the MAPC polymer.

Adsorption↗

PubMed2006

Lysis of intracerebral hematoma with stereotactically implanted tissue plasminogen activator polymers in a rabbit model.

OBJECT: Currently no adequate surgical treatment exists for spontaneous intracerebral hemorrhage (ICH). Implantable polymers can be used effectively to deliver therapeutic agents to the local site of the pathological process, thus reducing adverse systemic effects. The authors report the use of stereotactically implanted polymers loaded with tissue plasminogen activator (tPA) to induce lysis of ICH in a rabbit model. METHODS: Ethylene vinyl acetate (EVAc) polymers were loaded with bovine serum albumin (BSA) only or with BSA plus tPA. In vitro pharmacokinetic (three polymers) and thrombolysis (12 polymers) studies were performed. For the in vivo study, 12 rabbits were fixed in a stereotactic frame, and 0.2 ml of clotted autologous blood was injected into the right frontal lobe parenchyma. After 20 minutes, control BSA polymers were stereotactically implanted at the hemorrhage site in six rabbits, and experimental BSA plus tPA polymers were implanted in six rabbits. Animals were killed at 3 days, and blood clot volume was assessed. The pharmacokinetic study showed release of 146 ng of tPA over 3 days. The tPA activity correlated with in vitro thrombolysis. In the in vivo study, the six animals treated with tPA polymers had a mean (+/- standard error of the mean [SEM]) thrombus volume of 1.43 +/- 0.29 mm3 at 3 days, whereas the six animals treated with blank (BSA-only) polymers had a mean (+/- SEM) thrombus volume of 19.99 +/- 3.74 mm3 (p < 0.001). CONCLUSIONS: Ethylene vinyl acetate polymers release tPA over the course of 3 days. Stereotactic implantation of tPA-loaded EVAc polymers significantly reduced ICH volume. Polymers loaded with tPA may be useful clinically for lysis of ICH without the side effects of systemic administration of tPA.

Animals↗

PubMed1989

The immunogenicity of soluble haptenated polymers is determined by molecular mass and hapten valence.

T cell-independent Ag are believed to stimulate antibody formation in the relative absence of Ag processing and T cell help. Previous studies on the type 2 T cell independent (TI-2) Ag DNP-polyacrylamide, have shown that when one systematically varies the molecular mass and hapten valence, the immunogenic potential of this type of molecule depends on definable molecular characteristics. It was found that to be immunogenic, these molecules had to exceed a threshold molecular mass of 100,000 Da and a threshold hapten valence of 20. The present study was undertaken to determine whether such findings could be generalized to other molecules belonging to the TI-2 class of Ag. The molecular characteristics of five chemically different fluoresceinated (FL)-polymers were systematically varied, and their ability to stimulate an IgM antihapten immune response was measured. The polymers used as carriers were carefully size-fractionated and consisted of one natural polymer (dextran), one modified natural polymer (carboxymethyl cellulose), and three synthetic polymers (Ficoll, polyvinyl alcohol, and polyacrylamide). The carriers varied in physical structure from the highly cross-linked Ficoll, to the somewhat branched dextran, to the linear polyacrylamide, carboxymethyl cellulose, and polyvinyl alcohol. Polymers were haptenated with FL and size-fractionated so as to yield a panel of molecules with varying molecular mass, hapten valence, and hapten density. Anti-FL IgM response to these haptenated polymers was measured in vivo after i.p. injection of the FL-polymer in saline, and measured in vitro after culture with unfractionated spleen cells from naive mice. In agreement with the previous studies on DNP-polyacrylamide, it was found that to be immunogenic, each of the FL-polymers had to exceed a comparable threshold value of molecular mass and of hapten valence. Optimal immunogenicity occurred when the FL-polymers had values of mass and hapten density lying within a predictable range. Immunogenicity decreased when these optimal parameters were substantially increased or decreased. We conclude that the immunogenicity of soluble haptenated polymers depends on predictable physical molecular characteristics, and is relatively independent of the chemical composition and conformation of the carrier polymer.

Animals↗