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PubMed2002

Biodegradation of hydrophilic-hydrophobic hydrogels and its effect on albumin release.

The objective of this study was to examine the effects of composition ratio of a new class of bicomponent biodegradable hydrogels and the molecular weights of the constituents on the hydrolytic degradability of the hydrogels and their release of bovine serum albumin (BSA). Biodegradable hydrogels were prepared from dextran derivative of allyl isocyanate (dex-AI) and poly (D,L) lactide diacrylate macromer (PDLLAM) over a wide range of dex-AI to PDLLAM composition ratio. The results obtained indicated that the hydrolytic degradation of these biodegradable hydrogels could be controlled by adjusting the composition ratio of dex-AI to PDLLAM or by changing their molecular weights. Along with the hydrogel degradation, water content of the hydrogels changed, and 3D porous network structure was observed. Generally, as the PDLLAM composition in the hydrogels increased, the rate of weight loss increased due to the hydrolytic degradation of the PDLLAM. The increase in molecular weights of either dex-AI or PDLLAM would decrease the degradation rate of the dex-AI/PDLLAM hydrogels. BSA release data correlated well with the hydrogel degradation profiles, suggesting that the extent and rate of BSA release would be mainly controled by hydrogel degradation. As the PDLLAM composition in the hydrogel increased, the extent and rate of BSA release also increased. An increase in the molecular weights of the hydrogel constituents, however, led to a decrease in BSA release.

Journal Article↗

PubMed2006

Novel living cell sheet harvest system composed of thermoreversible methylcellulose hydrogels.

In this study, a novel yet simple method, using a thermoreversible hydrogel system coated on tissue culture polystyrene (TCPS) dishes, was developed for harvesting living cell sheets. The hydrogel system was prepared by simply pouring aqueous methylcellulose (MC) solutions blended with distinct salts on TCPS dishes at 20 degrees C. For the applications to cell culture, only those aqueous MC compositions that may form a gel at 37 degrees C were chosen for the study. It was found that the hydrogel coating composed of 8% MC blended with 10 g/L PBS (phosphate buffered saline) (the MC/PBS hydrogel, with a gelation temperature of approximately 25 degrees C) stayed intact throughout the entire course of cell culture. To improve cell attachments, the MC/PBS hydrogel at 37 degrees C was evenly spread with a neutral aqueous collagen at 4 degrees C. The spread aqueous collagen gradually reconstituted with time and thus formed a thin layer of collagen (the MC/PBS/collagen hydrogel). After cells reached confluence, a continuous monolayer cell sheet formed on the surface of the MC/PBS/collagen hydrogel. When the grown cell sheet was placed outside of the incubator at 20 degrees C, it detached gradually from the surface of the thermoreversible hydrogel spontaneously, without treating with any enzymes. The results obtained in the MTT assay demonstrated that the cells cultured on the surface of the MC/PBS/collagen hydrogel had an even better activity than those cultured on an uncoated TCPS dish. After harvesting the detached cell sheet, the remaining viscous hydrogel system is reusable. Additionally, the developed hydrogel system can be used for culturing a multilayer cell sheet. The obtained living cell sheets may be used for tissue reconstructions.

Biocompatible Materials↗

PubMed2002

Poly(glutamic acid) poly(ethylene glycol) hydrogels prepared by photoinduced polymerization: Synthesis, characterization, and preliminary release studies of protein drugs.

A class of new biodegradable hydrogels based on poly(ethylene glycol) methacrylate-graft-poly(glutamic acid) and poly(ethylene glycol) dimethacrylate was synthesized by photoinduced polymerization. Because all the polymeric constituents were highly hydrophilic, crosslinking could be performed in aqueous solutions. This type of crosslinked hydrogel was prepared by modifying a select number of acidic side-groups on poly(glutamic acid) with poly(ethylene glycol) methacrylate. These modified chains were then crosslinked in the presence of poly(ethylene glycol) dimethacrylate under a photoinduced polymerization at a wavelength of 365 nm. Swelling experiments were conducted to study the crosslinking density, pH-responsive behavior, and degradation of the hydrogel. Results showed that the degree of swelling of this type of hydrogels increased as the crosslinker concentration (or density) was reduced. Because of the presence of acidic side chains on poly(glutamic acid), swelling behavior was found to be pH-responsive, increasing at high pH in response to the increase in the amount of ionized acidic side chains. The degradation rate of these hydrogels also varied with pH. More rapid degradation was observed under stronger alkaline conditions because of the hydrolysis of the ester bonds between the crosslinker and the polymer backbone. Practically useful degradation rates could be achieved for such hydrogels under physiological conditions. Drug release rates from these hydrogels were found to be proportional to the protein molecular weight and the crosslinker density; increasing at lower protein molecular weight or crosslinker density. The preliminary findings presented in this article suggest that this class of biodegradable hydrogels could be an attractive avenue for drug delivery applications. The specific photoinduced crosslinking chemistry used would permit hydrogels to be synthesized in existence of the entrapped macromolecular drugs including peptides, proteins, and cells. In addition, the rapid feature of this polymerization procedure along with the ability to perform hydrogel synthesis and drug loading in an aqueous environment would offer great advantages in retaining drug activity during hydrogel synthesis.

Biocompatible Materials↗

PubMed2003

Injectable drug-delivery systems based on supramolecular hydrogels formed by poly(ethylene oxide)s and alpha-cyclodextrin.

Polymeric hydrogels long have attracted interest for biomaterials applications because of their generally favorable biocompatibility. High in water content, they are particularly attractive for delivery of delicate bioactive agents, such as proteins. However, because they require covalent crosslinking for gelation, many hydrogels can be applied only as implantables, and incorporation of drugs by sorption may be time-consuming and limiting with regard to the loading level. Therefore a delivery formulation where gelation and drug loading can be achieved simultaneously, taking place in an aqueous environment and without covalent crosslinking, would be attractive. Herein is described a new class of injectable and bioabsorbable supramolecular hydrogels formed from poly(ethylene oxide)s (PEOs) and alpha-cyclodextrin (alpha-CD) for controlled drug delivery. The hydrogel formation is based on physical crosslinking induced by supramolecular self-assembling with no chemical crosslinking reagent involved. The supramolecular structure of the hydrogels was confirmed with wide-angle X-ray diffraction studies. The gelation kinetics was found to be dependent on the concentrations of the polymer and alpha-CD as well as on the molecular weight of the PEO used. The rheologic studies of the hydrogels showed that the hydrogels were thixotropic and reversible and that they could be injected through fine needles. The components of the supramolecular hydrogels potentially are biocompatible and nontoxic. Drugs can be encapsulated directly into the hydrogels in situ at room temperature without any contact with organic solvents. The supramolecular hydrogels were evaluated in terms of their in vitro release kinetics. The rate-controlling mechanism of macromolecular drug release might be the erosion of the hydrogels.

Cyclodextrins↗

PubMed2006

Chitosan hydrogel as a drug delivery carrier to control angiogenesis.

An aqueous solution of photocrosslinkable chitosan containing azide groups and lactose moieties (Az-CH-LA) incorporating paclitaxel formed an insoluble hydrogel within 30 s of ultraviolet light (UV) irradiation. The chitosan hydrogel showed strong potential for use as a new tissue adhesive in surgical applications and wound dressing. The fibroblast growth factor (FGF)-2 molecules retained in the chitosan hydrogel and in an injectable chitosan/IO(4)-heparin hydrogel remain biologically active, and were gradually released from the hydrogels as they biodegraded in vivo. The controlled release of biologically active FGF-2 molecules from the hydrogels caused induction of angiogenesis and collateral circulation occurred in healing-impaired diabetic (db/db) mice and in the ischemic limbs of rats. Paclitaxel, which is an antitumor reagent, was also retained in the chitosan hydrogel and remained biologically active as it was released on degradation of the hydrogel in vivo. The chitosan hydrogels incorporating paclitaxel effectively inhibited tumor growth and angiogenesis in mice. The purpose of this review is to describe the effectiveness of chitosan hydrogel as a local drug delivery carrier for agents (e.g., FGF-2 and paclitaxel) to control angiogenesis. It is thus proposed that chitosan hydrogel may be a promising new local carrier for drugs such as FGF-2 and paclitaxel to control vascularization.

Animals↗

PubMed2006

Hydrogels in controlled release formulations: network design and mathematical modeling.

Over the past few decades, advances in hydrogel technologies have spurred development in many biomedical applications including controlled drug delivery. Many novel hydrogel-based delivery matrices have been designed and fabricated to fulfill the ever-increasing needs of the pharmaceutical and medical fields. Mathematical modeling plays an important role in facilitating hydrogel network design by identifying key parameters and molecule release mechanisms. The objective of this article is to review the fundamentals and recent advances in hydrogel network design as well as mathematical modeling approaches related to controlled molecule release from hydrogels. In the first section, the niche roles of hydrogels in controlled release, molecule release mechanisms, and hydrogel design criteria for controlled release applications are discussed. Novel hydrogel systems for drug delivery including biodegradable, smart, and biomimetic hydrogels are reviewed in the second section. Several mechanisms have been elucidated to describe molecule release from polymer hydrogel systems including diffusion, swelling, and chemically-controlled release. The focus of the final part of this article is discussion of emerging hydrogel delivery systems and challenges associated with modeling the performance of these devices.

Chemistry, Pharmaceutical↗

PubMed2004

In situ crosslinked biodegradable hydrogels loaded with IL-2 are effective tools for local IL-2 therapy.

We investigated the therapeutic efficacy of recombinant human interleukin-2 (rhIL-2)-loaded, in situ gelling, physically crosslinked dextran hydrogels, locally applied to SL2 lymphoma in mice. The physical crosslinking was established by stereocomplex formation between d-lactic acid oligomers and l-lactic acid oligomers grafted separately to dextrans. The stereocomplex hydrogel as described in our manuscript has several favourable characteristics, which enables its use as system for the controlled release of pharmaceutically active proteins. Firstly, the hydrogel system is a physically crosslinked system. In physically crosslinked gels, the use of chemical crosslinking agents is avoided. Such agents can potentially inactivate the protein and can covalently link the protein to the hydrogel network. Secondly, the hydrogel formation takes place at room temperature and physiological pH, and, importantly, in an all-aqueous environment. All factors are important to preserve the three-dimensional structure, and thus the biological activity, of the protein to be entrapped and released from the gels. Thirdly, the gel formation does not occur instantaneously. This means that a liquid formulation can be injected which solidifies after injection (in situ gel formation is possible). Fourthly, no pH drop during degradation is expected during degradation. As a control, free rhIL-2 was administered locally in either a single injection or at five consecutive days. All mice received the same total dose of rhIL-2. The rhIL-2-loaded hydrogels released most IL-2 over a period of about 5 days. The biocompatibility and biodegradability of the gels were excellent, as there were no acute or chronic inflammatory reaction and as the gels were replaced completely by fibroblasts after 15 days. The therapeutic efficacy of rhIL-2-loaded in situ gelled hydrogels is very good, as was demonstrated in DBA/2 mice bearing SL2. The therapeutic effect of a single application of gels loaded with 1 x 10(6) IU rhIL-2 is at least comparable to the therapeutic effect of injection of an equal dose of free rhIL-2. All mice cured with rhIL-2-loaded hydrogels survived a subsequent challenge, rejecting 10(6) intraperitoneal (i.p.) injected SL2 cells. In conclusion, this study demonstrates that in situ gelling, physically crosslinked dextran hydrogels slowly release encapsulated rhIL-2 in such a way that it is intact and biologically and therapeutically active. These hydrogels may greatly enhance the clinical applicability of rhIL-2 immunotherapy as only a single treatment is required and as these hydrogels are completely biodegradable.

Animals↗

PubMed2004

A novel pH-sensitive hydrogel composed of N,O-carboxymethyl chitosan and alginate cross-linked by genipin for protein drug delivery.

A novel pH-sensitive hydrogel system composed of a water-soluble chitosan derivative (N,O-carboxymethyl chitosan, NOCC) and alginate blended with genipin was developed for controlling protein drug delivery. Genipin, a naturally occurring cross-linking agent, is significantly less cytotoxic than glutaraldehyde and may provide a less extent of cross-linking to form a semiinterpenetrating polymeric network (semi-IPN) within the developed hydrogel system. The drug-loading process used in the study was simple and mild. All procedures used were performed in aqueous medium at neutral environment. In the study, preparation of the NOCC/alginate-based hydrogels was reported. Swelling characteristics of these hydrogels as a function of pH values were investigated. Additionally, release profiles of a model protein drug (bovine serum albumin, BSA) from test hydrogels were studied in simulated gastric and intestinal media. The semi-IPN formation of the genipin-cross-linked NOCC/alginate hydrogel was confirmed by means of the scanning electron microscopy-energy dispersive X-ray spectrometer (SEM-EDS) and the ninhydrin assays. The percentage of decrease of free amino groups and cross-linking density for the NOCC/alginate hydrogel cross-linked with 0.75 mM genipin were 18% and 26 mol/m(3), respectively. At pH 1.2, the swelling ratio of the genipin-cross-linked NOCC/alginate hydrogel was limited (2.5) due to formation of hydrogen bonds between NOCC and alginate. At pH 7.4, the carboxylic acid groups on the genipin-cross-linked NOCC/alginate hydrogel became progressively ionized. In this case, the hydrogel swelled more significantly (6.5) due to a large swelling force created by the electrostatic repulsion between the ionized acid groups. The amount of BSA released at pH 1.2 was relatively low (20%), while that released at pH 7.4 increased significantly (80%). The results clearly suggested that the genipin-cross-linked NOCC/alginate hydrogel could be a suitable polymeric carrier for site-specific protein drug delivery in the intestine.

Alginates↗

PubMed1998

In vitro sorption and desorption of basic fibroblast growth factor from biodegradable hydrogels.

In vitro interaction of basic fibroblast growth factor (bFGF) with biodegradable gelatin hydrogels was investigated, focusing on its sorption into the hydrogels and desorption from them. Basic bFGF was sorbed to the hydrogel of acidic gelatin with an isoelectric point (IEP) of 5.0 over time at 4 degrees C, in contrast to that of basic gelatin with an IEP of 9.0 and type I collagen. The bFGF sorption was almost independent of the sorption temperature except for 4 degrees C and the hydrogel water content. Fluorescent microscopic observation revealed that bFGF was sorbed into the interior of the acidic gelatin hydrogel. The binding molar ratio of bFGF to the acidic gelatin was around 1.0. The bFGF sorption to the acidic gelatin hydrogel increased when gelatin was further carboxylated. bFGF was sorbed into the acidic gelatin hydrogel more slowly than into the poly(acrylic acid) (PAAc) hydrogel, probably because of the lower density of negative charge of gelatin. The bFGF sorption decreased with an increase in solution ionic strength, indicating that an electrostatic interaction was the main driving force for bFGF sorption to the acidic gelatin hydrogel. However, even at higher ionic strengths of solution, the sorbed bFGF was not desorbed from the acidic gelatin hydrogel, in contrast to the PAAc hydrogel.

Acrylic Resins↗

PubMed2004

Preparation of reversibly glucose-responsive hydrogels by covalent immobilization of lectin in polymer networks having pendant glucose.

Glucose-responsive hydrogels were prepared by copolymerization of a monomer having a pendant glucose with modified lectin (concanavalin A (ConA)) having vinyl groups. Swelling behavior of ConA-copolymerized glucosyloxyethyl methacrylate (GEMA) hydrogels was discussed from the viewpoint of their synthetic condition and structures. The swelling ratio of the ConA-copolymerized GEMA hydrogels was strongly dependent on the glucose concentration in a buffer solution. As free glucose resulted in the dissociation of the complex between ConA and pendant glucose in the networks and the cross-linking density in the hydrogel decreased, the hydrogels swelled gradually in the presence of free glucose. Leak of ConA from the ConA-entrapment hydrogel and ConA-copolymerized hydrogel was examined in order to discuss the reversible changes of their glucose-responsive behavior. During swelling in the presence of free glucose, ConA leaked out of the ConA-entrapment GEMA hydrogel but did not out of the ConA-copolymerized GEMA hydrogel. As a result, the ConA-copolymerized GEMA hydrogel showed the reversible swelling changes in response to a stepwise change in the glucose concentration. This study revealed that covalent immobilization of ConA in the GEMA networks is very important for development of reversibly glucose-responsive hydrogels.

Biocompatible Materials↗

PubMed2004

Modified carrageenan. 2. Hydrolyzed crosslinked kappa-carrageenan-g-PAAm as a novel smart superabsorbent hydrogel with low salt sensitivity.

A novel pH-responsive superabsorbing hydrogel based on K-carrageenan (kappaC) was prepared through polyacrylamide crosslinking grafting followed by alkaline hydrolysis. The hydrogel structure was confirmed using FT-IR spectroscopy. The hydrolysis conditions were systematically optimized to obtain a hydrogel with maximum swelling capacity. Thus, the reaction variables, including the hydrolysis time and temperature, concentration of sodium hydroxide, amount of hydrogel hydrolyzed and post-neutralization pH, were optimized. The swelling measurements of the hydrogels were conducted in 0.15 M aqueous solutions of LiCl, NaCl, KCI, CaCl2 and AlCl3. As observed for the hydrolyzed hydrogel (H-carragPAM), it was found that a 'charge screening' action of small cations and carboxylate anions affected the swelling in univalent salt solutions. In the case of the non-hydrolyzed hydrogel (carragPAM), however, a converse trend was observed. As a result, carragPAM and H-carragPAM superabsorbent hydrogels showed a maximum swelling of 45 and 135 g/g in LiCl and KCl solutions, respectively. Due to the high swelling capacity in salt solutions, the hydrogels may be referred to as anti-salt superabsrbents. The swelling of superabsorbing hydrogels was examined in buffer solutions with pH values ranging between 1 and 13. The H-carragPAM hydrogel exhibited a pH-responsie character so that a swelling-deswelling pulsatile behavior was recorded at pH 4 and 9. The swelling kinetics of H-carragPAM were preliminary investigated.

Absorption↗

PubMed1991

Poly(vinyl alcohol)-heparin hydrogels as sensor catheter membranes.

Poly(vinyl alcohol)-heparin hydrogels with varying water content were synthesized for use as sensor catheter membranes. Films were cast from aqueous mixtures of poly(vinyl alcohol) (PVA), a photosensitive cross-linker p-diazonium diphenyl amine polymer (PA), glutaraldehyde (GA) and heparin. After drying, the films were cross-linked by successive UV irradiation and heat treatment. To get an indication about the cross-linking density of the networks, the water content of the hydrogels was measured after equilibration in water. Hydrogels from PVA, PA, GA and heparin, with a water content of 35-95%, could be obtained if the components were dissolved in saline instead of water. The release of heparin from PVA-heparin or PVA-PA-heparin hydrogels was studied using different receiving phases. The cumulative amount of released heparin appeared to be dependent on the initial water content of the hydrogels and the composition of the receiving phase. For the PVA-PA-heparin hydrogels as well as the PVA-heparin hydrogels the cumulative amount of released heparin in water was about six times higher than in a Tris buffer. Using Tris buffer as receiving phase PVA-PA-heparin hydrogels with water contents of 53, 61 or 71% released heparin for at least 3 wk. The cumulative amount of released heparin increased with initial water content of these hydrogels. Recalcification times (RCT) of plasma exposed to PVA-PA-heparin hydrogels (water content 53%), which released heparin at a low rate (2 micrograms/cm2 per day), were markedly prolonged compared with the RCT values for PVA-PA hydrogels without heparin.(ABSTRACT TRUNCATED AT 250 WORDS)

Albumins↗

PubMed2005

Self-organization of cationic dendrimers in polyanionic hydrogels.

Protonated poly(propylene imine) dendrimers (Astramol) of five generations: DAB-dendr-(NH2)x (where x=4, 8, 16, 32 or 64) are sorbed by slightly cross-linked polyanionic hydrogels: poly(sodium acrylate) and poly(sodium 2-acrylamido-2-methylpropane sulfonate). As a result highly swollen original hydrogel transforms into compact cross-linked polyelectrolyte-dendrimer complexes. Sorption of dendrimers by the hydrogels is a chemically drawn frontal diffusion process. Driving force comes from the gain in the free energy of interpolyelectrolyte coupling reaction between the charged dendrimer molecules and the oppositely charged hydrogel network, accompanied with entropically favourable release of low molecular salt into environment. The amount of a simple salt released is equivalent to a number of intermolecular salt bonds, formed between protonated dendrimers and hydrogel networks. Apparently the mechanism of dendrimer uptake involves a "relay-race" transfer of dendrimer polycations from one fragment of polyelectrolyte network to the other via interpolyelectrolyte exchange reaction. As a result "core-shell" constructs consisting of outer weakly swollen complex shell and highly swollen hydrogel core are formed at intermediate stages of the process. The rate of sorption is determined by the rate of the interpolyelectrolyte exchange reaction that is the rate of the formation of free fragments of polyelectrolyte network (vacancies) on the inner complex-hydrogel boundary. The amount of vacancies depends on the area of this boundary. Consequently kinetics of dendrimer uptake could not be fitted in terms of Fickian diffusion (except DAB-dendr-(NH2)4), but expressed in terms of the kinetic equation derived for a frontal heterogeneous reaction. Sorbed dendrimers of all studied generations at pH values ensuring complete protonation of primary and tertiary amine groups are closely packed in hydrogel networks, so that all dendrimer cationic units form ion pairs with anionic units of hydrogels. In other words polyanionic network fragments are able to penetrate into the interior of fully protonated DAB-dendr-(NH2)x species as it was earlier shown for flexible linear polyanions. In such case the ultimate amount of sorbed dendrimer molecules is always determined by the condition n(a)/N- = 1, where n(a) is the total number of dendrimer amine groups, N- is the number of the anionic hydrogel units. The latter is also true for the complex shell composition in the heterogeneous reacting samples formed at intermediate stages of dendrimers uptake. Variation of pH and sorption extent is an effective tool to control dendrimer distribution, self-organization and the final structure of dendrimer-hydrogel constructs.

Journal Article↗

PubMed2005

Covalently immobilized gradients of bFGF on hydrogel scaffolds for directed cell migration.

Basic fibroblast growth factor (bFGF) was immobilized to hydrogel scaffolds with retention of mitogenic and chemotactic activity. The bFGF was functionalized in order to incorporate it covalently within polyethylene glycol (PEG) hydrogel scaffolds by reaction with acryloyl-PEG-NHS. Hydrogels were formed by exposing aqueous solutions of PEG diacrylate, acryloyl-PEG-RGDS, and acryloyl-PEG-bFGF to long-wavelength ultraviolet light in the presence of a photoinitiator. These bFGF-modified hydrogels with RGD adhesion sites were evaluated for their effect on vascular smooth muscle cell (SMC) behavior, increasing SMC proliferation by approximately 41% and migration by approximately 15%. A covalently immobilized bFGF gradient was formed using a gradient maker to pour the hydrogel precursor solutions and then photopolymerizing to lock in the concentration gradient. Silver staining was used to detect the bFGF gradient, which increased linearly along the hydrogel's length. Cells were observed to align on hydrogels modified with a bFGF gradient in the direction of increasing tethered bFGF concentration as early as 24 h after seeding. SMCs also migrated differentially, up the concentration gradient, on bFGF-gradient hydrogels compared to control hydrogels with and without a constant bFGF concentration. These hydrogel scaffolds may be useful for studying protein gradient effects on cell behavior and for directing cell migration in tissue-engineering applications.

Aorta↗

PubMed2000

Synthesis and characterization of dextran-methacrylate hydrogels and structural study by SEM.

The objectives of this study were to develop a simple and reproducible method for the preparation of the hydrogel precursor dextran-methacrylate and to conduct a visual observation of the interior structure of the swollen dextran-methacrylate hydrogel with minimum artifacts. A dextran-methacrylate hydrogel precursor was synthesized by reacting dextran with methacrylic anhydride in the presence of triethylamine as a catalyst. The effects of reaction time, temperature, concentration, and catalyst amount were studied to obtain a wide range of degree of substitution (DS) in dextran by methacrylate. The dextran-methacrylate synthesized showed an enhanced solubility in water and common organic solvents. UV irradiation of dextran-methacrylate by a long-wave UV lamp (365 nm) generated a photocrosslinked hydrogel. This dextran-methacrylate hydrogel showed a range of swelling ratio from 67 to 227% and exhibited an increase in swelling ratio with a decrease in methacrylate substitution. The pH of the swelling media did not affect the swelling behavior of the dextran-methacrylate hydrogels at all the degrees of substitution used. Special cryofixation and cryofracturing techniques were used to prepare aqueous swollen dextran-methacrylate hydrogel samples for SEM observation of their surface and interior structures. A unique three-dimensional porous structure was observed in the swollen hydrogel but was absent in the unswollen hydrogel. Different pore sizes and morphologies between the surface and the interior of swollen hydrogels also were observed.

Biocompatible Materials↗

PubMed2003

Surface-modified poly(lactide-co-glycolide) nanospheres for targeted bone imaging with enhanced labeling and delivery of radioisotope.

Surface-modified nanospheres can be utilized for targeting drugs and diagnostic agents to the bone and bone marrow while extending their circulation time in the blood stream. The surface modification of poly(lactide-co-glycolide) (PLGA) nanospheres by radioisotope carrying poly(ethylene oxide)-poly (propylene oxide)-poly (ethylene oxide) triblock copolymers (Poloxamer 407) has been assessed by in vitro characterization and in vivo biodistribution studies after intravenous administration of the nanospheres to the mouse. A hydroxyphenylpropionic acid, a ligand for (125)I and (131)I labeling, was conjugated to the hydroxyl group of the Poloxamer 407 by using dicyclohexyl carbodiimide. The ligand-conjugated Poloxamer 407 was adsorbed onto the surface of PLGA nanospheres. Surface coating was confirmed by measuring both size distribution and the surface charge of the nanospheres. Besides, (125)I-labeling efficiency, radiolabeling stability, whole body imaging, and biodistribution of the radioisotope-labeled nanospheres were examined. Ligand-labeled, surface-modified PLGA nanospheres were in 100-nm size ranges, which may be adequate for long-circulation and further bone imaging. (125)I-labeling efficiency was >90% and was more stable at human serum for 24 h. A noticeable decrease in liver or spleen uptake was obtained by the surface-modified nanospheres. (125)I-labeled nanospheres showed higher blood maintenance and bone uptake compared with stannous colloid with the same size distribution. Therefore, a fully biodegradable, radioisotope-carrying, surface-modified nanosphere system has been developed as a promising tool for targeting bone and bone marrows.

Animals↗

PubMed2006

Controlled release of fibroblast growth factor-2 from an injectable 6-O-desulfated heparin hydrogel and subsequent effect on in vivo vascularization.

We prepared a 6-O-desulfated (DS-) heparin (Hep) hydrogel as an excellent carrier for the controlled release of Hep-binding growth factors, such as fibroblast growth factor (FGF)-2. This material, which is partially derived from photoreactive groups, such as cinnamate, is easily crosslinked upon ultraviolet light (UV)-irradiation, resulting in a water-insoluble, viscous, and injectable hydrogel. In the present study, we examined the capacity of 6-O-DS-Hep hydrogel to immobilize FGF-2, as well as the controlled release of FGF-2 molecules from this hydrogel in vitro and in vivo. Only 10% of FGF-2 was gradually released from the FGF-2-containing 6-O-DS-Hep hydrogel (photocrosslinked 6-O-DS-Hep (4%; w/w) hydrogel containing 50 microg/mL FGF-2) into PBS (phosphate-buffered saline) within first 7 days. The 6-O-DS-Hep hydrogel in vitro maintained the original form through 1 weeks incubation in PBS, but it was gradually fragmented and could not maintain the original form by 2-3 week-washing. When the FGF-2-containing 6-O-DS-Hep hydrogel was subcutaneously injected into the back of rats, significant neovascularization and fibrous tissue formation were induced near the injected site from day 3 after the injection. And, the hydrogel had been biodegraded and completely disappeared from the injected sites in vivo within about 15-20 days after the injection. These findings indicate a controlled release of biologically active FGF-2 molecules together with fragmentation and biodegradation of 6-O-DS-Hep hydrogel and the subsequent induction of neovascularization in vivo.

Animals↗

PubMed2007

Biocompatibility and drug release behavior of spontaneously formed phospholipid polymer hydrogels.

Hydrogels containing 2-methacryloyloxyethyl phosphorylcholine (MPC) moieties were formed from aqueous solutions with water-soluble MPC polymers with carboxylic acid and alkyl groups because of hydrogen bonding formation. To investigate the biocompatibility and drug release behavior of the hydrogels, we used random- and block-type carboxylic acid MPC polymers, such as poly [MPC-co-methacrylic acid (MA)] (rPMA), poly[MPC-co-4-(2-methacryloyloxyethyl) trimellitic acid (MET)] (rPMT), poly (MA-block-MPC-block-MA) (bPMA) and poly(MET-block-MPC-block-MET) (bPMT), and alkyl MPC polymers, such as poly[MPC-co-n-butyl methacrylate] (PMB) and poly(MPC-co-benzyl methacrylate) (PMBz). We investigated the biocompatibility of the spontaneously formed MPC polymer hydrogels by a hemolysis test and an in vivo injection test. The random MPC polymers having carboxylic acid groups expressed more hemolytic activity compared to the block polymers. The results of the in vivo injection test also indicated low biocompatibility of the carboxylic acid polymers especially at high concentration. The alkyl MPC polymers, the PMB and PMBz showed excellent biocompatibility in both hemolysis and in vivo injection test. However, the hydrogels, the rPMA/PMB hydrogel (rABgel) and the rPMT/PMBz hydrogel (rTZgel) lowered the hemolytic activity of elemental polymers, the rPMA and rPMT. Thus, suppression of the ionization of the carboxylic acid groups is necessary for biocompatibility. We also investigated the drug release behavior with attention to the interaction between the polymer and the drugs. The release behavior of a relatively low-molecular-weight hydrophilic drug, 5-fluorouracil, did not depend on the structure of the polymers. The higher-molecular-weight drugs, ketoprofen and indomethacin, were released faster from the block polymer hydrogel than the random polymer hydrogel, the rABgel, while the highest-molecular-weight drug, doxorubicin, was released faster from the random polymer hydrogel. A probable reason for this is the difference in the molecular structure; that is, the separated hydrophilic and hydrophobic sections in the block polymers constructed pathways where a drug can diffuse. In addition, the rTZgel suppressed the release of a drug with a large number of aromatic rings probably because of the stacking effect. The results of the compression test also suggested the existence of the stacking effect between the rTZgel and the drugs. Based on these results, control of drug release is possible by selecting a reservoir with an appropriate chemical structure to interact with the drug. For example, release of a relatively linear-structured drug with less aromatic rings can be suppressed in the rABgel rather than in the rTZgel. Thus, it can be concluded that if the ionization is suppressed, these MPC polymer hydrogels can be used as a material for a drug reservoir that can be selected according to the drug.

Animals↗