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At least 415 records · Page 23Linked to original sources
PubMed2002

Endovascular microcoil gene delivery using immobilized anti-adenovirus antibody for vector tethering.

BACKGROUND AND PURPOSE: Endovascular microcoils are widely used in interventional procedures to treat cerebral aneurysms. In the present study we report for the first time successful use of an endovascular microcoil as a gene delivery system. METHODS: Anti-adenoviral monoclonal antibodies were covalently attached to the collagen-coated surface of either platinum or polyglycolic acid microcoils. These antibodies were used to tether replication-deficient adenovirus (Ad-GFP [encoding green fluorescent protein] or Ad-LacZ [encoding beta-galactosidase]). Cell culture studies with rat arterial smooth muscle cells (A10) assessed transduction on or near the coil. Platinum coils coated with Ad-GFP were implanted into the ligated common carotid artery (CCA) of adult rats in a model of arterial stasis and pressurization. After 7 days, CCA segments were harvested, and coils were removed for histopathology and GFP expression studies, while organs were evaluated by polymerase chain reaction to assess viral biodistribution. RESULTS: In cell culture studies, GFP-positive smooth muscle cells were detected only on the platinum coil surface, while LacZ-positive cells were detected only on the polyglycolic acid coil surface, thus demonstrating localized gene delivery. After 7-day implantation, GFP (according to fluorescence microscopy and confirmed with immunohistochemistry) was detected on the harvested platinum coil and in the organizing thrombus within the CCA but not in the arterial wall. Morphometric analyses revealed that 13.3+2.0% of cells within the organized thrombus were transduced with Ad-GFP via the gene delivery system. However, arterial smooth muscle cells were negative for GFP according to fluorescence microscopy and immunohistochemistry. Ad-GFP was not detectable by polymerase chain reaction in lung, liver, or kidney. CONCLUSIONS: It is concluded that catheter deployment of platinum or biodegradable gene delivery endovascular microcoils represents an interventional device-based gene therapy system that can serve as a suitable platform for either single or multiple gene therapy vectors.

Adenoviridae↗
PubMed2006

A polymeric micelle system with a hydrolysable segment for drug delivery.

A potential anti-cancer drug-delivery polymeric micelle system with an in vitro degradation half-life of about 48 h that releases its drug upon application of ultrasound was synthesized. This vehicle was composed of an amphiphilic co-polymer, poly(ethylene oxide)-b-poly(N-isopropylacrylamide-co-2-hydroxyethyl methacrylate-lactate(n)). The degree of polymerization of the lactate side group, n, was 0, 3 or 5. The molar ratio of NIPAAm to HEMA-lactate(n) to PEO in polymerization was optimized to produce an in vitro polymeric micelle half-life of about 48 h at 40 degrees C. 1,6-Diphenyl-1,3,5-hexatriene (DPH) was used as a fluorescent probe to study the hydrophobicity of the cores of the polymeric micelles. The results showed that the cores of the polymeric micelles were hydrophobic enough to sequester DPH and the anti-cancer drug doxorubicin (Dox). Dox was encapsulated into the polymeric micelles having a molar feed ratio of NIPAAm to HEMA-lactate3 to PEO equal to 20:5:1; this drug was released upon the application of low-frequency ultrasound. The Dox release was about 2% at room temperature and 4% at body temperature, and the drug returned to the polymeric micelles when insonation ceased.

Acrylic Resins↗
PubMed2000

Comparison of poly(acryl starch) and poly(lactide-co-glycolide) microspheres as drug delivery system for a rotavirus vaccine.

Drug delivery systems allowing controlled release of antigen are of particular interest in the development of vaccines. We have compared poly(acrylic starch) microspheres (PAS) and poly(lactide-co-glycolide) microspheres (PLG) as drug delivery systems for a rotavirus vaccine. The polymers are both biodegradable but have different degradation mechanisms and antigen release profiles. PAS are enzymatically degraded and have a continuous fast antigen release rate compared to the hydrolytically degraded PLG which release the incorporated antigen in a pulsatile manner. In this study mice were immunised intramuscularly and orally on three occasions with formalin-inactivated rotavirus (FRRV) incorporated in PAS and PLG and with FFRV alone. Serum and faeces samples were collected and analysed by ELISA for rotavirus specific IgG and IgA antibodies. A neutralising assay was also conducted on both serum and faeces antibodies. The two different polymer drug delivery systems induced different immune responses depending on administration route. PAS elicited significant antibody levels and neutralising effect after oral administration while PLG showed high antibody levels after intramuscular administration. The immune response appears to be dependent on the differences in antigen release and degradation mechanism for the two polymer systems.

Animals↗
PubMed2002

Assessment of biodegradable controlled release rod systems for pain relief applications.

Control of chronic, severe pain is a difficult and important clinical problem for most patients, especially those with cancer. Although current applications are insufficient for a satisfactory solution to this problem, the rate of disease incidence is increasing worldwide, thus making the problem more apparent. Based on this fact, this study was designed with the ultimate goal of formulating a controlled release system of pain relievers, mainly opioids, for the local treatment of pain to achieve satisfactory, fast, and less side effect-related relief and to provide a better life status for chronic pain patients. Two copolymers of a biodegradable polymer poly(L-lactide-co-glycolide) (PLGA) were used to prepare an implantable rod type drug release system containing either an analgesic or anesthetic type of pain reliever. In vitro drug release kinetics of these systems were studied. It was observed that release from PLGA 85 : 15 was more zero-order than it was from PLGA 50 : 50. A zero-order release rate was obtained for codeine, hydromorphone, and bupivacaine from PLGA (85 : 15) rods. They, however, were released from PLGA (50 : 50) rods with Higuchi kinetics. The drug solubility was also influential on release rate, as shown by the zero-order morphine release from PLGA (50 : 50) rods. Scanning electron micrographs (SEMs) of the monolithic rods revealed erosion of the rods and the removal of drug crystals from the rod structure.

Analgesics, Opioid↗
PubMed2002

Oral immunogenicity of the inactivated Vibrio cholerae whole-cell vaccine encapsulated in biodegradable microparticles.

Vibrio cholerae (VC)-loaded microparticles as an oral vaccine delivery system were prepared with 6% w/v poly(DL-lactide-co-glycolide)(PLG) in the oil phase as well as 10% w/v PVP and 5% w/v NaCl in the aqueous phase, by an water-in-oil-in-water emulsion/solvent extraction technique. VC was successfully entrapped in the microparticles with trapping efficiencies up to 97.8% and a loading level of 55.4+/-6.9 microg/mg. The microparticle delivery system with a particle size of 3.8 microm had different distribution of VC content in the core region (25.7+/-1.9 microg/mg) and surface (6.2+/-0.9 microg/mg). The immunogenic potential of VC-loaded microparticles in comparison with PLG microparticles or VC solution was evaluated in adult mice by oral immunization, in which mice received one dose of 20 mg VC-loaded microparticles or 20 mg VC-loaded microparticles physical mixed with amphotericin B. The control group received 20 mg PLG microparticle or VC solution. Serum samples were collected from all tested mice on the day of immunization and at 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10 weeks postimmunization. Sera were examined for vibriocidal antibodies by microtitration and Vibrio-specific serum IgG and IgM antibodies were assessed by the ELISA method. IgG and IgM antibodies to intact VC were detected in sera from all animals immunized with VC. The response was specific and of high magnitude. Significantly higher antibody responses were obtained when sera from both VC-loaded microparticles and VC-loaded microparticles physical mixed with amphotericin B immunized mice were titrated against VC. The immunogenicity of VC-loaded microparticles mixed with amphotericin B in evoking serum IgG and IgM responses was higher than that of VC-loaded microparticles only. These results demonstrate that VC-loaded microparticles physical mixed with amphotericin B and VC-loaded microparticles orally administered evoke Vibrio-specific serum IgG and IgM responses as well as vibriocidal antibody activity in mice. The VC incorporation, physicochemical characterization data, and the animal results obtained in this study may be relevant in optimizing the vaccine incorporation and delivery properties of these potential vaccine targeting carriers.

Administration, Oral↗
PubMed1998

Oral particulate delivery: status and future trends.

Oral delivery of complex molecules such as peptides and proteins is one of the most intensively studied research subjects. However, its success has been hampered by the degradation of these molecules in the gastrointestinal tract. As a result, various types of particulate systems such as biodegradable microspheres and liposomes have been proposed as potential delivery vehicles to protect these drugs in the gastrointestinal tract. Unfortunately, these particulates generally display low oral absorption efficiencies. This renders most encapsulated drugs ineffective after oral administration and therefore remains as the main obstacle to their practical application as oral delivery vehicles. In attempts to improve particle absorption efficiency, strategies such as using mucoadhesive polymers and targeted delivery systems have been studied in animals. In this chapter, the usefulness of these strategies are briefly reviewed. Potential applications and future prospects of particulates in oral delivery of complex molecules are also highlighted.

Journal Article↗
PubMed1996

Estimation of antigenic tetanus toxoid extracted from biodegradable microspheres.

Microspheres made from poly (lactic/glycolic acid) polymers have been considered as a new delivery system for single-dose tetanus toxoid (TT) vaccines. One of the most critical properties of the proposed vaccines is the loading and distribution of TT as this will have a profound effect on immunogenicity. As the concentration of TT in microspheres is very low sensitive assay methods are required. An assay incorporating monoclonal antibody (MAb) recognizing a neutralizing epitope and cross-reacting with TT was developed (MAp capture ELISA) which provided a sensitivity of 0.001 Lf/ml. An extraction procedure was devised which did not destroy the antigenicity and gave a recovery of 90.6 +/- 3.39% when applied to different preparations. The extracted TT was then quantified by MAb capture ELISA which was estimated to be 250-fold more sensitive than single-site ELISA for toxoid. The loading of 20 microspheres preparations (12 filled and 8 placebo) was determined by both protein micro-BCA assay and the developed assay for TT. The TT content obtained for the 12 filled microspheres preparations from different sources varied up to 400-fold (range 0.01-4.0 Lf/mg microspheres). The utility of the MAb capture ELISA for detection of total antigenic content in microspheres was confirmed by the observation that the determine TT loading correlated with the theoretical loading predicted from the protein content for the best preparations. Preparations with high loading gave the greatest peak response. There was no relationship between dose and the in vivo immunogenic response, suggesting that encapsulated vaccines with differential loading, release properties and presence of excipients will have different response curves in vivo. Hence, the present assay, when combined with information on toxoid release rate and presence and effect of excipients may be of value in predicting in vivo response.

Animals↗
PubMed1995

Properties of water-insoluble mitomycin C-albumin conjugate as a sustained release drug delivery system in mice inoculated with Sarcoma 180.

In order to improve the deposition of mitomycin C (MMC) in the administered site, water-insoluble mitomycin C-albumin conjugate (MMC-G-BSA) was prepared. MMC was covalently attached to the glutarylated bovine serum albumin (G-BSA) in the presence of 1-ethyl-3-(3-dimethyl-aminopropyl) carbodiimide hydrochloride (EDC) to give MMC-G-BSA. The MMC content of the conjugate (16.3% (w/w)) was higher than that of water-soluble mitomycin C-albumin conjugates. MMC was liberated from MMC-G-BSA suspended in a phosphate buffer (pH 7.4, 37 degrees C) with a half-life of 155.3 h. In the same buffer system containing alpha-chymotrypsin, MMC-G-BSA was dissolved perfectly within 24 h due to enzymatic degradation, and the liberation of MMC from the conjugate was significantly accelerated (t1/2 = 24.5 h). After intraperitoneal injection in mice, most of the MMC-G-BSA was retained in the abdominal cavity. Furthermore, the survival time of mice inoculated with Sarcoma 180 was significantly increased by the intraperitoneal injection of MMC-G-BSA. These findings suggest that MMC-G-BSA is a biodegradable macromolecular hybrid which acts as a sustained release delivery system of MMC.

Albumins↗
PubMed1993

Cell transplantation of genetically altered cells on biodegradable polymer scaffolds in syngeneic rats.

Many severe metabolic deficiencies in children are caused by a single gene defect with a resultant single gene product deficiency. These diseases may be amenable to permanent cure using new techniques of gene transfer and cell transplantation. In many in vivo models of retroviral mediated gene therapy, a significant limiting factor is the ability to transplant a sufficient number of modified cells. To potentially circumvent this problem, we have developed a biodegradable polymer implant system capable of supporting large numbers of genetically modified cells. In this study, we inserted a reporter gene into syngeneic cultured normal fibroblasts and then transplanted these genetically modified cells into animals using synthetic biodegradable polymer fibers as temporary cell delivery scaffolds. To begin to develop a system capable of delivering desirable proteins secreted by genetically modified cells, Fischer 344 adult rat fibroblasts were transduced in tissue culture with a retrovirus containing the reporter gene Lac Z. These genetically modified cells (1.1 x 10(7) cells/graft) were then attached to the biodegradable polymer fibers and the polymer-cell graft was transplanted subdermally into syngeneic recipients (n = 9). There was persistence of the modified cells with expression of the reporter gene for at least 30 days. The estimated number of genetically modified cells per implanted graft decreased from a pretransplant value of 1.1 +/- 0.6 x 10(7) to 3.2 +/- 0.7 x 10(6) by 15 days after transplantation (P < 0.01). Thereafter, the cell number did not vary significantly to the conclusion of the study at day 30 (3.6 +/- 1.0 x 10(6) cells/graft). Evidence of ingrowth and incorporation of other stromal elements was present in the graft by 1 week post-transplantation, as judged by counterstained hematoxylin and eosin micrograph sections. Migration of modified cells to areas outside of the polymer-cell graft was not detected. Over the course of the study, there was little degradation of the polymer implant, although by day 30, evidence of early dissolution was evident. The number of polymer fibers per high power field increased slightly from 62.5 +/- 5.8 on day 1 to 77.3 +/- 26.6 on day 30 (P > 0.2). These data suggest that the use of biodegradable polymer fibers may permit the transplantation of genetically modified cells in sufficient numbers to deliver a therapeutically useful product. Polymer matrices allow for the attachment and site-specific transplantation of genetically modified cells.

Animals↗
PubMed1993

Immunization of rabbits with enterotoxigenic E. coli colonization factor antigen (CFA/I) encapsulated in biodegradable microspheres of poly (lactide-co-glycolide).

We have searched for an effective oral delivery system for a purified enterotoxigenic Escherichia coli (ETEC) fimbrial adhesin, CFA/I, which elicits anti-colonization immunity. Purified CFA/I antigen encapsulated in biodegradable polymer microspheres of poly (DL-lactide-co-glycolide) (PLG) induced a vigorous, systemic CFA/I IgG antibody response in rabbits immunized once via intragastric tube; oral, unencapsulated CFA/I induced little or no circulating antibody. CFA/I-specific, S-IgA coproantibody was detected in one of three rabbits fed with the CFA/I-PLG microsphere vaccine. We conclude that PLG microspheres protected CFA/I from degradation in the stomach and effectively delivered the antigen for processing by the host's immune system.

Adhesins, Escherichia coli↗
PubMed2002

Design of poly-epsilon-caprolactone nanospheres coated with bioadhesive hyaluronic acid for ocular delivery.

This study was performed to design a new ocular drug delivery system based on poly-epsilon-caprolactone (PCL) biodegradable nanospheres (NS) coated with a bioadhesive polymer, hyaluronic acid (HA), in order to combine ophthalmic prolonged action with the ease of application. The aim of this work was to investigate three strategies to attach HA on NS surface: (1) coating the core by chain entanglement with HA; (2) coating NS by HA adsorption; (3) coating NS by electrostatic interactions between negatively charged HA and a cationic surfactant (stearylamine, SA, or benzalkonium chloride, BKC). A radioimmunoassay technique, usually used for HA quantification in serum, was transposed to determine the amount of HA on the NS. The results show that HA is strongly attached on NS positively charged by cationic surfactant. This system is stable and not influenced by dilution. These results show the possibility of using cationic surfactants to obtain a HA coating by electrostatic interactions. BKC, approved for ophthalmic administration, was retained because it was more firmly anchored within the PCL matrix and the amount of HA attached was high (41.6 microg HA/mg PCL). Moreover, the yield of fixation reached 50%. Therefore, by using a simple preparation method, it was possible to obtain stable HA and intact HA-coated NS.

Adhesives↗
PubMed2005

Experimental spinal fusion with recombinant human bone morphogenetic protein-2 delivered by a synthetic polymer and beta-tricalcium phosphate in a rabbit model.

STUDY DESIGN: An experimental animal study to achieve posterolateral intertransverse process spine fusion with recombinant bone morphogenetic protein in combination with a new delivery system. OBJECTIVE: To evaluate the efficacy of a new synthetic biodegradable bone-inducing material containing recombinant human bone morphogenetic protein-2 (rhBMP-2) as a bone-graft substitute for posterolateral intertransverse process fusion in a rabbit model. SUMMARY OF BACKGROUND DATA: rhBMP-2, a powerful bone-inducing cytokine, has been used as a bone graft substitute in combination with animal-derived collagen to achieve spinal fusion in animal models. However, the minimum dose of rhBMP-2 required to obtain solid posterolateral intertransverse process fusion was high on the basis of previous reports (>100 microg in rabbit models). To improve the efficacy, performance of rhBMP-2, and the safety of the delivery system for this protein, a more sophisticated system is required. METHODS: To fabricate one implant for one-side L4-L5 intertransverse process fusion, beta-tricalcium phosphate (beta-TCP) powder (300 microg), a polymer gel (PLA-DX-PEG block copolymer; 300 microg) and rhBMP-2 (7.5, 15, or 30 microg) were mixed and manually shaped to resemble a rod. Through a posterolateral approach, two implants were placed on both sides (1 per side) by surgery so as to bridge the transverse processes of adult New Zealand white rabbits (n = 27). In control animals, implants without rhBMP or autogenous cortico-cancellous bone chips from the iliaccrest were placed in a similar location. The lumbar vertebrae were recovered 6 weeks after surgery. The posterolateral fusion was examined by manual palpation, radiography, biomechanical testing, and histology. RESULTS: Rabbits that received 15 or 30 microg of rhBMP-2 showed consistent fusion. However, solid fusion was seen in 2 of 5 rabbits with autografting and rabbits that received 7.5 microg of rhBMP-2. Fusion was not observed in the rabbits that did not receive rhBMP-2. CONCLUSIONS: Consistent spinal fusion was obtained by implanting a biodegradable bone-inducing implant composed of beta-TCP, PLA-DX-PEG, and rhBMP-2 within a period of 6 weeks. The rhBMP-2 doses required for the spinal fusion were significantly lower than those reported previously.

Animals↗
PubMed1994

Feasibility of drug targeting to the retinal pigment epithelium with biodegradable microspheres.

There are several systems of delivering drugs to cells with phagocytic activity. We studied the possibility of targeting drugs to retinal pigment epithelial (RPE) cells with the use of surface-modified microspheres. A fluorescent dye, 1,4-bis[2-(5-phenyloxazolyl)]-benzene (POPOP), was incorporated into microspheres of poly(lactic acid) for use as a marker to evaluate drug delivery. Phagocytosis of the microspheres, with or without gelatin precoating, was carried out at 37 degrees C and 4 degrees C. The cell-incorporated fluorescence of POPOP was measured, and scanning electron microscopy was used to confirm phagocytosis. At 4 degrees C, no uptake of POPOP was noted; however at 37 degrees C, cell-associated fluorescence was observed to increase for up to 24 hr. In comparison with bare microspheres, gelatin precoating significantly enhanced phagocytosis (P < 0.001) at the same incubation times. These results suggested that drug delivery to RPE cells may be feasible by means of surface-modified polymer microspheres.

Animals↗
PubMed2002

Drug-releasing scaffolds fabricated from drug-loaded microspheres.

Biodegradable scaffolds serve a central role in many strategies for engineering tissue replacements or in guiding tissue regeneration. Typically, these scaffolds function to create and maintain a space and to provide a support for cell adhesion. However, these scaffolds also can serve as vehicles for the delivery of bioactive factors (e.g., protein or DNA) in order to manipulate cellular processes within the scaffold microenvironment. This study presents a novel approach to fabricate tissue-engineering scaffolds capable of sustained drug delivery whereby drug-loaded microspheres are fabricated into structures with controlled porosity. A double-emulsion process was used to fabricate microspheres with encapsulated DNA that retained its integrity and was released from the microspheres within 24 h. These DNA-loaded microspheres subsequently were formed into a nonporous disk or an interconnected open-pore scaffold (>94% porosity) via a gas-foaming process. The disks and scaffolds exhibited sustained plasmid release for at least 21 days and had minimal burst during the initial phase of release. This approach of assembling drug-loaded microspheres into porous and nonporous structures may find great utility in the fabrication of synthetic matrices that direct tissue formation.

Biocompatible Materials↗
PubMed2003

Polymeric matrices based on graft copolymers of PCL onto acrylic backbones for releasing antitumoral drugs.

Graft copolymers of poly(epsilon-caprolactone) (PCL) on poly(dimethylacrylamide) (PDMAm), poly(methylmethacrylate) (PMMA), or on copolymers of poly(DMAm-co-MMA) have been synthesized and characterized by (1)H NMR spectroscopy, differential scanning calorimetry (DSC), and size exclusion chromatography (SEC). These partially biodegradable copolymer matrices have been proposed as drug delivery systems for the release of low-molecular-weight glycosides. Octyl-N-acetyl-6-O-[2,2-bis(hydroxymethyl)-3-hydroxypropyl]-alpha-D-glucosamide, a synthetic carbohydrate able to inhibit the proliferation of human malignant glioma cells in culture and transplanted glioma in rats was selected as drug model. The in vitro aqueous behavior of four drug-loaded and unloaded graft copolymers of different MMA: DMAm and PCL ratios has been analyzed performing swelling, degradation, and drug release experiments. An intimate dependence of the aqueous behavior with the composition has been found. The higher was the DMAm content, the higher was the hydrophilicity of the synthesized systems as well as the swelling, degradation, and drug release rate. In vivo experiments in pigs demonstrated the very good tolerance of drug-loaded implanted polymeric discs, and that >95% of the charged drug is released after 2 months' implantation.

Acrylamides↗
PubMed2006

Preparation and swelling behavior of chitosan-based superporous hydrogels for gastric retention application.

Chitosan and glycol chitosan hydrogels were prepared, and their swelling behaviors in acidic solution were studied to investigate their application for gastric retention device. The optimum preparation condition of superporous hydrogels was obtained from the gelation and blowing kinetics measured at varying acidic conditions. Both the swelling rate and swelling ratio of glycol chitosan hydrogels were higher than those of chitosan hydrogels. Swelling behaviors were significantly affected by not only foaming/drying methods but also crosslinking density, as the sizes and structures of pores generated were highly dependent on those preparation conditions. The prepared superporous hydrogels were highly sensitive to pH of swelling media, and showed reversible swelling and de-swelling behaviors maintaining their mechanical stability. The degradation kinetics in simulated gastric fluid was also studied.

Biocompatible Materials↗
PubMed2004

Novel biodegradable copolyesters containing blocks of poly(3-hydroxyoctanoate) and poly(epsilon-caprolactone): synthesis and characterization.

Novel biodegradable polyester block copolymers have been synthesized by using well-defined poly(3-hydroxyoctanoate) (PHO) oligomers having a hydroxyl end group and an ester end group with M(n) values of 800, 2,500, 5,300, 8,000, or 20,000 as an elastomeric soft segment and poly(epsilon-caprolactone) as a more crystalline segment. These PHO oligomers prepared by methanolysis were subjected to block copolymerization with epsilon-caprolactone. The chemical structure of the copolymers was confirmed by (1)H NMR and (13)C NMR spectroscopy. All the copolyesters are semi-crystalline and two T(g) were observed by differential scanning calorimetry when the molecular weight of the PHO block is about 20,000.

Animals↗