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At least 919 records · Page 51Linked to original sources
PubMed1995

Intratumoral chemotherapy.

In an effort to improve survival from malignant gliomas, investigators have used intratumoral chemotherapy protocols to deliver high doses of tumoricidal agents directly to the brain. Theoretically, these infusions bypass the blood-brain barrier, minimize systemic drug levels and the side effects of chemotherapy, and achieve prolonged elevations of intracerebral chemotherapeutic agents relative to those obtainable by systemic administration. Almost all major classes of chemotherapeutic agents have been examined as possible intratumoral therapies via delivery approaches ranging from simple intratumoral injections to implantable computer-driven constant infusion pumps and biodegradable polymer matrices. In this review, we summarize the major clinical trials and experimental investigations underlying the development of intratumoral chemotherapy as a treatment for gliomas.

Animals↗
PubMed1994

Mucosal immunity and strategies for novel microbial vaccines.

Infectious diseases continue to be the leading cause of morbidity and mortality worldwide. Increased awareness of the fact that mucosal membranes are the most frequent portals of entry of pathogenic microorganisms has prompted studies aimed at the development of vaccination protocols and antigen delivery systems that would lead to an increased protection of mucosae. Although systemic and strictly local immunizations are of limited effectiveness in the induction of mucosal protection, ingestion or inhalation of antigens results in a generalized immune response manifested by the appearance of specific antibodies of the secretory immunoglobulin (Ig) isotype in external secretions due to the dissemination of IgA precursor cells from IgA-inductive lymphoid tissues. Furthermore, additional inductive sites strategically positioned at the opening of the respiratory and digestive tracts may also be suitable targets for induction of immune responses at desired effector sites. To prevent degradation and the increase of ingested antigens absorption, novel strategies including enclosure of antigens into biodegradable microspheres, liposomes or their expression in viral and bacterial vectors and plants are currently being considered. Forthcoming technological advances in antigen preparation and routes of delivery will undoubtedly have a profound impact on immunization practices in the future.

Animals↗
PubMed2003

Spectrophotometric determination of polyethylenimine in the presence of an oligonucleotide for the characterization of controlled release formulations.

Polyethylenimine (PEI) is a cationic polymer that can be associated to oligonuclotides to promote their transfection both in vitro and in vivo. The controlled release of oligonucleotide/polyethylenimine complexes from biodegradable systems can result in an increased cellular internalisation of the oligonucleotide and a reduced cytotoxicity of the complex. This effect strongly depends on the amount of PEI loaded in and released from the delivery system. In this work we describe a rapid, sensitive and reproducible spectrophotometric method for the quantitative analysis of PEI by itself or in the presence of an associated oligonucleotide. PEI does not possess chromophores, hence the determination by ordinary spectrophotometry is not possible. However, upon addition of copper (II) ions, PEI forms a dark blue cuprammonium complex that can be detected by UV-vis spectrophotometry. The optimum conditions in terms of optical parameters, copper (II) concentration required for a quantitative PEI complexation, and the most suitable medium for the reaction were ascertained. A linear relationship (r(2)=0.9997) between absorbance and amounts of PEI was found at lambda(max) of 285 nm over the concentration range 5.0-50.0 microg ml(-1). The detection limit (QOD) was 4.0 microg ml(-1). The method was validated for the quantitation of PEI in the presence of an oligonucleotide, which absorbs at 285 nm as well.

Algorithms↗
PubMed2004

Development of novel 5-FU-loaded poly(methylidene malonate 2.1.2)-based microspheres for the treatment of brain cancers.

In order to treat malignant brain tumors by local delivery of antineoplastic agents, the feasibility of 5-fluorouracil (5-FU)-sustained release biodegradable microspheres with a novel material, poly(methylidene malonate 2.1.2), was investigated using an emulsion/extraction method. This polymer was expected to present a slow degradation rate, thus leading to a long term local delivery system. Microparticles were successfully obtained and characterized in terms of drug loading, size, morphology and release profile. The size of the particles was between 40 and 50 microm, which was compatible with a stereotactic injection through a needle. Sufficient drug loadings were obtained (i.e. compatible with the preparation of therapeutic 5-FU doses in a minimal volume of injection), and perfectly spherical microspheres were observed. The respective influences of the polymer molecular weight, the polymer concentration, and the emulsion time on the release profiles were studied using a 2(3) factorial design. In the same objective, the solvent extraction time was extended while keeping all the previous parameters fixed at their optimal values. The in vitro study of these different parameters allowed a reduction of the initial burst release, with a percentage of 5-FU released after 24 h that was lowered from 90 to 65%, and the achievement of a long term drug delivery system, since the release was still ongoing after 43 days. Moreover, the microparticles could be gamma-sterilized (25 kGy) without modification of the release kinetics. Thus, the requested specifications to perform animal experiments were attained.

Brain Neoplasms↗
PubMed2003

Potential applications of polymeric microsphere suspension as subcutaneous depot for insulin.

The objective of this investigation was to develop an injectable, depot-forming drug delivery system for insulin based on microparticle technology to maintain constant plasma drug concentrations over prolonged period of time for the effective control blood sugar levels. Formulations were optimized with two well-characterized biodegradable polymers namely, poly(DL-lactide-co-glycolide) and poly-epsilon-caprolactone and evaluated in vitro for physicochemical characteristics, drug release in phosphate buffered saline (pH 7.4), and evaluated in vivo in streptozotocin-induced hypoglycemic rats. With a large volume of internal aqueous phase during w/o/w double emulsion solvent evaporation process and high molecular weight of the polymers used, we could not achieve high drug capture and precise control over subsequent release within the study period of 60 days. However, this investigation revealed that upon subcutaneous injection, the biodegradable depot-forming polymeric microspheres controlled the drug release and plasma sugar levels more efficiently than plain insulin injection. Preliminary pharmacokinetic evaluation exhibited steady plasma insulin concentration during the study period. These formulations, with their reduced frequency of administration and better control over drug disposition, may provide an economic benefit to the user compared with products currently available for diabetes control.

Animals↗
PubMed1995

The effect of TCPL devices on tissue-implant interface analysis using adult sheep as a model.

Inflammatory response and the subsequent fibrous capsule formation are often used as a screening method to determine biocompatibility of an implanted material. In this study, porous implants of tricalcium phosphate-lysine (TCPL) delivery devices were implanted subcutaneously in adult rams. The fibrous capsule surrounding the implant was studied histochemically to determine the resorbability rate of the device. Fibrous capsular tissues were carefully dissected away from the capsule noting the tissue closest to the implanted material. Evaluation of the sections (5um, H&E) collected from various areas of the implants (n = 127) revealed that: vascularity, macrophages, multinucleated giant cells and plasma cells at the TCPL implant-interface were evident after the first month. Persistence of these cell types and progressive angiogenesis in subsequent months was apparent in all tissues collected from experimental animals. The formation of distinct cell layers was remarkable at the six and twelve month phases. After the first month, macrophages were the predominant cell type at the interface and as the tissue progressed away from the implant the presence of fibroblast and plasma cells were observed. The layer of tissue furthest from the implant mostly consisted of structured collagen fibers with minimal number of microvasculature. The presence of inflammatory cells at the interface sites in all phases was further evidenced by immunohistochemical analysis (IL-1 and IL-6). The inflammatory cells seen at the interface along with the formation of a structured fibrous tissue resembles a normal repair process and supports our previous observations regarding the biocompatibility and biodegradability of TCPL delivery device.

Animals↗
PubMed1996

Cytological evaluation of capsular tissue surrounding TCPL implant in adult rats.

Inflammatory response and the subsequent fibrous capsule formation are often used as a screening method to determine biocompatibility of an implanted material. In this study, porous implants of tricalcium phosphate-lysine (TCPL) delivery devices were implanted intraperitoneally (i.p.) and subcutaneously (s.c.) using adult male rats as a model. The fibrous capsule surrounding the implant was studied histochemically to determine the resorbability rate of the devices. Fibrous capsular tissues were carefully dissected away from the capsule noting the tissue closest to the implanted material. Evaluation of the sections (5um, H&E) collected from various areas of the implants (n = 15 per group) revealed that: (1) regardless of the site of surgical implantation, all devices were encapsulated with fibrous tissue within three days post implantation and the thickness of the capsular tissue was found to be directly proportional to duration of implantation, (2) the thickness of fibrous tissues collected from i.p. site were significantly higher than those collected from s.c. site of implantation, (3) vascularity, macrophages, multinucleated giant cells and plasma cells at the TCPL implant-interface were evident after the first week, and the persistence of these cell types and progressive angiogenesis in subsequent weeks was apparent. The formation of distinct cell layers was remarkable in the fifth week phase, (4) SEM and radiographic analysis of retrieved devices showed a significant (P < 0.05) increase in the number of macropores (12 to 36 um2) in TCPL devices implanted s.c. than the number of macropores in TCPL devices implanted i.p. The mechanism of biodegradation process in an in vivo environment is not fully elucidated. This observation and previous observations led us to suggest that the site of surgical implantation is an instrumental key in designing TCPL delivery system.

Animals↗
PubMedDate not supplied

Novel fast degradable thermosensitive polymeric micelles based on PEG-block-poly(N-(2-hydroxyethyl)methacrylamide-oligolactates).

The aim of this study was to design a thermosensitive polymeric micelle system with a relatively fast degradation time of around 1 day. These micelles are of interest for the (targeted) delivery of biologically active molecules. Therefore, N-(2-hydroxyethyl)methacrylamide-oligolactates (HEMAm-Lac(n)()) were synthesized and used as building blocks for biodegradable (block co) polymers. p(HEMAm-Lac(2)) is a thermosensitive polymer with a cloud point (CP) of 22 degrees C which could be lowered by copolymerization with HEMAm-Lac(4). The block copolymer PEG-b-((80%HEMAm-Lac(2))-(20%HEMAm-Lac(4))) self-assembled into compact spherical micelles with an average size of 80 nm above the CP of the thermosensitive block (6 degrees C). Under physiological conditions (pH 7.4; 37 degrees C), the micelles started to swell after 4 h and were fully destabilized within 8 h due to hydrolysis of the lactate side chains. Rapidly degrading thermosensitive polymeric micelles based on PEG-b-((80%HEMAm-Lac(2))-(20%HEMAm-Lac(4))) have attractive features as a (targeted) drug carrier system for therapeutic applications.

Chromatography, Gel↗
PubMed2006

Electronically-responsive delivery from a calcified mesoporous silicon structure.

The controlled release of substances from a semiconducting calcium phosphate/porous Si structure is reported. This is demonstrated principally for the case of the reversible adsorption and release of dyes (such as an anionic salt of fluorescein) upon the switching of the direction of bias to the underlying porous Si/Si substrate. The effect of bias on the diffusion of the cationic dyes ethidium bromide and acridine orange has also been investigated. For these species, their delivery can be mediated in part by the use of a surface layer of the biodegradable polymer poly-caprolactone (PCL).

Biocompatible Materials↗
PubMed2001

Microencapsulation of dissociable human growth hormone aggregates within poly(D,L-lactic-co-glycolic acid) microparticles for sustained release.

For the sustained release formulation of recombinant human growth hormone (rhGH), dissociable rhGH aggregates were microencapsulated within poly(D,L-lactic-co-glycolic acid) (PLGA) microparticles. rhGH aggregates were first produced by adding a small volume of aqueous rhGH solution into a partially water miscible organic solvent phase (ethyl acetate, EtAc) containing PLGA. These rhGH aggregates were then microencapsulated within PLGA polymer phase by extracting EtAc into an aqueous phase pre-saturated with EtAc. Release profiles of rhGH from these microparticles were greatly affected by changing the volume of incubation medium. The released rhGH species consisted of mostly monomeric form having a correct conformation. This study reveals that sustained rhGH release could be achieved by microencapsulating reversibly dissociable protein aggregates within biodegradable polymers.

Capsules↗
PubMed2005

Hyaluronic acid hydrogel as Nogo-66 receptor antibody delivery system for the repairing of injured rat brain: in vitro.

Nogo-66 and NgR are important receptors inhibiting neuronal regeneration and therefore are targets for treating CNS injury. Antagonists of this receptor including blocking antibodies are potential therapeutic agents for CNS axonal injuries such as spinal cord and brain trauma. A new antibody (IgG) releasing system has been developed by covalently attaching IgG to the biodegradable hyaluronic acid (HA) hydrogel via the hydrolytically unstable hydrazone linkage, aiming to deliver the antibody of CNS regeneration inhibitors to the injured brain. In this paper we describe the synthesis, physico-chemical characteristics and test results of biological activity of antibody released from hyluronic acid hydrogel. To form the conjugates the antibody is attached to the polymer backbone using a condensation reaction between aldehyde group of the antibody and hydrazide group of the HA hydrogel. Furthermore, pH sensitive linkage-hydrozone has been formed between hydrogel and antibody. The amount of conjugated antibodies can reach 135 microg antibody/mg hydrogel in the dry state. At low pH, the antibodies released quite fast. However, the antibodies released much slower in neutral and alkaline environment. The bioactivity of antibody released from hydrogel was retained as demonstrated by indirect immunofluorescence technique.

Amino Acid Sequence↗
PubMed2007

A biodegradable copolymer for the slow release of growth hormone expedites scarring in diabetic rats.

In many diseases wound healing is impaired. This study was designed to establish whether the healing process in diabetes could be improved using a site-specific polymer delivery system containing hGH. The system was first optimized in in vitro experiments performed on cultured fibroblasts taken from healthy and diabetic rats and then tested in an incisional wound model created in the diabetic Wistar rat. In the in vitro experiments using cultured fibroblasts, cell viability, growth, and proliferation were determined, along with polymer degradation, hormone release rates and the expression of TGFbeta1 in the culture medium. For the in vivo experiments, polymer discs with/without GH were inserted through 3 cm incisions made on the backs of the animals. Wound specimens were obtained 7 and 30 days after surgery to evaluate inflammatory/apoptotic cells, metalloprotease expression and neoangiogenesis using microscopy and immunohistochemical techniques. The local administration of GH using a polymer delivery system did not affect the normal wound healing process. Conversely, when used in diabetic animals, epidermal and dermal repair was expedited. Our findings indicate that GH induces cell proliferation, enhances CD4(+) infiltration; increases extracellular matrix protein deposition; stimulates angiogenesis; and diminishes apoptosis at the diabetic wound site. These effects give rise to a comparable wound healing process to that observed in healthy animals.

Animals↗
PubMed2000

[Long-term controlled release of drugs].

The surveys of long-term controlled drugs supply systems have become recently one of more important branches of pharmacy. Many systems were elaborated. The systems differ from each other by the mechanism and time of drug release and the way of administering it. A large number of polymers have been developed with the capability of controlling the release rate over a long period of time (from 12 hr to 5 years). The programmed delivery of drugs offers advantages over conventional methods of administration. Controlled release drug delivery systems include oral, transdermal, injectable, implanted, intrauterine and intravaginal systems. In this paper different sustained-release systems in current use are reviewed.

Administration, Cutaneous↗
PubMed2006

Alginate/PEI/DNA polyplexes: a new gene delivery system.

AIM: To avoid the limitation of the use of cationic polyethlenimine (PEI)-complexed plasmid DNA use for in vitro or in vivo gene delivery due to its cytotoxicity and lower efficiency in the presence of serum. METHODS: A polyplex with decreased positive charge on the complex surface was designed. The PEI/DNA (PD) complexes coated with an anionic biodegradable polymer, alginate were prepared and their gene delivery behavior with PD was compared. RESULTS: The alginate-coated PD polyplex, where alginate : PEI : DNA [alginate : DNA, 0.15 (w/w); PEI : DNA, N : P = 10] showed about 10 - 30 fold-increased transfection efficiency compared to corresponding non-coated complexes to C3 cells in the presence of 50% serum. The surface charge of the alginate-coated complex was approximately half of that of the alginate-lacking complex. The size of alginate-coated complex was slightly smaller than that of the corresponding complex without alginate. The former complex also showed a reduced erythrocyte aggregation activity and decreased cytotoxicities to C3 cells in comparison with PD complex. CONCLUSION: The alginate-coated PD polyplexes as a new gene delivery system can improve transfection efficiency in high serum concentration with low cytotoxicity to C3 cells.

Alginates↗
PubMed2000

Intracerebral implantation of NGF-releasing biodegradable microspheres protects striatum against excitotoxic damage.

Intrastriatal implantation of genetically modified cells synthesizing nerve growth factor (NGF) constitutes one way to obtain a long-term supply of this neurotrophic factor and a neuronal protection against an excitotoxic lesion. We have investigated if NGF-loaded poly(d,l-lactide-co-glycolide) microspheres could represent an alternative to cell transplantations. These microspheres can be implanted stereotaxically and locally release the protein in a controlled and sustained way. In order to test this paradigm, the NGF release kinetics were characterized in vitro using radiolabeled NGF, immunoenzymatic assay, and PC-12 cells bioassay and then in vivo after implantation in the intact rat striatum. These microspheres were thus implanted into the rat striatum 7 days prior to infusing quinolinic acid. Control animals were either not treated or implanted with blank microspheres. The extent of the lesion and the survival of ChAT-, NADPH-d-, and DARPP-32-containing neurons were analyzed. In vitro studies showed that microspheres allowed a sustained release of bioactive NGF for at least 1 month. Microspheres implanted in the intact striatum still contained NGF after 2.5 months and they were totally degraded after 3 months. After quinolinic acid infusion, the lesion size in the group treated with NGF-releasing microspheres was reduced by 40% when compared with the control groups. A marked neuronal sparing was noted, principally concerning the cholinergic interneurons, but also neuropeptide Y/somatostatin interneurons and GABAergic striatofuge neurons. These results indicate that implantation of biodegradable NGF-releasing microspheres can be used to protect neurons from a local excitotoxic lesion and that this strategy may ultimately prove to be relevant for the treatment of various neurological diseases.

Animals↗
PubMed2005

Development of a parathyroid hormone-controlled release system as a potential surgical treatment for hypoparathyroidism.

BACKGROUND/PURPOSE: The aim of this study was to develop a surgically implantable controlled release delivery system for parathyroid hormone (PTH) that will maintain calcium homeostasis without the adverse side effects of long-term calcium and vitamin D replacement and can be used for the treatment of hypoparathyroidism. METHODS: Biodegradable poly(lactide-co-glycolide) (PLGA) microspheres loaded with PTH were made using a modification of the double emulsion (water/oil/water) solvent evaporation technique. To simulate the release of PTH from microspheres after implantation in an animal, the in vitro release profile for the PTH microspheres was determined by incubating the PTH microspheres in phosphate-buffered saline, serially sampling the effluent, and determining the concentration of PTH in the effluent over time using an enzyme-linked immunosorbent assay. RESULTS: (1) PTH was successfully incorporated into PLGA microspheres. (2) Controlled release of PTH was demonstrated in vitro over a 3-week period. (3) Release of physiological significant concentrations of PTH was achieved using this methodology. CONCLUSIONS: Controlled release of physiological concentrations of PTH can be achieved using PLGA microsphere encapsulation.

Biocompatible Materials↗