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PubMedDate not supplied

Vitamin B12 mediated oral delivery systems for granulocyte-colony stimulating factor and erythropoietin.

As a prelude to the development of orally active erythropoietin (EPO) and granulocyte-colony stimulating factor (G-CSF), conjugates have been formed between these molecules and vitamin B12. During the formation of these conjugates intramolecular cross-linking of the proteins was avoided by the use of hydrazidyl derivatives of vitamin B12. A potentially biodegradable linkage was formed between vitamin B12 and G-CSF by reaction of the buried thiol in G-CSF with a long chain dithiopyridyl derivative of vitamin B12. In vitro and in vivo testing of the conjugates showed that their bioactivity was substantially maintained and that they were actively transported in an intrinsic factor dependent fashion across CaCo-2 cells and from the intestine to the circulation in a biologically active form.

Administration, Oral↗
PubMed2002

Biological characterization of a novel biodegradable antimicrobial polymer synthesized with fluoroquinolones.

Biomaterial-related infections continue to represent a significant challenge to the medical community. Several approaches have been utilized to incorporate antimicrobial agents at the surface of implant devices in attempts to delay or eliminate the formation of biofilms. To date, most of these strategies have focused on drug conjugation or diffusion-limited systems for the delivery of such pharmaceutical agents. More recently, work has been presented on the feasibility of incorporating drugs into the backbone of polymers as a main-chain monomer. When sequenced into the backbone of the polymer with other monomers that are hydrolytically sensitive to enzyme-catalyzed breakdown, it is thought that drugs may be able to be selectively released. Specifically, degradable polyurethanes have been synthesized with fluoroquinolone antibiotics and have shown an ability to kill bacteria when released following degradation of the polymer chains by the macrophage-derived enzyme cholesterol esterase. However, specificity of the cleavage sites in the polymer was difficult to control. Since cholesterol esterase has specificity for hydrophobic moieties, it is desirable to alter the formulation of the polyurethanes to incorporate long hydrophobic monomers immediately adjacent to the ciprofloxacin molecule. Hence, the current study focuses on evaluating the enzyme-catalyzed degradation of a degradable polyurethane synthesized with 1,12 diisocyanatododecane as a substitute for 1,6 diisocyanatohexane, which was used in previous work. Validation of specific ciprofloxacin release and the generation of antimicrobial are shown. A preliminary cell study to assess the cytotoxicity of this biodegradable antibiotic polymer shows that the material has no observable effects on cell proliferation or cell membrane structure.

Animals↗
PubMed2004

The current status of material used for depot delivery of drugs.

The ideal local antibiotic delivery system has not been created. Antibiotic-laden bone cement has become the gold standard in the treatment of infected orthopaedic implants and there are confirmatory laboratory and clinical data that support the use of these materials. Heat-stable antibiotics elute from antibiotic-laden bone cement and do not have a notable influence on the compressive strengths of bone cement if the antibiotics are used in appropriate amounts. If the proper antibiotic is chosen, placed in the appropriately porous materials in sufficient amounts, and implanted in bone, antibiotic levels in the surrounding bone are many times greater than can be achieved by safe systemic antibiotic doses. Although the materials that have been manufactured commercially have been used for over 30 years in Europe, until recently, they have not been available in the United States. Currently, there are five antibiotic-laden bone cement composites that have been approved by the FDA and that are available for clinical use. Studies are being done to search for biodegradable implants preferable to antibiotic-laden bone cement; however, these studies and the materials are still in early stages and development. Currently, there are no FDA-approved biodegradable materials available for use to treat infected orthopaedic implants. As new materials become available and their elution characteristics are recorded, it is important for surgeons to understand how the data were collected so they can have a clear understanding of the elution characteristics of the material used and how the material acts in different environments. Even with extensive historic, clinical, and research data that prove the effectiveness of antibiotic-laden cement, the ideal drug delivery system is neither agreed on nor available.

Absorbable Implants↗
PubMed2002

Insulin-like growth factor-1 and transforming growth factor-beta1 accelerates osteotomy healing using polylactide-coated implants as a delivery system: a biomechanical and histological study in minipigs.

Stimulation of bone healing and bone formation through local application of growth factors from implants may improve the clinical outcome in fracture treatment. Previous studies demonstrated a high mechanical stability of a thin poly(D,L-lactide) (PDLLA) coating on metallic implants that can withstand the process of intramedullary insertion. Following an initial peak, 80% of incorporated insulin-like growth factor-1 (IGF-1) and transforming growth factor-beta1 (TGF-beta1) were released continuously, within 42 days. The goal of the present study is evaluation of the coated implants on fracture healing in a large animal model. A midshaft osteotomy (1 mm gap) of the right tibia of Yucatan minipigs was stabilized with uncoated vs. coated titanium interlocking nails (5 mm). X-ray examinations and blood analyses (including IGF-1 and IGF-binding proteins) were performed, and body weight and body temperature were taken throughout the experiment. After 28 days, both tibiae were dissected for mechanical torsional testing and histomorphometric analyses. No differences were found in the blood analyses, body weight, or temperature due to the coating or the incorporated growth factors between the groups. X-ray examinations revealed a faster consolidation of the osteotomy in the growth factor-treated group. Biomechanical testing showed a significantly higher torsional stiffness and maximum load. Progressive remodeling was observed in the histological and histomorphometric analyses with a larger callus volume in the growth factor group compared with the control groups. We conclude that local application of growth factors from a biodegradable PDLLA coating of intramedullary implants accelerates bone healing in a large animal model without systemic side effects.

Animals↗
PubMed1999

Biodegradable cross-linked starch/protein microcapsules containing proteinase inhibitor for oral protein administration.

The objective of this study is to demonstrate the feasibility of microcapsules containing a protein and a proteinase inhibitor in order to allow the oral administration of proteic or peptidic drug. Starch/bovine serum albumin mixed-walled microcapsules were prepared using interfacial cross-linking with terephthaloyl chloride. The microcapsules were loaded with native or amino-protected aprotinin by incorporating protease inhibitors in the aqueous phase during the cross-linking process. Microcapsules can be degraded in the presence of alpha-amylase. The influence of the formulation parameters on the in vitro release of the inhibitor activity and the protein was studied. The protective effect of microcapsules with aprotinin for bovine serum albumin was revealed in vitro. The presence of the native bovine serum albumin was demonstrated after incubation of the microcapsules with aprotinin in a mixture of alpha-amylase (5.4 U/ml) and trypsin (900 spectrophotometric BAEE units/ml) for 3 h at 37 degrees C, whereas the protein was completely degraded in the release medium of the microcapsules without aprotinin.

Administration, Oral↗
PubMed2002

Polymer delivery of camptothecin against 9L gliosarcoma: release, distribution, and efficacy.

Camptothecin is a potent antineoplastic agent that has shown efficacy against multiple tumor lines in vitro; unfortunately, systemic toxicity has limited its in vivo efficacy. This is the first study to investigate the release, biodistribution, and efficacy of camptothecin from a biodegradable polyanhydride polymer. Tritiated camptothecin was incorporated into biodegradable polymers that were implanted intracranially in 16 male Fischer 344 rats and the animals were followed up to 21 days post-implant. A concentration of 11-45 microg of camptothecin-sodium/mg brain tissue was within a 3 mm radius of the polymer disc, with levels of 0.1 microg at the outermost margin of the rat brain, 7 mm from the site of implantation. These tissue concentrations are within the therapeutic ranges for human and rat glioma lines tested against camptothecin-sodium in vitro. The in vivo efficacy of camptothecin-sodium was evaluated with male Fischer 344 rats implanted intracranially with 9L gliosarcoma and compared with the efficacy of 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU). The animals were divided into four groups. Group 1 (control) had a median survival of 17 days. Group 2 (3.8% BCNU polymer) had a median survival of 23 days (P = 0.006). Group 3 (20% camptothecin polymer) had a median survival of 25 days (P = 0.023). Group 4 (50% camptothecin polymer) had a median survival of 69 days (P < 0.001). Drug loadings of 20% and 50% camptothecin released intact camptothecin for up to 1000 h in vitro. We conclude that the biodegradable polymer p(CPP: SA) releases camptothecin-sodium, produces tumoricidal tissue levels, results in little or no systemic toxicity, and prolongs survival in a rat glioma model.

Animals↗
PubMed1992

The development of polyanhydrides for drug delivery applications.

This paper reviews the development of the polyanhydrides as bioerodible polymers for drug delivery applications. The topics include design and synthesis of the polymer, physical properties, techniques to fabricate the polymer into drug delivery devices, evaluation of biocompatibility, and example applications of the polyanhydrides. Discussion of the interrelationship between the physical-chemical properties of the polyanhydrides, fabrication methods, and drug release rates is included. One section is devoted to a case study to provide a historical perspective of the development a polyanhydride-based drug delivery treatment from the conception of the idea to the final stages of human clinical trials. This section includes an outline of the extensive in vitro and in vivo testing that is necessary for development of a new material for biomedical applications.

Alzheimer Disease↗
PubMed1999

Biomedical applications of polyurethanes: a review of past promises, present realities, and a vibrant future.

Polyurethanes, having extensive structure/property diversity, are one of the most bio- and blood-compatible materials known today. These materials played a major role in the development of many medical devices ranging from catheters to total artificial heart. Properties such as durability, elasticity, elastomer-like character, fatigue resistance, compliance, and acceptance or tolerance in the body during the healing, became often associated with polyurethanes. Furthermore, propensity for bulk and surface modification via hydrophilic/hydrophobic balance or by attachments of biologically active species such as anticoagulants or biorecognizable groups are possible via chemical groups typical for polyurethane structure. These modifications are designed to mediate and enhance the acceptance and healing of the device or implant. Many innovative processing technologies are used to fabricate functional devices, feeling and often behaving like natural tissue. The hydrolytically unstable polyester polyurethanes were replaced by more resistant but oxidation-sensitive polyether polyols based polyurethanes and their clones containing silicone and other modifying polymeric intermediates. Chronic in vivo instability, however, observed on prolonged implantation, became a major roadblock for many applications. Presently, utilization of more oxidation resistant polycarbonate polyols as soft segments, in combination with antioxidants such as Vitamin E, offer materials which can endure in the body for several years. The applications cover cardiovascular devices, artificial organs, tissue replacement and augmentation, performance enhancing coatings and many others. In situ polymerized, cross-linked systems could extend this biodurability even further. The future will expand this field by revisiting chemically-controlled biodegradation, in combination with a mini-version of RIM technology and minimally invasive surgical procedures, to form, in vivo, a scaffold, by delivery of reacting materials to the specific site in the body and polymerizing the mass in situ. This scaffold will provide anchor for tissue regeneration via cell attachment, proliferation, control of inflammation, and healing.

Animals↗
PubMed1999

In vivo tissue engineering: Part I. Concept genesis and guidelines for its realization.

A loss of function of an organ often represents a life-threatening situation. Transplantations are successful, but "replacement" availability, its compatibility with the host, and subsequent healing often pose serious questions. Tissue engineering, where a carefully prepared scaffold is populated, in vitro, by cells to form an artificial organ, addresses some of the problems mentioned above. Trauma associated with the implant introduction to the host often complicates the process. The novel concept of in vivo tissue engineering which is designed to mediate the healing and tissue regeneration process by providing an in vitro formed porous, microcellular scaffold is proposed. The scaffold (part or entire organ) is then populated by cells either spontaneously (the surrounding cells will spread and populate to inhabit the scaffold) or by cellular augmentation (encapsulated cells are delivered to this in statu nascendi scaffold). Minimally traumatic arthroscopic surgery combined with a unique polymer delivery system is envisioned for the introduction of this implant to a site to be repaired. Such an approach will require the formation of polymer in-situ, in a reasonable time. The scaffold-forming polymers will be, in principle, biodegradable. We propose to utilize biodegradable polyurethane systems for in vivo tissue engineering. Diversity of their structure/property relationships, relative "ease" of their preparation, and excellent biocompatibility predetermine polyurethanes to be the materials of choice. This paper describes the genesis of this concept and potentials for its realization. It is intended to initiate and stimulate discussion among the related scientific disciplines to form a basis for this field. The synthesis, application, and biodegradation of selected polyurethanes and variety of its medical utilization will be discussed in upcoming papers.

Artificial Organs↗
PubMed2004

Current developments in gene transfection agents.

DNA can be delivered into the cell nucleus either using physical means or specific carriers that carry the genes into the cells for gene expression). Various carriers for delivering genes have been investigated which can be divided into two main groups: viral carriers where the DNA to be delivered is inserted into a virus, and cationic molecular carriers that form electrostatic interactions with DNA). Successful gene therapy depends on the efficient delivery of genetic materials into the cells nucleus and its effective expression within these cells). Although at present the in vivo expression levels of synthetic molecular gene vectors are lower than for viral vectors and gene expression is transient, these vehicles are likely to present several advantages including safety, low-immunogenicity, capacity to deliver large genes and large-scale production at low-cost). The two leading classes of synthetic gene delivery systems that have been mostly investigated are cationic lipids and cationic polymers). This review discusses recent developments in viral vectors, physical means and molecular gene carriers). The last part focuses on our recent studies in developing a new series of biodegradable polycations for in vitro and in vivo gene transfection).

Animals↗
PubMed2005

Local treatment of malignant brain tumors using implantable chemotherapeutic polymers.

Malignant gliomas are among the most devastating human cancers. The infiltrating nature of these malignancies makes complete surgical resection nearly impossible. Conventional therapy for malignant gliomas consists primarily of surgical debulking followed by radiation therapy and possibly chemotherapy. The major factor limiting intracranial therapeutic levels of systemically administered chemotherapeutics is the physiologic barriers of the brain. This has led to the development of novel methods of drug delivery such as implantable polymers containing chemotherapeutic agents. Several phase III clinical trials show that implantation of carmustine-containing biodegradable polymers prolongs survival in patients with both recurrent and newly diagnosed malignant gliomas. In this article, we summarize these trials and discuss ongoing clinical trials involving implantable chemotherapy-containing polymers in the treatment of patients with malignant gliomas.

Antineoplastic Agents↗
PubMed1998

The potentiation of the effect of radiation treatment by intratumoral delivery of cisplatin.

PURPOSE: To compare potentiation of the effects of acute or fractionated radiation by cisplatin when the drug was delivered intratumorally by implanted biodegradable polymer, by intraperitoneal injection, or by intraperitoneal osmotic pump. METHODS AND MATERIALS: Radiation was delivered to a mouse tumor (RIF-1) either in a single dose or in a fractionated regime in conjunction with cisplatin delivered either as a bolus injection, with an osmotic pump, or with a biodegradable polymer rod containing cisplatin. The osmotic pump was implanted in the intraperitoneal cavity of the mouse while the polymer implants were placed directly in the tumor. As the polymer degrades, the drug is released at the treatment site leading to high local concentrations. The osmotic pump, in contrast, leads to prolonged systemic exposure to the drug at low concentrations. Tumor growth delay (TGD) was used as an endpoint in these experiments. RESULTS: The most effective treatment protocol, in terms of potentiating the effects of radiation was cisplatin delivered by polymer implanted 2 days before an acute dose of radiation (growth modification factor [DMF] = 2.2). Comparison of single and multifraction regimes where polymer implant was on the same day as the commencement of treatment showed greater potentiation of the effect of fractionated than of acute radiation treatment with the DMF for fractionated treatment remaining relatively constant (1.5-1.9) for 5, 8, and 12 fraction treatments. Cisplatin delivered via the osmotic pump did not deliver a high enough dose of cisplatin to produce therapeutic effect in this mouse tumor model and had little impact on response to treatment. CONCLUSIONS: Our results indicated that cisplatin delivered intratumorally by biodegradable polymer implant was effective in potentiating the effect of both acute and fractionated radiation. For the fractionated treatments the effect was maintained with increasing fraction numbers and treatment time.

Animals↗
PubMed1996

The role of scanning probe microscopy in drug delivery research.

The success of a drug delivery system is often dependent on the surface properties of the device. These surface properties will determine the complex dynamic interfacial events that occur when the system is introduced into the aqueous environment of a patient. Development of the scanning probe microscopes has provided a number of very powerful new surface analytical techniques that are making a significant contribution to the characterization of drug delivery systems and the interfacial processes that occur when such systems are exposed to aqueous living environments. In this review, we describe the design and attributes of these instruments and discuss the impact of the techniques on a wide range of drug delivery research. The scanning probe microscopes are providing new insights into important problems concerning drug delivery, including the molecular structure of polymeric biomaterial surfaces, the conformation of target biomolecules, the influence of morphology on biodegradation, the adsorption of proteins to synthetic surfaces, and the structure and interactions of colloidal particles. As the whole field of scanning probe microscopy continues to advance, drug delivery research is set to benefit; in the final section of the review, the future potential derived from the ability to characterize new surface properties under aqueous conditions is discussed.

Drug Delivery Systems↗
PubMed2005

Albumin-protamine-oligonucleotide nanoparticles as a new antisense delivery system. Part 1: physicochemical characterization.

In this paper, a ternary system of albumin-protamine-oligonucleotide nanoparticles (AlPrO-NP) recently developed by Vogel et al. [V. Vogel, D. Lochmann, J. Weyermann, G. Mayer, C. Tziatzios, J.A. van den Broek, W. Haase, D. Wouters, U.S. Schubert, J. Kreuter, A. Zimmer, D. Schubert, Oligonucleotide-protamine-albumin nanoparticles: preparation, physical properties and intracellular processing, J. Controlled Rel. (in press)] which could serve as a potential drug delivery system for antisense oligonucleotides. Former studies of binary protamine-oligonucleotide nanoparticles showed two main disadvantages: (i) aggregation of the particles within a few minutes in the presence of salt; (ii) low intracellular dissociation between protamine and oligonucleotide, especially phosphorothioates. To overcome these problems, human serum albumin (HSA) as a non-toxic, biodegradable macromolecule was introduced as protective colloid. The assembly process of AlPrO-NP was investigated by small angle X-ray scattering (SAXS), fluorescence correlation spectroscopy (FCS), photon correlation spectroscopy (PCS) measurements and scanning electron microscopy (SEM). 'Initial complexes' of HSA and protamine sulphate with a mean hydrodynamic diameter (dh) of about 10-14 nm were found. After adding oligonucleotides (unmodified, phosphorothioate DNA and small interfering RNA), nanoparticles (NPs) were assembled in water and in isotonic media with a dh in a range of 230-320 nm for most preparations. The chemical composition of the particles was investigated by high performance liquid chromatography and fluorescence spectrometry. The whole amount of oligonucleotides (30 microg) was entrapped into the particles at a 1:2 mass ratio (oligonucleotide/protamine). Approximately 7-10% (w/w) of the HSA was bound to the particles. The surface charge of the particles ranged from about +12 to -60 mV depending on the protamine concentration and the ionic conditions. The size and the molecular weight of the components, initial complexes and two model NP preparations were calculated from FCS data. These data verified the PCS, SEM and SAXS measurements.

Chemical Phenomena↗
PubMed2004

Comparison of biodegradable nanoparticles and multiple emulsions (water-in-oil-in-water) containing influenza virus antigen on the in vivo immune response in rats.

Multiple water-in-oil-water (w/o/w) emulsion and polymeric nanoparticle formulations containing influenza virus surface antigen hemagglutinin (HA) are thought to be suitable carriers for a vaccine delivery system. The multiple emulsion technique leads to high entrapment of HA, while the solvent evaporation technique encapsulates and adsorbs HA within the nanoparticle. Immune responses of these formulations were investigated in rats and compared with the immune response raised against the conventional vaccine. The responses were detected with the hemagglutinin inhibition (HAI) assay. A single administration of multiple emulsion (F1, F2, F3) and nanoparticle (F4) formulations proved to stimulate a more effective immune response in rats than conventional vaccine.

Animals↗
PubMed2001

Hydrogels for combination delivery of antineoplastic agents.

The systemic delivery of anticancer agents has been widely investigated during the past decade but localized delivery may offer a safer and more effective delivery approach. We have designed and synthesized a novel hydrogel to locally deliver antineoplastic agents, and demonstrate the different types of release that can be achieved from these hydrogels using three model drugs: methotrexate, doxorubicin, and mitoxantrone. Alginate was chemically modified into low molecular weight oligomers and cross-linked with a biodegradable spacer (adipic dihydrazide) to form biodegradable hydrogels. The model antineoplastic agents were loaded into the hydrogel via three different mechanisms. Methotrexate was incorporated within the pores of the hydrogel and was released by diffusion into the surrounding medium. Doxorubicin was covalently attached to the polymer backbone via a hydrolytically labile linker and was released following the chemical hydrolysis of the linker. Mitoxantrone was ionically complexed to the polymer and was released after the dissociation of this complex. These three release mechanisms could potentially be used to deliver a wide selection of antineoplastic agents, based on their chemical structure. This novel delivery system allows for the release of single or combinations of antineoplastic agents, and may find utility in localized antineoplastic agent delivery.

Alginates↗
PubMed2006

Characterization of pilocarpine-loaded chitosan/Carbopol nanoparticles.

Patients using ophthalmic drops are faced with frequent dosing schedules and difficult drop instillation. Therefore, a long-lasting pilocarpine-loaded chitosan (CS)/Carbopol nanoparticle ophthalmic formulation was developed. The physicochemical properties of the prepared nanoparticles were investigated using dynamic light scattering, zeta-potential, transmission electron microscopy, Fourier transform infrared ray spectroscopy (FT-IR) and differential scanning calorimetry (DSC). The sustained-release effects of pilocarpine-loaded nanoparticles were evaluated using in-vitro release and in-vivo miotic tests, and compared with pilocarpine in solution, gel and liposomes. We found that the prepared nanoparticles were about 294 nm in size. DSC and FT-IR studies suggested that an electrostatic interaction between CS and Carbopol contributes at least in part to the stabilization of pilocarpine/CS/Carbopol nanoparticles. When compared with pilocarpine in solution, gel or liposomes, the best slow-release profile of pilocarpine from the prepared nanoparticles occurred in a dissolution test. In the in-vivo miotic study, pilocarpine-loaded CS/Carbopol nanoparticles showed the most significant long-lasting decrease in the pupil diameter of rabbits. The advantages of CS and Carbopol are good biocompatibility, biodegradability and low toxicity. CS is also a mucoadhesive polymer. Thus, pilocarpine/CS/Carbopol nanoparticles may provide an excellent potential alternative ophthalmic sustained-release formulation of pilocarpine for clinical use. CS/Carbopol nanoparticles may also be useful for a variety of other therapeutic delivery systems.

Acrylic Resins↗
PubMed1999

Genetically engineered polymers for drug delivery.

Genetic engineering methodology offers the ability to synthesize protein-based polymers with precisely controlled structures. Protein-based polymers synthesized by recombinant techniques have a well-defined monomer composition and sequence, stereochemistry, and a narrow molecular weight distribution. The structure of the polymeric carrier at the molecular level influences its biological disposition and drug release profile. Current methodologies of polymer synthesis (chemical polymerization) result in the production of polymers with heterogeneous molecular weights, and with monomer sequences and compositions defined in terms of statistical distributions. Genetic engineering methodologies can be used to design new polymeric drug carriers with improved properties, such as better-defined biorecognition, pharmacokinetic, biodegradation, and drug release profiles. In this review article the rationale and methodology of polymer synthesis using genetic engineering techniques, the status of such polymers in drug delivery to-date, and the potential of these polymers for the development of new systems in the future are discussed.

Drug Delivery Systems↗