An inulin and doxorubicin conjugate for improving cancer therapy.

Chemotherapy is one of the primary treatment mechanisms for treating cancer. Current chemotherapy is systemically delivered and causes significant side effects; therefore the development of new chemotherapeutic agents or enhancing the effectiveness of current chemotherapeutic could prove vital to patients and cancer care. The purpose of this research was to develop a new conjugate composed of doxorubicin (chemotherapeutic) and inulin (polysaccharide chain) and evaluate its potential as a new therapeutic agent for cancer treatment. The synergistic effect of inulin conjugated to doxorubicin has allowed the same cytotoxic response to be maintained or improved at lower doses as compared to doxorubicin. Supporting results include cytotoxicity profiles, calf thymus DNA binding studies, confocal microscopy, and transport studies.

Precise control of synthetic hydrogel network structure via linear, independent synthesis-swelling relationships.

Hydrogel physical properties are tuned by altering synthesis conditions such as initial polymer concentration and polymer-cross-linker stoichiometric ratios. Traditionally, differences in hydrogel synthesis schemes, such as end-linked poly(ethylene glycol) diacrylate hydrogels and cross-linked poly(vinyl alcohol) hydrogels, limit structural comparison between hydrogels. In this study, we use generalized synthesis variables for hydrogels that emphasize how changes in formulation affect the resulting network structure. We identify two independent linear correlations between these synthesis variables and swelling behavior. Analysis through recently updated swollen polymer network models suggests that synthesis-swelling correlations can be used to make a priori predictions of the stiffness and solute diffusivity characteristics of synthetic hydrogels. The same experiments and analyses performed on methacrylamide-modified gelatin hydrogels demonstrate that complex biopolymer structures disrupt the linear synthesis-swelling correlations. These studies provide insight into the control of hydrogel physical properties through structural design and can be used to implement and optimize biomedically relevant hydrogels.

Biodegradable cationic nanogels with tunable size, swelling and pKa for drug delivery.

Cationic polymers have garnered significant interest for their utility in intracellular drug delivery and gene therapy. However, due to their associated toxicities, novel synthesis approaches must be explored to develop materials that are biocompatible. The novel library of nanoparticles synthesized in this study exhibit tunable hydrodynamic diameters, composition and pH-responsive properties as a function of synthesis parameters. In addition, differences in the responsiveness of these nanoparticles under different pH conditions affords greater control over intracellular drug release.

New challenges in biomaterials.

Significant opportunities and challenges exist in the creation and characterization of biomaterials. Materials have been designed for contact with blood, as replacements for soft and hard tissues, as adhesives, and as dental materials. Current methods of synthesis and characterization of these materials are outlined. Approaches for controlling the interface between tissue and biomaterials and ways in which the engineered materials may contribute to medicine are considered.

Pharmacokinetic Modeling of the Glucoregulatory System.

A pharmacokinetic model is proposed to describe the glucoregulatory process. The model describes the dynamics of glucose, amino acids, and fatty acids, as well as both the hormonal actions and dynamics of insulin, glucagon, epinephrine, and glucagon-like peptide-one. The model was developed assuming that the dynamics of each species occurrs in only one compartment. Several forms of the metabolic absorption and elimination rates, along with possibilities for increasing the complexity of each compartmental model are discussed. Once properly identified and validated, the novel model has the potential to be more descriptive than other models describing glucose dynamics in the body.

[New intelligent and targetted drug delivery systems. Pharmaceutical and biomedical applications]. / Vecteurs de médicaments innovants et "intelligents": leurs applications pharmaceutiques.

Biomaterials are widely used in numerous medical applications. Chemical engineering has played a central role in this research and development. We review herein polymers as biomaterials, materials and approaches used in drug and protein delivery systems, materials used as scaffolds in tissue engineering, and nanotechnology and microfabrication techniques applied to biomaterials.

Modeling of drug release from delivery systems based on hydroxypropyl methylcellulose (HPMC).

The objective of this article is to review the spectrum of mathematical models that have been developed to describe drug release from hydroxypropyl methylcellulose (HPMC)-based pharmaceutical devices. The major advantages of these models are: (i) the elucidation of the underlying mass transport mechanisms; and (ii) the possibility to predict the effect of the device design parameters (e.g., shape, size and composition of HPMC-based matrix tablets) on the resulting drug release rate, thus facilitating the development of new pharmaceutical products. Simple empirical or semi-empirical models such as the classical Higuchi equation and the so-called power law, as well as more complex mechanistic theories that consider diffusion, swelling and dissolution processes simultaneously are presented, and their advantages and limitations are discussed. Various examples of practical applications to experimental drug release data are given. The choice of the appropriate mathematical model when developing new pharmaceutical products or elucidating drug release mechanisms strongly depends on the desired or required predictive ability and accuracy of the model. In many cases, the use of a simple empirical or semi-empirical model is fully sufficient. However, when reliable, detailed information are required, more complex, mechanistic theories must be applied. The present article is a comprehensive review of the current state of the art of mathematical modeling drug release from HPMC-based delivery systems and discusses the crucial points of the most important theories.

The effect of angiotensin II on in vivo albumin transport in normal rabbit aortic tissue.

Angiotensin II and other vasoactive amines may have a direct effect on the permeability of the arterial wall. We have investigated the effect of angiotensin II in vivo albumin transport across the aortic wall in rabbits following intravenous injection of [125I]albumin. Transmural concentration profiles of 125I-labeled albumin across the intima and media of the aorta, generated during 25 min of either angiotensin or saline infusion, were measured by a serial-sectioning technique. The uptake of labeled albumin through the aortic wall was found to be dependent on position and to increase from the descending thoracic up to the arch. Angiotensin infusion increased albumin uptake in the region of the aorta proximal to the first pair of intercostal arteries and magnified the position dependence. Angiotensin infusion did not change the uptake of albumin in the descending thoracic aorta between intercostal arteries. The arterial blood pressure elevation associated with angiotensin infusion was not of prime importance in producing the uptake patterns described above.

Flory interaction parameter chi for hydrophilic copolymers with water.

In biomedical applications of hydrophilic polymers knowledge is required of the thermodynamic interactions between the candidate biomaterial and biological fluids. Since information on these interactions is not readily available, a new method is proposed here to estimate the copolymer-water Flory interaction parameter, chi, for biomaterials. The method is based on the pairwise thermodynamic interactions of copolymer segments and solvent molecules. It is validated using data for an important biomedical hydrogel, poly(2-hydroxyethyl methacrylate-co-methacrylic acid), in contact with water.

Prediction of feed comonomer and solvent composition for monomer-free polymer production.

A method has been developed to establish the desirable polymerization conditions for the production of monomer-free polymer at 100% conversion. The limits of desirable comonomer composition and solvent content in the feed are determined for both bulk and solution homo- and copolymerizations. An example of the result of the polymerization of 2-hydroxyethyl methacrylate and methyl methacrylate is used to illustrate the application of this method.

The use of ellipsometry to study adsorption on hydrogels.

This paper discusses the application of ellipsometry to film thickness measurements of materials deposited on hydrogel surface. The fundamentals of ellipsometry and modelling of ellipsometric readings are presented. A system of buffer/protein/hydrogel/metallic substrate is analysed in detail; the effects of optical properties of buffer, protein, polymer and thickness of protein film on ellipsometry readings are discussed. Cell window effects on ellipsometric results may also be quite important.

Bulk characterization and scanning electron microscopy of hydrogels of P(VA-co-NVP).

The bulk properties of uncrosslinked and crosslinked random copolymers of vinyl alcohol and N-vinyl-2-pyrrolidone [P(VA-co-NVP)] are reported. Analytical studies were performed by infrared and nuclear magnetic resonance spectroscopy, gel permeation chromatography, potentiometric titration, elemental analysis and scanning electron microscopy. The microscopic studies elucidated the effect of freeze-drying on the network surface topology. The results indicate macrosyneresis of the copolymer hydrogels upon freeze-drying even at -23 degrees C. Rapid collapse of the hydrogel structure is seen upon removal of the bulk and interfacial water in the frozen state.

Dynamic and equilibrium swelling behaviour of pH-sensitive hydrogels containing 2-hydroxyethyl methacrylate.

The equilibrium and dynamic swelling behaviour of hydrogels containing methacrylic acid or various acrylamides was studied as a function of copolymer composition. In all cases, the comonomer was 2-hydroxyethyl methacrylate, methyl methacrylate or N-vinyl-2-pyrrolidone. It is shown that pH-sensitive behaviour with a wide range of swelling ratios could be obtained using a range of compositional changes. The dynamic swelling behaviour was a function of the acidity of the buffered solution.

Fibrinolytic behaviour of streptokinase-immobilized poly(methacrylic acid-g-ethylene oxide).

Streptokinase was immobilized on poly(methacrylic acid-g-ethylene oxide) surfaces by means of a modified coupling reagent method. The surfaces were activated with a carbodiimide to form an O-acyl isourea derivative, which, upon addition of the enzyme, condensed to form the corresponding amide. The quantity of enzyme immobilized on the surface increased as the reaction time with carbodiimide and streptokinase increased. The fibrinolytic activity of the immobilized enzyme systems was measured by a clot lysis assay. The dynamics of fibrin clot lysis was investigated for a period of up to 500 min. The lysis reaction mechanism was found to approximate a first-order fibrin degradation. In addition, the kinetic rate constant was found to increase with increasing immobilized enzyme content.

Hydrogels as mucoadhesive and bioadhesive materials: a review.

The primary goal of bioadhesive controlled drug delivery is to localize a delivery device within the body to enhance the drug absorption process in a site-specific manner. Bioadhesion is affected by the synergistic action of the biological environment, the properties of the polymeric controlled release device, and the presence of the drug itself. The delivery site and the device design are dictated by the drug's molecular structure and its pharmacological behaviour. This review addresses several issues which clarify the central goals of bioadhesive drug delivery research. Subsequently, a brief review of a wide variety of techniques which have been used to characterize bioadhesives is presented. This is followed by an overview of several proposed mechanisms of adhesion. The primary mechanisms for polymer systems, adsorption and diffusion, are examined in more detail.

Photopolymerized multifunctional (meth)acrylates as model polymers for dental applications.

Polymer networks that can serve as model systems for dental applications were prepared by photopolymerizations of 1,1,1-trimethylolpropane triacrylate, 1,1,1-trimethylolpropane trimethacrylate, 1,1,1-trimethylolethane trimethacrylate, ethylene glycol dimethacrylate, triethylene glycol dimethacrylate, Photomer 2028 and Photomer 3015. The UV polymerizations were initiated by 2,2-dimethoxy-2-phenyl-acetophenone. Volume shrinkage was followed over the course of polymerization using a dilatometric technique. Incident light intensities ranged from 1 mW cm-2 to 20 mW cm-2. The effects of monomer structure on % volume shrinkage, including pendant group size, molecular weight between reactive double bonds, and acrylate versus methacrylate monomers were investigated. In addition, the effect of incident light intensity on % volume shrinkage was studied. Typical volume shrinkage varied from 3.5% to 13.5%. The volume shrinkage decreased with increasing monomer rank and increased pendant group size; the shrinkage for methacrylates was less than that for acrylates. Increased incident light intensity resulted in increased shrinkage rate, but not in statistically significant increases of the volume shrinkage. Conversion was calculated from shrinkage data and compared to data from monomer extraction experiments. Results indicate that although double bond conversion is low, conversion of monomer units is significantly higher.

Water, solute and protein diffusion in physiologically responsive hydrogels of poly (methacrylic acid-g-ethylene glycol).

Grafted poly (methacrylic acid-g-ethylene glycol) [P(MAA-g-EG)] copolymers were synthesized and their pH sensitivity was investigated. P(MAA-g-EG) membranes showed pH sensitivity due to complex formation and dissociation. Uncomplexed equilibrium swelling ratios were 40 to 90 times higher than those of the complexed states and varied according to copolymer composition and poly(ethylene glycol) (PEG) graft length. Mesh sizes in the two states were determined. Swelling under oscillatory pH conditions revealed the dynamic sensitivity of P(MAA-g-EG) membranes as well as the diffusional mechanisms causing network expansion and collapse. Network collapse (complexation) occurred more rapidly than network expansion (decomplexation). A Boltzmann superposition model was used to analyse this behaviour. Mechanical testing was used to evaluate the strength of P(MAA-g-EG) membranes and to elucidate the mesh size under various conditions. Solute diffusion coefficients were higher in uncomplexed than in complexed P(MAA-g-EG) membranes and decreased as solute size increased. Lower diffusion coefficients were observed with membranes or hydrogels containing longer PEG grafts, since in the uncomplexed state the PEG grafts dangled into the polymer mesh space. Membrane permeability was responsive to changing pH conditions, and separation of solutes was achieved.

Transmucosal delivery systems for calcitonin: a review.

The commercial availability of peptides and proteins and their advantages as therapeutic agents have been the basis for tremendous efforts in designing delivery systems for such agents. The protection of these agents from biological fluids and physiological interactions is crucial for the treatment efficacy. One such agent is salmon calcitonin, a 32 amino-acid polypeptide hormone used in the treatment of bone diseases such as Paget's disease, hypercalcemia and osteoporosis. Researchers have studied different routes to deliver salmon calcitonin more effectively, including nasal, oral, vaginal and rectal delivery. These systems are designed to protect the polypeptide from the biological barriers that each delivery route imposes. Oil-based and polymer-based delivery systems are discussed.

Swelling/deswelling of anionic copolymer gels.

Studies of dynamic and equilibrium swelling of ionic gels are important in understanding the diffusion of physiologically important fluids in materials for site-specific controlled drug delivery applications. The dynamic and equilibrium swelling properties of dry glassy poly(2-hydroxyethyl methacrylate-co-methacrylic acid) and poly(2-hydroxyethyl methacrylate-co-acrylic acid) polymeric networks were studied as a function of pH, ionic strength, nature of the counterion and buffer composition. The mechanism of water diffusion in these gels became more anomalous as the pH of the swelling medium increased and as the ionic strength decreased at a constant pH > or = pKa,gel. The mechanism of water diffusion was Fickian in all unbuffered swelling media at pH 4.0, which is lower than the pKa,gel. The pKa,gel of these gels was between 5.5 and 6. At pH 4.0, the diffusion mechanism was independent of ionic strength. This swelling behaviour is explained in terms of the concept of ion osmotic swelling pressure and ion exchange kinetics.

Complexation graft copolymer networks: swelling properties, calcium binding and proteolytic enzyme inhibition.

Graft copolymer networks of poly(methacrylic acid-g-ethylene glycol) were prepared by free radical solution UV-polymerization of methacrylic acid (MAA) and poly(ethylene glycol) monomethacrylate. Dynamic swelling studies indicated that complexation/decomplexation processes occurred due to hydrogen bonding between the carboxylic groups of the poly(methacrylic acid) (PMAA) and the ether groups of poly(ethylene glycol) (PEG). The effects of copolymer composition, graft chain molecular weight, environmental pH and ion content on network structure and gel behavior were studied. The largest change in swelling ratio and mesh size of the gel structure was observed in gels containing the highest content of PEG and the longest molecular weight PEG grafts. Complexation was greatest in hydrogels containing the longest PEG grafts and equimolar amounts of MAA and PEG. The swelling was much less pronounced in the presence of calcium chloride compared to sodium chloride which could be attributed to the complexation of calcium of the carboxylic groups in the polymer. The copolymers showed significant but less binding of calcium compared to poly(acrylates) like Carbopol 934P and polycarbophil. The P(MAA-g-EG) copolymers inhibited trypsin but to a lesser extent than the known protease inhibitors Carbopol 934P and polycarbophil. Results suggest that P(MAA-g-EG) copolymers are good drug delivery carrier candidates due to their pH-sensitive and controllable swelling behavior. Additionally, they possess some protease inhibition effect along with their bioadhesive properties which make them promising carriers for peptides or proteins.