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Biomedical subjects

Nicholas A Peppas

Publications and source records attributed to Nicholas A Peppas.

At least 19 recordsLinked to original sources
PubMed2005

Cellular evaluation of oral chemotherapy carriers.

Hydrogel nanospheres composed of methacrylic acid and poly(ethylene glycol) were loaded with bleomycin and tested as a potential oral delivery system for chemotherapeutic agents. The gastrointestinal epithelium was modeled through the use of Caco-2 monolayers for studies of permeation enhancement by the carriers as well as bleomycin transport. Bleomycin efficacy following release from the carrier was evaluated with a DLD-1 tumor cell model. The nanospheres release bleomycin in response to a pH increase similar to that seen when passing from the stomach into the upper small intestine. These carriers can also increase the permeability of a model of the epithelial barrier, which would hopefully improve drug transport into the bloodstream. Efficacy studies using a tumor cell model showed retention of activity for bleomycin following loading and release from the nanospheres. The carriers described performed well during in vitro evaluation and can hopefully expand the spectrum of chemotherapeutic agents capable of being administered orally.

Administration, Oral↗
PubMed2005

Oral chemotherapeutic delivery: design and cellular response.

The development of carriers to deliver a variety of cancer therapeutics orally would represent a significant advance in the treatment of this disease. This system is based on hydrophilic polymer carriers to deliver therapeutic agents to the upper region of the small intestine in response to the pH increase when passing from the stomach. Methacrylic acid (MAA) and ethylene glycol (EG) combined in a 1:1 molar ratio were reacted to form P(MAA-g-EG) nanospheres by UV-initiated free radical polymerization. Bleomycin was added prior to polymerization to allow in situ polymerization loading. Release studies were carried out in conditions to model the environment of the stomach and small intestine. Results showed that bleomycin is preferentially released at a higher pH due to the increased mesh size of the swollen hydrogel carrier. The potential cytotoxicity of bleomycin on the small intestine was investigated with the use of Caco-2 cells (human colon adenocarcinoma). Cytotoxicity studies showed maintenance of both viability and proliferation. The presence of the nanospheres decreases the transepithelial electrical resistance across Caco-2 cell monolayers. Complexation hydrogels are promising carriers to expand the number of chemotherapeutics capable of being administered orally.

Administration, Oral↗
PubMed2004

Biomimetic materials and micropatterned structures using iniferters.

In the preparation of biomimetic materials it is often required that efficient methods of polymerization be used, often methods that can lead to biomimetic polymers with relatively narrow molecular weight distribution. Living radical polymerization techniques have successfully been used to create low polydispersity linear polymers by free-radical polymerizations. Although this technique slows down the polymerization of multifunctional monomers, there is little effect on the network structure due to the high concentration of pendent double bonds. There are applications of the living radical polymerization in the synthesis of block copolymers. Essentially, the technique involves polymerizing a single type of monomer first to create a macromonomer that is capable of acting as an initiator because of the reversible bond between the polymer end group and the terminating group. This terminating group may be a thiol or a halogen and, under the right conditions, will dissociate to form radicals. A second monomer is then added to the system and the polymerization proceeds with the second monomer chemically attached to the polymer of the first monomer. We review methods of creating biomimetic block copolymers using the iniferter radical polymerization technique. The block copolymers would be used in the synthesis of micropatterned polymer films for use in biomaterials and other biomedical applications.

Biomimetic Materials↗
PubMed2004

Nanoscale technology of mucoadhesive interactions.

Nanoscale analysis may be used to design new types of mucoadhesive polymers. Understanding of the surface interactions between hydrophilic polymer surfaces and mucins can lead to improved adhesive bonding by hydrogen bonding. Alternatively, decoration of a mucoadhesive polymer surface with tethers of linear and block copolymers containing neutral or ionizable structures provides increased interdigitation and interpenetration with the mucus. Finally, formation of micro- or nanopatterns on these surfaces can lead to promising new systems of oral delivery applications.

Adhesives↗
PubMed2004

Mucosal insulin delivery systems based on complexation polymer hydrogels: effect of particle size on insulin enteral absorption.

Insulin-loaded polymer (ILP) microparticles composed of poly(methacrylic acid) and poly(ethylene glycol), which have pH-dependent complexation and mucoadhesive properties have been thought to be potential carriers for insulin via an oral route. Nevertheless, further optimization of the polymer delivery system is required to improve clinical application. Therefore, the effect of particle size of the ILP (L-ILP: 180-230 microm, S-ILP: 43-89 microm, SS-ILP: <43 microm) on insulin absorption was studied in the in situ loop system, hypothesizing smaller particle sizes of ILP could induce bigger hypoglycemic effects due to increase mucoadhesive capacity. To verify the hypothesis, the adhesive capacities of differently sized ILPs to the mucosal tissues were evaluated. Additionally, the intestinal site-specificity of ILP for insulin absorption was investigated. Intra- and inter-cellular integrity and/or damage were also examined by lactate dehydrogenase leakage and membrane electrical resistance change to ensure the safety of ILP as a carrier for oral route. As hypothesized, the smaller sized microparticles (SS-ILP) showed a rapid burst-type insulin release and higher insulin absorption compared with the microparticles having larger sizes, resulting in greater hypoglycemic effects without detectable mucosal damage. In fact, SS-ILP demonstrated higher mucoadhesive capacity to the jejunum and the ileum than those of L-ILP. Moreover, SS-ILP's enhancement effect of insulin mucosal absorption showed a site-specificity, demonstrating maximum effect at the ileal segment. These results imply that the particle size and delivery site are very important factors for ILP with respect to increasing the bioavailability of insulin following oral administration.

Animals↗
PubMed2004

Oral insulin delivery using P(MAA-g-EG) hydrogels: effects of network morphology on insulin delivery characteristics.

Hydrogels of poly(methacrylic acid-g-ethylene glycol) were prepared using different reaction water contents in order to vary the network mesh size, swelling behavior and insulin loading/release kinetics. Gels prepared with greater reaction solvent contents swelled to a greater degree and had a larger network mesh size. All of the hydrogels were able to incorporate insulin and protected it from release in acidic media. At higher pH (7.4), the release rates increased with reaction solvent content. Using a closed loop animal model, all of the insulin loaded formulations produced significant insulin absorption in the upper small intestine combined with hypoglycemic effects. In these studies, bioavailabilities ranged from 4.6% to 7.2% and were dependent on reaction solvent content.

Administration, Oral↗
PubMed2004

Responsive and recognitive hydrogels using star polymers.

Polymeric networks that have inherent capabilities to recognize different molecules and chemical changes in their environment are the next generation of materials that will aid in the diagnosis and treatment of diseases. We have prepared new networks based on star polymers that were designed to be responsive and recognitive. Using molecular imprinting with D-glucose and crosslinking with poly(ethylene glycol) dimethacrylate with an ethylene glycol chain of nominal molecular weight 600, we prepared star polymer networks, which exhibited over 300% more uptake for D-glucose compared to D-fructose. Using copolymerization with methacrylic acid, we prepared star polymer networks with pH-sensitivity, which showed a sharp transition in swelling around a pH of 4.5.

Acrylates↗
PubMed2004

Principles of transmucosal delivery of therapeutic agents.

Recent advances in medicine have led to new treatment options for patients and physicians as a more developed understanding of the molecular basis of disease states is translated into new therapeutic agents. Many of these new agents are compounds that are not able to reach the bloodstream when administered by the oral route preventing the ability to enjoy the benefits this delivery route provides such as lower cost and increased quality of life. Our laboratory has focused on the use of hydrogel carriers to increase the bioavailability of orally administered therapeutic agents ranging from proteins such as insulin to chemotherapeutics like bleomycin. The foundations of this research as well as recent advances are reviewed along with a discussion of the challenges of oral administration and other emerging strategies for oral administration.

Administration, Oral↗
PubMed2004

Investigation of the cytotoxicity and insulin transport of acrylic-based copolymer protein delivery systems in contact with Caco-2 cultures.

Microparticles or nanospheres of hydrogels of crosslinked poly(methacrylic acid) grafted with poly(ethylene glycol) as well as crosslinked poly(acrylic acid) grafted with poly(ethylene glycol) were prepared for use as oral insulin delivery carriers. The copolymer carriers were synthesized by precipitation/dispersion polymerization that led to gel nanospheres or by bulk polymerization and subsequent size reduction of thin films to obtain gel microparticles. The cytotoxicity of these copolymers was investigated in contact with Caco-2 cell cultures using a metabolic assay to measure the effect of the presence of copolymers on the cell viability. The copolymers were found to exhibit no cytotoxic effect on the cell cultures. Insulin-loaded formulations were also tested for cytotoxicity and insulin transport studies across cell monolayers. The copolymers were shown to open the tight junctions between cells, increasing the available area for diffusion across the cell monolayer, and thus increasing the permeability of insulin across the monolayer.

Acrylates↗
PubMed2004

Development of acrylic-based copolymers for oral insulin delivery.

We developed nanospheres of crosslinked networks of methacrylic acid grafted with poly(ethylene glycol), and acrylic acid grafted with poly(ethylene glycol) nanospheres for use as oral insulin delivery devices. The copolymer nanospheres were synthesized via free-radical precipitation/dispersion. The average particle diameter of the copolymer gel nanospheres at various physiologically relevant pH values was characterized using photon correlation spectroscopy. Their size increased dramatically as the surrounding pH rose above the pK(a) of the network. The nanospheres ranged in diameters from 200 nm at pH of 2.0 to 2 microm at pH around 6.0. Insulin was loaded into the copolymers at levels of 9.33 and 9.54 mg per 140 mg solid sample, by partitioning from concentrated insulin solutions. In vitro studies were performed to study the passage of the insulin-loaded copolymer samples in the gastrointestinal tract. Insulin was entrapped at low pH (pH=3.0) but released at more neutral pH (pH=7.0). Animal studies were performed to investigate the abilities of insulin-loaded copolymer samples to influence the serum glucose levels of rats. In studies with diabetic rats, the serum glucose level was lower than control values for the animals that received the insulin-loaded copolymers and lasted for at least 6 h. The insulin loaded copolymer nanospheres caused a significant reduction of serum glucose with respect to that of a control animal.

Acrylates↗
PubMed2004

Effect of poly (ethylene glycol) molecular weight and microparticle size on oral insulin delivery from P(MAA-g-EG) microparticles.

Five years of successful work in our lab have shown that graft copolymer networks of poly(methacrylic acid-g-ethylene) [P(MAA-g-EG)], are very promising candidates for oral drug delivery. In an acidic environment, these copolymers form interpolymer complexes, protecting the active agent from the harsh environment of the gastrointestinal tract. At high pH, these complexes dissociate, causing the polymer to swell and release the drug. Films of P(MAA-g-EG) with a monomer ratio of 1:1 (MAA:EG) were prepared by free radical solution UV-polymerization, washed in order to remove the unreacted monomer, and crushed to form microparticles with different particle size distribution. Previous studies in our lab have focused on using polymer disks in their swelling studies. The swelling properties of polymer disks vs. crushed particles were investigated via equilibrium swelling experiments in this study. Another goal in this study is to compare different PEG chain length (MW-400 and MW-1000) and different particle size (150-212 microns, 90-150 microns and 25-90 microns) in their loading and release behavior. After 6 hours of exposing the polymer with the insulin solution we achieved approximately 90% of insulin loading.

Administration, Oral↗
PubMed2004

Stimuli-sensitive hydrogels: ideal carriers for chronobiology and chronotherapy.

The development of solid-phase peptide synthesis in the early 1960s and recombinant DNA technology in the early 1970s boosted the scientific interest of utilizing proteins and peptides as potential therapeutic agents to battle poorly controlled diseases. While there has been rapid progress in the development and synthesis of new proteins and peptides as potential therapeutic agents, the formulation and development of the associated delivery systems is lacking. The development of delivery systems is equally important due to the problems of stability, low bioavailability and short half-life of proteins and peptides. The main problem in this field is that low stability leads to low bioavailability. In this review we draw attention to chrono-pharmacological drug-delivery systems, which can be used to match the delivery of therapeutic agents with the biological rhythm. They are very important especially in endocrinology and in vaccine therapy. We show that the treatment of hypopituitary dwarfism by administration of human growth-hormone-releasing hormone (GHRH) is more effective when GHRH is administered in a pulsatile manner that exhibits a period characteristic of the patient's circadian rhythm. Here we examine how to design novel chrono-pharmacological drug-delivery systems that should be able to release the therapeutic agents at predetermined intervals.

Chronobiology Phenomena↗
PubMed2004

Cellular evaluation of insulin transmucosal delivery.

P(MAA-g-EG) microparticles have been extensively investigated as carriers for oral delivery of proteins such as insulin. In this study, we investigated the effect of the molecular weight of the PEG tethered chains in the copolymer network and of the microparticle size on the transepithelial electrical resistance (TEER) and insulin epithelial permeability, using monolayers of human intestinal epithelial Caco-2 cells. Two molecular weights of the PEG chains, 400 and 1000, were investigated, as well as three different dry microparticle sizes: 25-90, 90-150 and 150-212 microm. Their effect on the cell monolayer integrity was studied by monitoring TEER as a fraction of time and determining insulin permeability. The presence of insulin-loaded P(MAA-g-EG) microparticles decreases the TEERs value by 50% with respect to the control. This disruption of the cell monolayer was recovered in 3 h after the removal of the polymer microparticles. Within the range of PEG molecular weights studied, there was no significant change of the TEER values. However, decreased microparticle sizes and short PEG chains systems led to higher permeability values. Insulin-loaded P(MAA-g-EG) microparticles enhanced the transport of insulin through the Caco-2 cell monolayers.

Biological Transport↗
PubMed2004

Hydrogels for oral delivery of therapeutic proteins.

In recent years there has been significant new interest in the development of transmucosal (mostly oral) pharmaceutical formulations for the delivery of therapeutic proteins. Emphasis has been given to the molecular design of new carriers for the delivery of insulin, calcitonin and various types of interferons for the treatment of diabetes, osteoporosis, multiple sclerosis and cancer. Most popular carriers include advanced designs of swollen hydrogels prepared from neutral or intelligent polymeric networks. In this review, the most successful of such systems are presented and their promise in the field described.

Administration, Oral↗
PubMed2003

In vitro release behavior and stability of insulin in complexation hydrogels as oral drug delivery carriers.

Novel pH-responsive complexation hydrogels containing pendent glucose (P(MAA-co-MEG)) or grafted PEG chains (P(MAA-g-EG)) were synthesized by photopolymerization. The feasibility of these hydrogels as oral protein delivery carriers was evaluated. The pH-responsive release behavior of insulin was analyzed from both P(MAA-co-MEG) and P(MAA-g-EG) hydrogels. In acidic media (pH 2.2), insulin release from the hydrogels was very slow. However, as the pH of the medium was changed to 6.5, a rapid release of insulin occurred. In both cases, the biological activity of insulin was retained. For P(MAA-co-MEG) hydrogels, the biological activity of insulin decreased when the pendent glucose content increased. In P(MAA-g-EG) hydrogels, when the grafted PEG molecular weight increased, the insulin biological activity decreased. Finally, hydrogels of P(MAA-co-MEG) prepared with an initial ratio of 1:4 MEG:MAA and P(MAA-g-EG) hydrogels containing PEG chains of molecular weights of 200 showed the greatest change in insulin release rate from acidic to basic pH solutions and the greatest protective effect for insulin in simulated GI tract conditions.

Animals↗
PubMed2003

Novel complexation hydrogels for oral peptide delivery: in vitro evaluation of their cytocompatibility and insulin-transport enhancing effects using Caco-2 cell monolayers.

Poly[methacrylic acid-grafted-poly(ethylene glycol)] [P(MAA-g-EG)] is a complexation hydrogel molecularly designed for oral peptide delivery. In this work, the cytotoxicity and insulin-transport enhancing effect of P(MAA-g-EG) microparticles on intestinal epithelial cells were evaluated using Caco-2 cell monolayers. A series of P(MAA-g-EG) microparticles with different polymer compositions were prepared by a photo-initiated free radical solution polymerization and subsequent pulverization. The hydrogel microparticles were preswollen in either Ca2+-containing (CM+) or Ca2+-free medium (CM-; pH 7.4) and applied to the apical side of the Caco-2 monolayers. No significant cytotoxic effects, as determined by a calorimetric assay with P(MAA-g-EG) microparticles preswollen in the CM+, were observed at doses ranging from 3 to 31 mg/cm2 of cell monolayer. Transepithelial electrical resistance (TEER) measurements showed that the P(MAA-g-EG) microparticles induced a Ca2+ concentration-dependent lowering in TEER values. The reduction effect in CM- media was greater than that in CM+ media (17 +/- 2% reduction in CM+ and 45 +/- 3% reduction in CM-, respectively). Insulin transport in the presence of the preswollen P(MAA-g-EG) microparticles was also strongly depended on the Ca2+ concentration in the medium. The respective estimated permeability for insulin alone and the insulin with hydrogels in CM+ were 0.77 and 1.16 x 10(-8) cm/s, whereas those in CM- were 1.18 and 24.78 x 10(-8) cm/s. The results demonstrate that the P(MAA-g-EG) hydrogel microparticles could be used as a cytocompatible carrier possessing the transport-enhancing effect of insulin on the intestinal epithelial cells.

Caco-2 Cells↗
PubMed2002

Elucidation of the mechanism of incorporation of insulin in controlled release systems based on complexation polymers.

The objective of this study was to investigate the insulin incorporation and release properties of poly(methacrylic acid-g-ethylene glycol) P(MAA-g-EG) microparticles as a function of copolymer composition. These microparticles exhibited unique pH-responsive characteristics in which interpolymer complexes were formed in acidic media and dissociated in neutral/basic environments. The microparticles containing equimolar amounts of MAA and PEG were capable of efficient insulin loading using equilibrium partitioning (>90%). Additionally, insulin release from the gel was significantly retarded in acidic media while rapid release occurred under neutral/basic conditions. In contrast, as the amount of MAA of the polymer was increased, the entrapment efficiency of insulin within the gel greatly reduced and the insulin was readily released from the polymer network in the acidic and neutral/basic media. In addition, in order to evaluate the potential application of the microparticles to other drugs, theophylline, vancomycin, fluorescein-isothiocyanate-labeled dextrans (FITC-Ds) with average molecular weights of 4400 (FITC-D-4), 12,000 (FITC-D-10) and 19,500 (FITC-D-20) were utilized as model hydrophilic drugs. The incorporation profiles showed that the uptake of theophylline and vancomycin to the microparticles was lower than that of insulin. Additionally, polymer microparticles loaded with theophylline and vancomycin exhibited pH-sensitive release behavior, however, the oscillatory behavior is less pronounced than those of insulin. The values of drug incorporation ratio showed that the microparticles were capable of incorporating almost 90% of insulin and 15% of vancomycin from solution. On the other hand, the other hydrophilic drugs showed very low incorporation efficiency to the microparticles. These data suggest that gels containing equimolar amounts of MAA:EG have the potential to be used as an oral carrier of peptide drugs, especially for insulin.

Delayed-Action Preparations↗