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Biomedical subjects

Andrew L Lewis

Publications and source records attributed to Andrew L Lewis.

At least 19 recordsLinked to original sources
PubMed2006

Facile synthesis of highly biocompatible poly(2-(methacryloyloxy)ethyl phosphorylcholine)-coated gold nanoparticles in aqueous solution.

Diblock copolymers comprising a highly biocompatible poly(2-(methacryloyloxy)ethyl phosphorylcholine) (PMPC) block and a poly(2-(dimethylamino)ethyl methacrylate) (PDMA) block were evaluated for the synthesis of sterically stabilized gold nanoparticles in aqueous solution. The PDMA block becomes partially protonated on addition of HAuCl4, and the remaining nonprotonated tertiary amine groups reduce the AuCl4- counterion to zerovalent gold in situ. This approach results in the adsorption of the PDMA block onto the gold nanoparticle surface while the PMPC chains serve as a stabilizing block, producing highly biocompatible gold sols in aqueous solution at ambient temperature without any external reducing agent. The size and shape of gold nanoparticles could be readily controlled by tuning synthesis parameters such as the block composition and the relative and absolute concentrations of the PMPC-PDMA diblock copolymer and HAuCl4. These highly biocompatible gold sols have potential biomedical applications.

Biocompatible Materials↗
PubMed2006

Irinotecan drug eluting beads for use in chemoembolization: in vitro and in vivo evaluation of drug release properties.

Drug eluting beads that release irinotecan in a controlled manner may be useful for application in the chemoembolization of colorectal cancer metastases to the liver. In this study, irinotecan drug eluting beads were prepared with loadings up to 50 mg drug/mL hydrated beads. Drug loading was via an ion-exchange mechanism with sulfonate binding sites in the bead. Release in vitro was shown to be sustained and dependent upon the presence of ions in the elution medium, drug loading and bead size. Drug elution in PBS was controlled by solute diffusion within the beads and gave rise to values for the diffusion coefficient, D, of between 2.4x10(-9) and 1.4x10(-7) cm(2)s(-1). The beads were shown to decrease in size (by a maximum 25-30%), and concomitantly their modulus of compression increased (from approximately 27 kPa to a maximum of about 49 kPa), with increasing drug loading. This did not however, influence their ability to be suspended homogeneously in contrast agent or delivered through a microcatheter. Following porcine hepatic artery embolization, maximum plasma levels were 70-75% lower for both irinotecan and SN-38 compared to intraarterial bolus administration, with peak levels observed at 2 and 5 min after completion of the embolization procedure. The in vivo data were shown to correlate well with the in vitro release measured using a T-apparatus model of embolization.

Animals↗
PubMed2006

Comparative in vitro evaluation of microspherical embolisation agents.

This study describes the comparative performance of four commercially available microspherical embolisation products: Embosphere, Embogold, Contour SE and Bead Block. A series of in vitro evaluations were designed to assess the mechanical and biological characteristics of these biomaterials. Size distribution analysis revealed sieving techniques used to fractionate the embolics produced similar size distributions. The forces required to compress Embosphere, Embogold and Bead Block were in the range 21-27.5 kPa. Contour SE was significantly more compressible at approximately 5 kPa. However, recoverability of Contour SE required several minutes in contrast to the other products, a phenomenon attributed to its macroporous structure. When time taken to reach and remain in suspension was studied, results showed that the products quickly reached equilibrium with contrast agent. Bead Block was maintained in suspension for twice as long as the other products. Catheter deliverability was assessed and found to be dependent upon both microsphere and catheter, the best combination being Bead Block delivered via the Progreat catheter. Both the blood contacting SEM and plasma coagulation time showed none of the products were pro-thrombic or pro-coagulatory, each producing comparable results. Small differences in physical properties such as compressibility, could play an important role in delivery and effectiveness of vessel blockage. Currently all products are used routinely in clinical practice.

Acrylic Resins↗
PubMed2006

Controlled delivery of antisense oligodeoxynucleotide from cationically modified phosphorylcholine polymer films.

Antisense strategy is a promising approach for the prevention of in-stent restenosis if therapeutic agents such as antisense oligodeoxynucleotides (AS-ODNs) can be successfully delivered to the implant site. Optimizing the routes and conditions for controlled loading and release of therapeutic agents from a biocompatible polymer coating is still required. In this study, phosphorylcholine (PC) polymer films bearing different cationic charge densities were deposited onto smooth silicon substrates. The thickness of these films was determined by spectroscopic ellipsometry (SE). Human c-myc AS-ODNs were incorporated into the PC polymer films by immersion in concentrated AS-ODN solution and eluted into PBS under physiological conditions. The elution profile was monitored by UV spectrometry and gel electrophoresis. Cellular uptake of the eluted AS-ODN into vascular smooth muscle cells (VSMCs) was evaluated by fluorescence microscopy. The results showed that ODN loading capacities increased with film thickness and were also strongly dependent on the cationic charge density. AS-ODN release was characterized by a slight initial burst in the first half hour followed by a period of sustained release up to 8 days. Gel electrophoresis demonstrated DNA integrity, and different transfection efficiencies were observed when the eluted ODNs were transfected into VSMCs. These results demonstrated that cationically modified PC polymers are capable of delivery of antisense ODNs in a controlled manner and that they are well suited for specific biomedical devices such as DNA-eluting stents.

Animals↗
PubMed2006

Phosphorylcholine-based pH-responsive diblock copolymer micelles as drug delivery vehicles: light scattering, electron microscopy, and fluorescence experiments.

The micellization behavior of a diblock copolymer comprising a highly hydrophilic and biocompatible poly(2-methacryloyloxyethyl phosphorylcholine) (PMPC) corona-forming block and a pH-sensitive poly(2-(diisopropylamino)ethyl methacrylate) (PDPA) core-forming block (PMPC-b-PDPA) has been studied by static and dynamic light scattering (SDLS), transmission electron microscopy (TEM), and potentiometry. Self-assembly of PMPC-b-PDPA copolymers with two different DPA volume fractions (phi(DPA)) leads to narrowly distributed and structurally distinct spherical micelles, as evidenced by their molecular weight (M(w,mic)), aggregation number (N(agg)), hydrodynamic radius (R(H)), corona width (W), and core radius (R(c)). The excellent potential of these pH-responsive micelles as nanosized drug delivery vehicles was illustrated by the encapsulation of dipyridamole (DIP), a model hydrophobic drug that dissolves in acid solutions and becomes insoluble above pH 5.8, which is comparable to the pK(a) of the PDPA block. The influence of micelle structure (namely M(w,mic), N(agg), R(H), W, and R(c)) on drug loading content, drug loading efficiency, partition coefficient, and release kinetics was investigated and confirmed by fluorescence spectroscopy studies. The maximum dipyridamole loadings within PMPC(30)-b-PDPA(30) (R(H) = 14.0 nm; W = 4.8 nm; R(c) = 9.2 nm) and PMPC(30)-b-PDPA(60) (R(H) = 27.1 nm; W = 11.0 nm; R(c) = 16.1 nm) micelles were 7 and 12% w/w(p), respectively. This preferential solubilization of DIP into micelles formed by copolymer chains having longer core-forming blocks (i.e., possessing larger core volumes) reflects the larger partition coefficient (K(V)) of DIP between the aqueous phase and PMPC(30)-b-PDPA(60) micelles (K(V) = 5.7 x 10(4)) compared to PMPC(30)-b-PDPA(30) micelles (K(V) = 1.1 x 10(4)). This enhanced ability of PMPC(30)-b-PDPA(60) aggregates to entrap/stabilize small hydrophobic molecules also produces slower release kinetics. Rapid release can be triggered by lowering the pH to induce micellar dissociation.

Dipyridamole↗
PubMed2006

DC bead: in vitro characterization of a drug-delivery device for transarterial chemoembolization.

PURPOSE: The purpose of this investigation is to present the in vitro characterization and detailed drug-loading procedure for DC Bead, a microsphere product that can be loaded with chemotherapeutic agents for embolization. MATERIALS AND METHODS: DC Bead is an embolic microsphere product that is capable of being loaded with anthracycline drugs such as doxorubicin just before administration in a transarterial chemoembolization (TACE) procedure. Beads can be loaded from solutions prepared from doxorubicin powder or the doxorubicin HCl formulation. In this evaluation, bead sizes were measured by optical microscopy with video imaging. Gravimetric analysis demonstrated the effect of drug loading on bead water content, and its consequent impact on bead compressibility was determined. The subsequent deliverability of the beads was assessed by mixing the beads with contrast medium and saline solution and passing the beads through an appropriately sized microcatheter. A T-cell apparatus was used to monitor the in vitro elution of the drug from the beads over a period of 24 hours in various elution media. RESULTS: DC Bead spheres could be easily loaded with doxorubicin to a recommended level of 25 mg/mL of hydrated beads by immersion of the beads in the drug solution for 10-120 minutes depending on microsphere size. Other commercial embolic microspheres were shown not to load doxorubicin to the same extent or release it in the same fashion and were considered unsuitable for local drug delivery. Maximum theoretic capacity for DC Bead was approximately 45 mg/mL. Increase in doxorubicin loading resulted in a concomitant decrease in water content and consequential increase in bead resistance to compression force. Drug loading also resulted in a decrease in the average size of the beads, which was dependent on bead size and drug dose. This did not impact bead delivery at any drug loading level to a maximum of 37.5 mg/mL. Beads 100-700 microm in size could be delivered through 2.7-F microcatheters, whereas the 700-900-microm range required 3-F catheters. Modeling of the kinetics of drug elution from the beads in vitro at a loading dose of 25 mg/mL yielded calculated half-lives of 150 hours for the 100-300-microm range to a maximum of 1,730 hours for the 700-900-microm size range, which was dependent on the ionic strength of the elution medium. For comparison, there was a rapid loss of drug from an unstable Lipiodol emulsion with a half-life of approximately 1 hour. CONCLUSIONS: DC Bead can be loaded with doxorubicin to provide an accurate dosage of drug per unit volume of beads. Drug elution is dependent on ion exchange with the surrounding environment and is controlled and sustained, unlike the rapid separation of the drug from Lipiodol. Drug loading has no impact on the handling and deliverability of the beads, making them suitable for superselective TACE.

Antibiotics, Antineoplastic↗
PubMed2006

Pharmacokinetic and safety study of doxorubicin-eluting beads in a porcine model of hepatic arterial embolization.

PURPOSE: To present the pathologic and pharmacokinetic findings from hepatic embolization in a porcine model comparing doxorubicin-eluting beads with bland embolization and to correlate these findings with in vitro release kinetics. MATERIALS AND METHODS: Drug-eluting beads (DEB; 100-300 microm and 700-900 microm) loaded with 37.5 mg doxorubicin per milliliter hydrated beads were used to embolize the hepatic artery feeding the left lobe of the liver in young adult Yucatan pigs (n = 5 per group). Control animals underwent embolization with bland beads (100-300 microm; n = 5). Systemic plasma levels of doxorubicin were measured and correlated to in vitro drug release. Blood sampling and histopathologic examination were performed during the 90-day follow-up. RESULTS: All animals underwent successful embolization, and the treatment was well tolerated. Mean volumes of beads administered were 2.0-3.4 mL, with mean doses of 127.5 mg and 78.7 mg of doxorubicin for the 100- to 300-microm and 700- to 900-microm DEB groups, respectively. Gross pathologic examination revealed no effects on organs other than the liver. There was a transient increase in liver enzyme levels, particularly in the groups of animals who underwent embolization with 100- to 300-microm DEB. Histopathologic study showed mostly nonnecrotic changes with bland beads, whereas the effects of DEB were more severe, with large areas of pannecrosis evident with the 100- to 300-microm DEB. Maximum plasma concentrations were 651 ng/mL and 42.8 ng/mL for the 100- to 300-microm and 700- to 900-microm DEB groups, respectively, observed at 1 minute for both groups. Correlation with in vitro data showed a strong linear relationship. CONCLUSIONS: Hepatic arterial embolization with DEB was shown to be safe and well tolerated. The locoregional delivery of doxorubicin from DEB caused targeted tissue damage with minimal systemic impact and could be a promising new approach to transarterial chemoembolization of solid tumors.

Alanine Transaminase↗
PubMed2006

PC Technology as a platform for drug delivery: from combination to conjugation.

Hydrogel polymers incorporating phosphorylcholine have found widespread use in the manufacture of medical devices with improved haemo- and biocompatibility. Examples include soft contact lenses or coatings for devices, such as coronary stents and extracorporeal circuits. The advent of drug-device combinations has prompted the application of PC Technology (Biocompatibles UK Ltd) as a bioinert drug delivery vehicle, particularly in the form of coatings, for targeted delivery from a device surface. The flexible polymer chemistry employed in the synthesis of these materials offers a range of molecular architectures that could find applicability in a wide variety of drug delivery applications, including micellar, vesicular and gel systems, and even drug conjugation.

Coated Materials, Biocompatible↗
PubMed2005

pH-sensitive vesicles based on a biocompatible zwitterionic diblock copolymer.

Highly biocompatible pH-sensitive diblock copolymer vesicles were prepared from the self-assembly of a biocompatible zwitterionic copolymer, poly[2-(methacryloyloxy)ethyl phosphorylcholine-block-2-(diisopropylamino)ethyl methacrylate], PMPC-b-PDPA. Vesicle formation occurred spontaneously by adjusting the solution pH from pH 2 to above 6, with the hydrophobic PDPA chains forming the vesicle walls. Transmission electron microscopy (TEM), dynamic laser light scattering (DLS), and UV-visible absorption spectrophotometry were used to characterize these vesicles. Gold nanoparticle-decorated vesicles were also obtained by treating the vesicles with HAuCl4, followed by NaBH4.

Biocompatible Materials↗
PubMed2005

Investigation into potential mechanisms promoting biocompatibility of polymeric biomaterials containing the phosphorylcholine moiety. A physicochemical and biological study.

Phosphorylcholine (PC) moieties were chemically attached to surfaces of polymer microparticles by addition of 2-methylacryloyloxyethyl phosphorylcholine monomer to the seeded, semi-continuous polymerisations of methyl methacrylate (MMA) and butyl acrylate (BA). The surface of the bio-functionalised polymer microparticles was principally characterised using X-ray photoelectron spectroscopy (XPS), dynamic nuclear magnetic resonance (NMR) spectroscopy, scanning electron microscopy (SEM), photon correlation spectroscopy (PCS), acoustophoresis and enzyme-linked immunosorbent assays (ELISA). It was found that the persulphate initiating species are concealed behind the phosphorylcholine containing monomer sequence located on the surface of the microparticles. The combination of analytical techniques showed that the surfaces of the polymer microparticles are extremely mobile above the glass transition temperature of the co-polymer and able to rearrange depending on the environment in which they are placed. This allows the phosphorylcholine moiety to be preferentially expressed at the surface in aqueous media, but not so in the dry state or conditions of ultra-high vacuum. In terms of the nature of the biocompatibility of phosphorylcholine containing polymers, no evidence was found for the irreversible structuring of water molecules around the phosphorylcholine moiety in the wet state. The results of this work suggest that a more likely contributory reason for the protein-resistant nature of phosphorylcholine containing polymers is the mobility of the phosphorylcholine moiety. Increases in biocompatibility correspond with increases in the hydrophilicity of a polymer surface when phosphorylcholine is preferentially expressed. A large free water fraction may be present in the phosphorylcholine containing monomer sequence, as part of a hydrogel structure located at the surface of the polymer microparticles. This, coupled with concomitant modification of the local electrical double-layer very close to the surface may also play a critical role in reducing protein-surface interactions.

Biocompatible Materials↗
PubMed2005

Synthesis and characterization of biocompatible, thermoresponsive ABC and ABA triblock copolymer gelators.

The synthesis of doubly thermoresponsive PPO-PMPC-PNIPAM triblock copolymer gelators by atom transfer radical polymerization using a PPO-based macroinitiator is described. Provided that the PPO block is sufficiently long, dynamic light scattering and differential scanning calorimetry studies confirm the presence of two separate thermal transitions corresponding to micellization and gelation, as expected. However, these ABC-type triblock copolymers proved to be rather inefficient gelators: free-standing gels at 37 degrees C required a triblock copolymer concentration of around 20 wt%. This gelator performance should be compared with copolymer concentrations of 6-7 wt% required for the PNIPAM-PMPC-PNIPAM triblock copolymers reported previously. Clearly, the separation of micellar self-assembly from gel network formation does not lead to enhanced gelator efficiencies, at least for this particular system. Nevertheless, there are some features of interest in the present study. In particular, close inspection of the viscosity vs temperature plot obtained for a PPO43-PMPC160-PNIPAM81 triblock copolymer revealed a local minimum in viscosity. This is consistent with intramicelle collapse of the outer PNIPAM blocks prior to the development of the intermicelle hydrophobic interactions that are a prerequisite for macroscopic gelation.

Acrylic Resins↗
PubMed2005

Biomimetic stimulus-responsive star diblock gelators.

Novel biomimetic gelators with star diblock copolymer architectures have been synthesized by atom-transfer radical polymerization (ATRP). Two types of trifunctional ATRP initiator were used to polymerize 2-(methacryloyloxy)ethyl phosphorylcholine [MPC] at 20 degrees C, followed by sequential monomer addition of various tertiary amine methacrylates or mixtures thereof. Poor living character was achieved using an amide-based trifunctional initiator, but the analogous triester initiator gave reasonably well-defined thermo-responsive and pH-responsive star diblock copolymers. The most effective thermo-responsive gelators were obtained by the statistical terpolymerization of 2-(dimethylamino)ethyl methacrylate [DMA], 2-(diethylamino)ethyl methacrylate [DEA], and a monomethoxy-capped poly(propylene oxide) methacrylate [PPOMA], whereas pH-responsive gelators were prepared using 2-(diisopropylamino)ethyl methacrylate [DPA] as the second monomer. Star diblock copolymer gelators that were both thermo-responsive and pH-responsive were obtained by the statistical copolymerization of DMA with DPA. Copolymer compositions were assessed by 1H NMR spectroscopy, and the molecular weight distributions of the three-arm star MPC homopolymer precursors were assessed by aqueous gel permeation chromatography. Static light scattering was used to obtain weight-average molecular weights of selected star diblock copolymers and rheological measurements and variable-temperature 1H NMR were used to probe the onset of gelation.

Biomimetics↗
PubMed2005

Solution pH-regulated interfacial adsorption of diblock phosphorylcholine copolymers.

Spectroscopic ellipsometry has been used to examine the pH-responsive interfacial adsorption of a series of biocompatible diblock copolymers incorporating 2-methacryloyloxyethyl phosphorylcholine-based (MPC) residues and 2-(dialkylamino)ethyl methacrylate residues, with a specific focus on 2-(diethylamino)ethyl groups (referred to as MPCm-DEAn, where m and n refer to the mean degrees of polymerization of each block) at the hydrophilic silicon oxide/water interface. For all the copolymers studied the surface excess shows only weak concentration dependence. Increasing the length of the DEA block has little effect on the dynamic or equilibrated adsorption at pH 7, indicating that the DEA block adopts a flat conformation on the silicon oxide surface at this pH. With increasing pH, however, the surface excess shows a dramatic increase, followed by a subsequent decline. The observed maximum in surface excess represents a balance between charge over-compensation of the copolymer with the oppositely charged surface and the subsequently reduced charge density of the copolymer. Variations in the observed maxima for various MPCm-DEAn diblock copolymers indicate different surface conformations at high pH. Salt addition does not affect copolymer adsorption. This behavior is attractive for biomedical applications in which the ionic strength is variable. It was also found that the preadsorbed diblock copolymers immobilized DNA from solution to an extent that is proportional to the relative charge ratio between the anionic DNA and the cationic DEA block of the copolymer.

Adsorption↗
PubMed2005

Phosphorylcholine is favorable for antibody production from hybridoma cells.

Growth of antibody-secreting hybridomas requires special conditions such as serum-free defined media containing growth factors and vitamins. However, the surface on which these cells can proliferate has been shown to play an important role. Phosphorylcholine (PC)-based polymers are zwitterionic compounds with nonbiofouling properties. These polymers are characterized by having reduced protein absorption properties. Our aim was to determine whether well-established hybridoma cell lines were able to proliferate and produce measurable amounts of monoclonal antibodies when grown on PC-polymer-coated surfaces. Comparative experiments using four well-known hybridoma cell lines (PAb421, PAb246, PAb1801 which recognize p53, and PAb280 which recognizes SV40 small t antigen) grown on PC-polymer-coated, uncoated, and two commercially available tissue culture plates showed that PC-polymer-coated plates were more efficient than uncoated plates in sustaining cell growth and monoclonal antibody production/secretion as defined by growth assays and ELISA. Also, results demonstrated that PC-polymer-coated plates were able to perform better than commercially available plates. These observations suggest that PC polymers could be used as an alternative, efficient surface coating to grow hybridoma cell lines and allow detectable antibody secretion.

Antibodies, Monoclonal↗
PubMed2005

Novel biocompatible phosphorylcholine-based self-assembled nanoparticles for drug delivery.

Major challenges associated with nano-sized drug delivery systems include removal from systemic circulation by phagocytic cells and controlling appropriate drug release at target sites. 2-methacryloyloxyethyl phosphorylcholine (MPC) has been copolymerised in turn with two pH responsive comonomers (2-(diethylamino)ethyl methacrylate (DEA) and 2-(diisopropylamino)ethyl methacrylate (DPA), to develop novel biocompatible drug delivery vehicles. Micelles were prepared from a series of copolymers with varying block compositions and their colloidal stability and dimensions were assessed over a range of solution pH using photon correlation spectroscopy. The drug loading capacities of these micelles were evaluated using Orange OT dye as a model compound. The cytotoxicity of the micelles was assessed using an in vitro assay. The MPC-DEA diblock copolymers formed micelles at around pH 8 and longer DEA block lengths allowed higher drug loadings. However, these micelles were not stable at physiological pH. In contrast, MPC-DPA diblock copolymers formed micelles of circa 30 nm diameter at physiological pH. In vitro assays indicated that these MPC-DPA diblock copolymers had negligible cytotoxicities. Thus novel non-toxic biocompatible micelles of appropriate size and good colloidal stability with pH-modulated drug uptake and release can be readily produced using MPC-DPA diblock copolymers.

Biocompatible Materials↗
PubMed2004

Biomimetic thermo-responsive star diblock gelators.

We report the synthesis of novel biomimetic gelators with star diblock copolymer architectures by sequential monomer addition via alcoholic ATRP at 20 degrees C; free-standing gels can be formed from 5% aqueous copolymer solutions at 37 degrees C.

Journal Article↗