Biodegradable recombinant human erythropoietin loaded microspheres prepared from linear and star-branched block copolymers: influence of encapsulation technique and polymer composition on particle characteristics.

Recombinant human erythropoietin (EPO) and fluorescein isothiocyanate labeled dextran (FITC-dextran) loaded microspheres were prepared by a modified W/O/W double-emulsion technique. Biodegradable linear ABA block copolymers consisting of poly(L-lactide-co-glycolide) A blocks attached to central poly(ethyleneoxide) (PEO) B blocks and star-branched AB block copolymers containing A blocks of poly(L-lactide) or poly(L-lactide-co-glycolide) and star-branched poly(ethyleneoxide) B blocks were investigated for their potential as sustained release drug delivery systems. Microsphere characteristics were strongly influenced by the polymer composition. In the case of the linear block copolymers, a reduced lactic acid content in a linear block copolymer yielded smaller particles, a lower encapsulation efficiency, and a higher initial drug release both in the case of EPO and FITC-dextran. The investigation of the effects of several manufacturing parameters on microsphere formation showed that the process temperature plays an important role. Microsphere formation in a +1 degrees C environment resulted in higher drug loadings without increasing the amount of residual dichloromethane inside the particles. Other parameters such as the homogenization of the primary W/O emulsion and of the W/O/W double-emulsion have less impact on microsphere characteristics. Branched block copolymers containing star-shaped PEO also showed potential for the preparation of drug loaded microspheres. A certain amount of glycolic acid in the copolymer was necessary for the successful preparation of non-aggregating microspheres at room temperature. Again, the processing temperature strongly affected particle characteristics. Microsphere preparation at +1 degrees C allows the formation of microspheres from a polymer not containing glycolic acid, a result which could not be achieved at room temperature. Moreover, compared to microsphere formation at room temperature, the effective FITC-dextran loading was increased. Concerning the EPO loaded microspheres, the amount of EPO aggregated was comparable to that using the linear ABA polymers. A continuous release of the protein from these star-shaped polymers could not be achieved. In conclusion, apart from microsphere preparation in a +1 degrees C environment the choice of the polymer represents the main factor for a successful entrapment of proteins into biodegradable microspheres.     

Branched biodegradable polyesters for parenteral drug delivery systems.

Continuous, 'infusion-like' drug release profiles from biodegradable parenteral delivery systems are difficult to achieve for proteins and other hydrophilic macromolecular drugs with commonly used linear polyesters from lactic acid (PLA) and its random copolymers with glycolic acid (PLG). Drug release rates can be modified either by increasing the hydrophilicity of polyesters or by manipulating the polymer architecture to adjust polymer degradation rates and thus drug release. Therefore, we investigated different branching concepts for biodegradable polyesters of PLA and PLG. For one four- and eight-arm poly(ethylene oxide)s (PEO) were grafted with shorter polyester chains leading to star-branched structures. Secondly we obtained comb-like polyesters using both charged and uncharged dextrans or poly(vinyl alcohol)s (PVA) as hydrophilic backbones. The star-shaped and brush-like grafted polymers were intensively characterized by methods, such as NMR, IR, SEC-SLS, DSC and viscosity measurements. Tailor-made properties make these novel biodegradable polyesters promising candidates for parenteral protein delivery systems. While the star-branched polyesters have shown some interesting properties with respect to their degradation behavior, retaining the PEO blocks longer than ABA triblock copolymers, their release properties need further optimization. Brush-like branched polyesters on the other hand seem to possess both degradation and release properties meriting further investigations for parenteral protein delivery systems.     

New biodegradable polymers for injectable drug delivery systems.

Many biodegradable polymers were used for drug delivery and some are successful for human application. There remains fabrication problems, such as difficult processability and limited organic solvent and irreproducible drug release kinetics. New star-shaped block copolymers, of which the typical molecular architecture is presented, results from their distinct solution properties, thermal properties and morphology. Their unique physical properties are due to the three-dimensional, hyperbranched molecular architecture and influence microsphere fabrication, drug release and degradation profiles. We recently synthesized thermosensitive biodegradable hydrogel consisting of polyethylene oxide and poly(L-lactic acid). Aqueous solution of these copolymers with proper combination of molecular weights exhibit temperature-dependent reversible sol-gel transition. Desired molecular arrangements provide unique behavior that sol (at low temperature) form gel (at body temperature). The use of these two biodegradable polymers have great advantages for sustained injectable drug delivery systems. The formulation is simple, which is totally free of organic solvent. In sol or aqueous solution state of this polymer solubilized hydrophobic drugs prior to form gel matrix.     

Hydrotropic polymer micelle system for delivery of paclitaxel.

Hydrotropic polymer micelle system has been developed for delivery of poorly water-soluble drugs such as paclitaxel. Hydrotropic polymers based on N,N-diethylnicotinamide were synthesized and used as a hydrophobic block for constructing amphiphilic block copolymers. The hydrotropic block copolymers self-assembled to form micelles in aqueous media. The size of the prepared polymer micelles was in the range of 30-50 nm, and increased to 100-120 nm after paclitaxel loading. The critical micelle concentrations (CMCs) of the block copolymers were higher by an order of magnitude than those of other typical polymer micelles, due to less hydrophobicity of the hydrotropic blocks. The drug loading capacity and physical stability of the polymer micelles were characterized and compared with those of other polymer micelles. The hydrotropic polymer micelles containing hydrotrope-rich cores showed not only higher loading capacity but also enhanced physical stability in aqueous media. They could be redissolved in aqueous media by simple vortexing and/or a mild heating. The hydrotropic polymer micelles provide an alternative approach for formulation of poorly soluble drugs.     

Folate-conjugated methoxy poly(ethylene glycol)/poly(epsilon-caprolactone) amphiphilic block copolymeric micelles for tumor-targeted drug delivery.

Amphiphilic block copolymers composed of methoxy poly(ethylene glycol) (MPEG) and poly(epsilon-caprolactone) (PCL) were synthesized and then conjugated with folic acid to produce a folate-receptor-targeted drug carrier for tumor-specific drug delivery. Folate-conjugated MPEG/PCL micelles containing the anticancer drug paclitaxel were prepared by micelle formation in aqueous medium. The size of the folate-conjugated MPEG/PCL micelles formed was about 50-130 nm, depending on the molecular weight of block copolymers, and was maintained at less than 150 nm even after loading with paclitaxel. The in vitro release profile of the paclitaxel from the MPEG/PCL micelles exhibited no initial burst release and showed sustained release. Paclitaxel-loaded folate-conjugated MPEG/PCL micelles (PFOL50) exhibited much higher cytotoxicity for cancer cells, such as MCF-7 and HeLa cells, than MPEG/PCL micelles without the folate group (PMEP50). Confocal image analysis revealed that fluorescent paclitaxel-loaded PFOL50 micelles were endocytosed into MCF-7 cells through the interaction with overexpressed folate receptors on the surface of the cancer cells.     

Effects of ethylene glycol-based graft, star-shaped, and dendritic polymers on solubilization and controlled release of paclitaxel.

New methods and pharmaceutical compositions were developed to increase the aqueous solubility of paclitaxel (PTX), a poorly water-soluble drug. Graft and star-shaped graft polymers consisting of poly(ethylene glycol) (PEG400) graft chains increased the PTX solubility in water by three orders of magnitude. Polyglycerol dendrimers (dendriPGs) dissolved in water at high concentrations without significantly increasing the viscosity and, at 80 wt.%, were found to increase the solubility of PTX 10,000-fold. The solubilized PTX was released from graft polymers, star-shaped graft polymers, and the dendriPGs into the surrounding aqueous solution. The release rate was a function of the star shape and the dendrimer generation. The availability of the new graft, star and dendritic polymers having ethylene glycol units should permit development of novel delivery systems for other poorly water-soluble drugs.     

Polymeric micelles of poly(2-ethyl-2-oxazoline)-block-poly(epsilon-caprolactone) copolymer as a carrier for paclitaxel.

Polymeric micelles based on amphiphilic block copolymers of poly(2-ethyl-2-oxazoline) (PEtOz) and poly(epsilon -caprolactone) (PCL) were prepared in an aqueous phase. The loading of paclitaxel into PEtOz-PCL micelles was confirmed by 1H-NMR spectra. Paclitaxel was efficiently loaded into PEtOz-PCL micelles using dialysis method, and the loading content of paclitaxel in micelles was in the range 0.5-7.6 wt.% depending on the block composition of block copolymers, organic solvent used in the dialysis, and feed weight ratio of paclitaxel to block copolymer. The higher the content of hydrophobic block in the block copolymers, the higher the loading efficiency of micelles for paclitaxel. When acetonitrile was used as solvent, a higher drug loading efficiency was obtained than with THF. The loading efficiency decreased with increasing feed weight ratio of paclitaxel to block copolymer from 0.1:1 to 0.2:1. The hydrodynamic diameters of paclitaxel-loaded micelles were in the range 18.3-23.4 nm with narrow size distribution. The hemolysis test of PEtOz-PCL performed in vitro indicated that the toxicity of PEtOz-PCLs to lipid membrane was not significant compared with Tween 80, and was comparable to that observed with Cremophore EL. The proliferation inhibition activity of paclitaxel-loaded micelles for KB human epidermoid carcinoma cells was also evaluated in vitro. Paclitaxel-entrapped polymeric micelles exhibited comparable activity to that observed with Cremophore EL-based paclitaxel formulations in inhibiting the growth of KB cells.     

Novel pH-sensitive supramolecular assemblies for oral delivery of poorly water soluble drugs: preparation and characterization.

The objective of the present study was to synthesize novel pH-sensitive block copolymers forming supramolecular assemblies and to explore their potential as poorly water-soluble drug carriers for oral delivery. Diblock copolymers of polyethylene glycol and t-butyl methacrylate (tBMA), ethyl acrylate (EA) or n-butyl acrylate (nBA) were synthesized by atom transfer radical polymerization (ATRP). The pH-sensitive polymers obtained by hydrolysis of t-butyl groups were characterized for aggregation behaviour. Poorly water-soluble model drugs, i.e., indomethacin (IND), fenofibrate (FNB) and progesterone (PRG), were incorporated in supramolecular assemblies by dialysis or oil-in-water (O/W) emulsion methods. Process parameters for emulsion method were studied to maximize drug loading. Progesterone release was evaluated in vitro as a function of pH. Polymers with controlled molecular weights and low polydispersities were obtained by ATRP. All polymers exhibited pH-dependent aggregation behaviour and their critical aggregation concentration (CAC) decreased with increase in the hydrophobic block length. Drug loadings of <6% and 6-14% w/w were achieved by the dialysis and emulsion methods, respectively. Polymer composition, drug concentration and solubilization of polymer in water or dichloromethane (DCM) affected the loading. Progesterone release from supramolecular assemblies increased when the pH of the release medium was raised from 1.2 to 7.2. The results suggest that these supramolecular assemblies with high drug loadings and pH-dependent release kinetics can potentially enhance the oral bioavailability of poorly water-soluble drugs.     

Novel drug release profiles from micellar solutions of PLA-PEO-PLA triblock copolymers.

We have achieved nearly zero order sustained release behavior for periods up to 10-20 days for two hydrophobic drugs, sulindac and tetracaine, from 5wt.% micellar solutions of poly(lactide)-poly(ethylene oxide)-poly(lactide) (PLA-PEO-PLA) triblock copolymer. The effect of PLA block length and crystallinity on the drug release profiles was studied. A series of polymers with constant PEO molecular weight of 8900Da and PLA molecular weight varying in the range of 4100-6500Da were examined. Drug release was found to be much faster for polymers with crystalline PLA blocks as compared to those with amorphous PLA blocks. The drug release rate also depends significantly on the length of the PLA block. Sustained release of sulindac was observed up to 20 days, and for tetracaine up to 10 days. By comparison, release of these drugs without polymeric carriers occurs over 4-6h. This result, along with a proposed mechanism for drug release, suggests that polymer-drug interactions significantly impact release profiles, causing slow and sustained release of the drug.     

核交联聚(N-异丙基丙烯酰胺-co-N,N-二甲基丙酰胺)-b-聚己内酯胶束及紫杉醇的温敏控制释放行为

背景:高分子纳米胶束是近几年正在发展的一类新型药物载体,其载药范围广、结构稳定、具有优良的组织渗透性,体内滞留时间长,能使药物有效地到达靶点.而使其带有智能靶向性以及减弱其初期爆发释放行为成为了最近研究的热点.目的:得到一种低临界溶液浓度在40℃左右的智能靶向药物载体,可以通过对温度的改变而改变其药物释放行为,并进一步通过核交联改善胶束的稳定性以及其药物释放行为.方法:通过N-异丙基丙烯酰胺(NIPAAm)和N,N-二甲基丙烯酰胺(DMAAm)的自由基共聚,合成端羟基聚(N-异丙基丙烯酰胺-co-N,N-二甲基丙烯酰胺)(P(NIPAAm-co-DMAAm)).通过调节巯基乙醇和单体的比例,以及NIPAA m和DMAAm的比例,调节P(NIPAAm-co-DMAAm)的相对分子质量和低临界溶液温度.然后在异辛酸亚锡的催化下,利用P(NIPAAm-co-DMAAm)端羟基引发己内酯开环聚合,得到端羟基P(NIPAAm-co-DMAA m)-b-PCL两亲性嵌段共聚物.该嵌段共聚物再与丙烯酰氯反应得到末端带有不饱和双键的两亲性嵌段共聚物.用透析法制备具有不同核交联程度的纳米载药胶束,并对其释放行为进行研究.结果与结论:得到了温敏段相对分子质量为3 600、PCL段相对分子质量为1600的两亲性嵌段共聚物,其低临界溶液浓度为42℃.采用不同比例端羟基和端羧基P(NIPAAm-co-DMAAm)-b-PCL混合,制备得到具有不同核交联程度的温敏性纳米载药胶束.胶束的药物释放速度在43℃快于37℃,随着核交联程度的增高,紫杉醇的释放速度变慢.结果提示以低临界溶液浓度在40℃左右的温敏性P(NIPAAm-co-DMAAm)-b-PCL所制备的胶束,具有一定的温敏控制释放行为,药物释放速度可进一步通过核交联程度来控制.     

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.     

Incorporation and release behavior of hydrophobic drug in functionalized poly(D,L-lactide)-block-poly(ethylene oxide) micelles.

The poly(ethylene oxide)-poly(lactide) (PEO-PLA) block copolymers containing a small quantity of carboxylic acid in the PLA block were synthesized. The microscopic characteristics of nanoparticles with carboxylic acid content in the copolymer were analyzed, and the effect of specific interactions between the copolymer and the model drug on the drug loading capacity and the release behavior were investigated systematically. The sizes of nanoparticles prepared by a dialysis method are within the range of 30-40 nm. The nanoparticles prepared from functionalized block copolymers have a very low critical micelle concentration (CMC) value as low as approximately 10(-3) mg/ml, which indicates a good stability of the nanoparticles in spite of the presence of carboxylic acid. The drug loading efficiency of nanoparticles dramatically increased when carboxylic acid content was increased in the block copolymer. This result may be attributed to the increase of interactions between the copolymer and the drug. The release rate of the drug was much slower from nanoparticles containing higher amounts of carboxylic acid in the copolymer, which might be associated with the enhanced interaction between the carboxylic group of copolymers and the drug. These experimental results suggest that the nanoparticles prepared from functionalized PEO-PLA block copolymers could be a good candidate for an injectable drug delivery carrier.     

Effect of PEG conformation and particle size on the cellular uptake efficiency of nanoparticles with the HepG2 cells.

Core-shell nanoparticles were prepared from di-block copolymer of methoxy poly(ethylene glycol)-polycaprolactone (MePEG-PCL) and tri-block copolymer of polycaprolactone-poly(ethylene glycol)-polycaprolactone (PCL-PEG-PCL). The MePEG-PCL copolymers form nanoparticles with PEG "brush" on their surfaces and PCL-PEG-PCL copolymers form nanoparticles with a "mushroom-like" structure on their surfaces in aqueous solution. The morphology and size of nanoparticles were measured by field emission scanning electron microscopy (FESEM) and laser light scattering (LLS). All the nanoparticles are in spherical shape and the sizes are less than 200 nm. The sizes of the nanoparticles increases with increasing PCL segment length. The drug-loading content results showed that the optimal feeding ratio of paclitaxel to copolymer is dependent upon the copolymer composition and 5% is a suitable feeding ratio. The in vitro release behavior exhibits a sustained release manner and is affected by copolymer composition. Experimental results showed that cells would prefer to attach to more hydrophobic polymers. Comparing between MePEG-PCL and PCL-PEG-PCL of similar hydrophobicity, more HepG2 cells have attached to the MePEG-PCL copolymer films because a denser PEG layer was formed on the surfaces of PCL-PEG-PCL copolymers. In vitro cellular uptake experimental results indicated that HepG2 cells prefer smaller nanoparticles with the same PEG configuration on their surfaces. The cytotoxicity of paclitaxel-loaded nanoparticles seemed to increase with increasing drug loading of nanoparticles against HepG2 cells.     

Pyrimethamine sustained release systems based on bioresorbable polyesters for chemoprophylaxis of rodent malaria

Pyrimethamine-containing microspheres and implants were prepared, from various bioresorbable polymers and copolymers derived from lactic acid enantiomers and from glycolic acid. Release patterns of the temporarily entrapped drug were examined in vitro for the various systems. The efficacy of these polymer-drug systems against Plasmodium berghei was also investigated using mouse as the model animal. Both in vitro sustained release and therapeutic efficacy depend on the drug content, the respective amounts of l- and d-repeating units in lactic acid stereocopolymers and the composition in lactic and glycolic repeating units in lactic/glycolic copolymers. For some of the pyrimethamine-containing implants, protection over a period as long as 6 months has been observed which is consistent with long-term chemoprophylaxis of rodent malaria.     

Molecular design of biodegradable polymeric micelles for temperature-responsive drug release.

We designed thermo-responsive and biodegradable polymeric micelles for an ideal drug delivery system whose target sites are where external stimuli selectively release drugs from the polymeric micelles. The thermo-responsive micelles formed from block copolymers that were composed both of a hydrophobic block and a thermo-responsive block. Poly(N-isopropylacrylamide-co-N,N-dimethylacrylamide) showing a lower critical solution temperature (LCST) around 40 degrees C was synthesized for the thermo-responsive block, while biodegradable poly(D,L-lactide), poly(epsilon-caprolactone), or poly(D,L-lactide-co-epsilon-caprolactone) was used for the hydrophobic block. By changing both the block lengths of the poly(D,L-lactide)-containing block copolymers, physical parameters such as micelle diameter and critical micelle concentration were varied. On the other hand, the choice of the hydrophobic block was revealed to be critical in relation to both on the thermo-responsive release of the incorporated anti-cancer drug, doxorubicin, and the temperature-dependent change of the hydrophobicity of the micelles' inner core. One polymeric micelle composition successfully exhibited rapid and thermo-responsive drug release while possessing a biodegradable character.     

Synthesis and characterization of 4-arm star-shaped amphiphilic block copolymers consisting of poly(ethylene oxide) and poly(ε-caprolactone)

Star-shaped polymers exhibit lower hydrodynamic volume, glass transition temperature, critical micelles concentration (CMC), and higher viscosity and drug-loading capacity compared to their linear counterparts. In the present study, amphiphilic biodegradable 4-arm star-shaped block copolymers, based on poly(ethylene oxide) (PEO) as a hydrophilic part and poly(ε-caprolactone) (PCL) as a hydrophobic segment, are synthesized by ring-opening polymerization of ε-caprolactone employing pentaerythritol as an initiator and stannous octoate as a catalyst, followed by the coupling reaction with carboxyl-functionalized monomethoxy poly(ethylene oxide) (MeO-PEO-COOH). The structures of intermediates were deduced through ¹H-NMR and FT-IR spectroscopy. Average chemical composition of the star block copolymer is determined by proton NMR. Information related to molar mass distribution of targeted products and their precursors is obtained by size exclusion chromatography (SEC). However, due to its inherent poor resolution SEC could not reveal whether all the parent homopolymers are coupled to each other or remained unattached to the other segment. In order to comprehensively characterize the synthesized star-block copolymers, liquid chromatography at critical conditions of both blocks is employed. The study allowed for separation of homopolymer precursors from targeted star-block copolymers. The study exposed heterogeneity of star block copolymers that was not possible by conventional techniques.

LCCC on RP columns proves to be efficient for separation of precursors from targeted star block copolymers in a single run.     

Novel reduction-sensitive micelles for triggered intracellular drug release

Novel reduction-sensitive micelles based on poly(ethylene oxide)-b-poly(N-methacryloyl-N′-(t-butyloxycarbonyl)cystamine) (PEO-b-PMABC) diblock copolymers were developed and applied for triggered intracellular drug release. PEO-b-PMABC block copolymers were synthesized by reversible addition-fragmentation chain transfer (RAFT) polymerization of MABC with dithioester-capped PEO as macroRAFT agent. Gel permeation chromatography (GPC) and ¹H NMR analysis showed that the copolymers have controlled compositions and molecular weights, indicating the living nature of polymerization. These copolymers were self-assembled into micelles. The physicochemical characteristics and reduction-sensitivity of the resultant micelles were investigated by fluorescence measurement, transmission electron microscopy (TEM), and dynamic light scattering (DLS). The results showed that PEO-b-PMABC micelles are stable at normal physiologic condition but readily cleaved into free copolymers under reducing environment. In vitro release of doxorubicin (DOX) and cell experiments showed that the drug-loaded PEO-b-PMABC micelles accomplished much faster drug release under reducing condition and higher anticancer efficacy as compared to the control without reduction-sensitivity, indicating great potential of PEO-b-PMABC micelles for efficient intracellular drug delivery.     

Novel biomimetic polymersomes as polymer therapeutics for drug delivery.

Novel amphiphilic diblock copolymers, cholesterol-end-capped poly(2-methacryloyloxyethyl phosphorylcholine) (CMPC), which have poly(2-methacryloyloxyethyl phosphorylcholine) (poly(MPC)) as hydrophilic segment and cholesterol as hydrophobic segment, was specially designed as drug delivery systems. Fluorescence probe technique and transmission electron microscope (TEM) characterizations indicated that this novel amphiphilic copolymer formed micelles structure in water and the critical micelle concentration (CMC) was determined to be 1.57 x 10(-7) mol/l. A commercial obtained polymeric amphiphiles, Cholesterol end capped PEO (CPEO), which had a similar structure with CMPC, was used as a control in the cytotoxicity test. While CPEO showed obvious cytotoxicity, cytotoxicity of this novel amphiphiles was not observed as indicated by cell culture. Anti-cancer drug adriamycin (ADR) was incorporated into the micelles by oil-in-water method. The size of the drug-containing micelles was less than 200 nm, and the size distribution of the drug-containing micelles showed a narrow and monodisperse unimodal pattern. The release rate of ADR from the nanosphere was slow and the release continued over 7 days and the release rate decreased with the increase of molecular weights of the copolymer and the amount of the drug entrapped. These experimental results suggested that the nanoparticles prepared from CMPC block copolymers could be a good candidate for injectable drug delivery carrier.     

New derivatives of polyglutamic acid as drug carrier systems.

PEG-grafted dextran and PHEG derivatives were synthetized to be used as drug carriers. The PEG-containing copolymers showed potential tensioactive properties. Dynamic light-scattering measurements and surface tension measurements indicated that phase separation of dextran/PHEG and PEG occurs on a molecular level in the conjugates and results in the formation of aggregates with a PEG core in which free PEG can be trapped. Blood clearance and body distribution studies were performed on female BALB/c mice. PEG-modified polymers with a high hydrodynamic volume stay longer in the blood stream compared with the non-modified polymers. These high molecular weight conjugates stay in the blood for several hours. Conjugates with a molecular weight below the renal threshold barrier are cleared much faster from the blood and excreted from the body. Concerning the body distribution, the PEG conjugates are not excreted very fast and are not taken up by any organ in particular. It is notable that PEG substitution prevents dextran from liver uptake. Furthermore, a method was developed to link an oligopeptide spacer-drug model and PEG to the same polymer. It was shown that PEG substitution has only little influence on the enzymatic release of the model drug. The above-mentioned results showed that the PEG-grafted polymers were promising candidates for drug carriers.     

Release profiles in drug-eluting stents: Issues and uncertainties

This review presents the current data on drug release from drug-eluting stents and the effects of the release profiles on animal and human data for coronary stenosis. Data for the two most important drugs, sirolimus (rapamycin) and paclitaxel, are presented, the polymers used are described and the observed release profiles are discussed for various polymer carriers. The current literature on the tissue compatibility of the polymers commonly used in drug-eluting stents is also discussed.

The range of release rates from stents studied to date is limited for sirolimus, but somewhat broader for paclitaxel. Animal and human data comparing the different release profiles are limited to about 6 months for animals and 2–4 years for humans. From the data available, it appears that for both sirolimus and paclitaxel, a slow-releasing drug-eluting stent leads to slightly more favorable angiographic outcomes than more rapid release.

Most of the complications arising from the use of drug-eluting stents are attributed to incomplete healing; one possible clinical consequence of this delay in healing is that anti-platelet therapy needs to be maintained over a much longer period than is the case for bare metal stents.