Evasion of the accelerated blood clearance phenomenon by coating of nanoparticles with various hydrophilic polymers.

The accelerated blood clearance (ABC) phenomenon is induced upon repeated injections of poly(ethylene glycol) (PEG)-coated colloidal carriers. It is essential to suppress this phenomenon in a clinical setting because the pharmacokinetics must be reproducible. In this study, we evaluated the induction of the ABC phenomenon using nanoparticles coated with various hydrophilic polymers instead of PEG. Nanoparticles encapsulating prostaglandin E1 were prepared by the solvent diffusion method from a blend of poly(lactic acid) (PLA) and block copolymers consisting of various hydrophilic polymers and PLA. Coating of nanoparticles with poly(N-vinyl-2-pyrrolidone) (PVP), poly(4-acryloylmorpholine), or poly(N,N-dimethylacrylamide) led to extended residence of the nanoparticles in blood circulation in rats, although they had a shorter half-life than the PEG-coated nanoparticles. The ABC phenomenon was not induced upon repeated injection of PVP-coated nanoparticles at various time intervals, dosages, or frequencies, whereas it was elicited by PEG-coated nanoparticles. In addition, anti-PVP IgM antibody, which is estimated to be one of the crucial factors for induction of the ABC phenomenon, was not produced after injection of PVP-coated nanoparticles. These results suggest that the use of PVP, instead of PEG, as a coating material for colloidal carriers can evade the ABC phenomenon.

Treatment of experimental arthritis with stealth-type polymeric nanoparticles encapsulating betamethasone phosphate.

We examined the therapeutic activity of betamethasone disodium 21-phosphate (BP) encapsulated in biocompatible and biodegradable blended nanoparticles of poly (D,L-lactic/glycolic acid) (PLGA)/poly(D,L-lactic acid) (PLA) homopolymers and polyethylene glycol (PEG)-block-PLGA/PLA copolymers (stealth nanosteroid) in experimental arthritis models. Various stealth nanosteroids with a size of 45 to 115 nm were prepared and then intravenously administered to rats with adjuvant arthritis (AA) rats and mice with anti-type II collagen antibody-induced arthritis (AbIA). The accumulation of stealth nanoparticles with Cy7 in inflamed joints was determined using an in vivo imaging system. The type A stealth nanosteroid, composed of PLA (2.6 kDa) and PEG (5 kDa)-PLA (3 kDa), with a PEG content of 10% and a diameter of 115 nm, exhibited the highest anti-inflammatory activity. In AA rats, a 35% decrease in paw inflammation was obtained in 1 day and maintained for 9 days with a single injection of the type A stealth nanosteroid (40 microg of BP), whereas the same does of nonstealth nanosteroid and 3 times higher free BP showed a significantly weaker response. In AbIA mice, a single injection of the type A stealth nanosteroid (3 microg of BP) resulted in complete remission of the inflammatory response after 1 week. Furthermore, in AbAI mice, the accumulation of type A stealth nanoparticles in inflamed joints was shown to parallel the severity of inflammation. The observed strong therapeutic benefit obtained with the type A stealth nanosteroid in experimental arthritis may have been due to prolonged blood circulation and targeting to the inflamed joint in addition to its sustained release in situ.

Effect of betamethasone phosphate loaded polymeric nanoparticles on a murine asthma model.

Although inhaled steroids are the treatment of first choice to control asthma, administration of systemic steroids is required for treatment of asthmatic exacerbation and intractable asthma. To improve efficacy and reduce side effects, we examine the effects of betamethasone disodium phosphate (BP) encapsulated in biocompatible, biodegradable blended nanoparticles (stealth nanosteroids) on a murine model of asthma. These stealth nanosteroids were found to accumulate at the site of airway inflammation and exhibit anti-inflammatory activity. Significant decreases in BALF eosinophil number were maintained for 7 days with a single injection of nanosteroids containing 40 microg BP. Airway responsiveness was also attenuated by the injection of stealth nanosteroids. A single injection of 40 microg of free BP and 8 microg of free BP once daily for 5 days did not show any significant effects. We conclude that stealth nanosteroids achieve prolonged and higher benefits at the site of airway inflammation compared to free steroids.

Synthesis of prostaglandin E(1) phosphate derivatives and their encapsulation in biodegradable nanoparticles.

PURPOSE: Prostaglandin E(1) (PGE(1)) is an effective treatment for peripheral vascular diseases. The encapsulation of PGE(1) in nanoparticles for its sustained-release would improve its therapeutic effect and quality of life (QOL) of patients. METHODS: In order to encapsulate PGE(1) in nanoparticles prepared with a poly(lactide) homopolymer (PLA) and monomethoxy poly(ethyleneglycol)-PLA block copolymer (PEG-PLA), we synthesized a series of PGE(1) phosphate derivatives and tested their efficacy. RESULTS: Among them, PGE(1) 2-(phosphonooxy)ethyl ester sodium salt (C2) showed the most efficient hydrolysis to yield PGE(1) in human serum. An in vitro platelet aggregation assay showed that C2 inhibited aggregation only after pre-incubation in serum, suggesting that C2 is a prodrug of PGE(1). In vivo, intravenous administration of C2 caused increase in cutaneous blood flow. In the presence of zinc ions, all of the synthesized PGE(1) phosphate derivatives could be encapsulated in PLA-nanoparticles. Use of L-PLA instead of D,L-PLA, and high molecular weight PLA resulted in a slower release of C2 from the nanoparticles. CONCLUSIONS: We consider that C2-encapsulated nanoparticles prepared with L-PLA and PEG-D,L-PLA have good sustained-release profile of PGE(1), which is useful clinically.

Accelerated blood clearance phenomenon upon repeated injection of PEG-modified PLA-nanoparticles.

PURPOSE: We recently developed prostaglandin E(1) (PGE(1))-encapsulated nanoparticles, prepared with a poly(lactide) homopolymer (PLA, Mw = 17,500) and monomethoxy poly(ethyleneglycol)-PLA block copolymer (PEG-PLA) (NP-L20). In this study, we tested whether the accelerated blood clearance (ABC) phenomenon is observed with NP-L20 and other PEG-modified PLA-nanoparticles in rats. METHODS: The plasma levels of PGE(1) and anti-PEG IgM antibody were determined by EIA and ELISA, respectively. RESULTS: Second injections of NP-L20 were cleared much more rapidly from the circulation than first injections, showing that the ABC phenomenon was induced. This ABC phenomenon, and the accompanying induction of anti-PEG IgM antibody production, was optimal at a time interval of 7 days between the first and second injections. Compared to NP-L20, NP-L33s that were prepared with PLA (Mw = 28,100) and have a smaller particle size induced production of anti-PEG IgM antibody to a lesser extent. NP-L20 but not NP-L33s gave rise to the ABC phenomenon with a time interval of 14 days. NP-L33s showed a better sustained-release profile of PGE(1) than NP-L20. CONCLUSIONS: This study revealed that the ABC phenomenon is induced by PEG-modified PLA-nanoparticles. We consider that NP-L33s may be useful clinically for the sustained-release and targeted delivery of PGE(1).

Efficient encapsulation of a water-soluble corticosteroid in biodegradable nanoparticles.

Solid nanoparticles consisting of biodegradable polymers have emerged as a promising carrier for various drugs, but unfortunately the encapsulation of drugs remains challenging. In this study, a technique for encapsulation of water-soluble drugs in solid nanoparticles was developed. Nanoparticles were prepared from a blend of biodegradable polymers, including poly(lactic acid) (PLA) and poly(lactic/glycolic acid) (PLGA), and monomethoxypolyethyleneglycol-polylactide block copolymer by an oil-in-water solvent diffusion method. Betamethasone sodium phosphate (BP) was not encapsulated by the nanoparticles due to its hydrophilicity, but it was effectively encapsulated in the presence of appropriate amounts of zinc and diethanolamine. It was found that BP formed an ionic complex with zinc at a certain pH range obtained by addition of diethanolamine. Furthermore, a carboxyl group located at the end of PLA/PLGA was shown to be essential for encapsulation of BP in nanoparticles, and the molar ratio among BP, zinc, and carboxyl groups in various nanoparticles was almost constant. These results strongly suggested that the encapsulation was promoted by zinc creating an ionic bridge between a carboxyl group on PLA/PLGA and a phosphate group on BP. This technique for entrapment of water-soluble drugs in solid biodegradable nanoparticles may expand the use of nanoparticles for various therapeutic applications.

Injectable porous hydroxyapatite microparticles as a new carrier for protein and lipophilic drugs.

Hydroxyapatite (Ca10 (PO4)6(OH)2) is a biodegradable material that forms a major component of bones and teeth. We prepared injectable spherical porous hydroxyapatite microparticles (SP-HAp) as a drug carrier by the spray-drying method. We then examined the usefulness of SP-HAp as a carrier for drugs such as interferon alpha (IFNalpha), testosterone enanthate (TE), and cyclosporin A (CyA). SP-HAp had an average diameter of 5 mum and a porosity of approximately 58%. It could be injected subcutaneously through a 27-gauge needle. SP-HAp was observed to be biodegradable. The speed of degradation of SP-HAp could be regulated by altering the calcination temperature. IFNalpha was adsorbed well to SP-HAp particles, but INFalpha was released faster from the particles, than the particles could degrade in both in vitro and in vivo experiments. Addition of human serum albumin and zinc (reinforcement) to IFNalpha-adsorbed SP-HAp caused marked prolongation of release in vivo. The in vivo release of testosterone enanthate and CyA from SP-HAp preparation, which was easily injectable, was similarly prolonged to that from the oil preparation. In conclusion, the SP-HAp seems to be useful as a biodegradable and subcutaneously injectable drug carrier. It is suggested that the reinforcement of the SP-HAp is very effective on the sustained release of drugs.

[Corticosteroid-loading PLA/PLGA-nanospheres].

We developed nanospheres for the intravenous injection that have had sustained release and targeting to the efficiently anti-inflammation effect. These nanospheres formed by poly(D,L-lactic/glycolic acid) (PLGA) or poly(D,L-lactic acid) (PLA), biodegradability and biocompatibility polymer, that were encapsulated betamethasone phosphate and zinc. Result of experimental inflammation models shown that there nanospheres increased effect by targeting to inflammatory sites and also promoted sustained release of betamethasone phosphate from the nanospheres. Moreover, the effect of nanospheres were stronger than clinical pharmaceutical preparation. We propose that these nanospheres are the pharmaceutical preparation to have efficient powerful inflammation action.

Role of zinc in formulation of PLGA/PLA nanoparticles encapsulating betamethasone phosphate and its release profile.

The purpose of this study was to develop poly(D,L-lactic/glycolic acid) (PLGA) or poly(D,L-lactic acid) (PLA) nanoparticles of less than 200 nm in diameter that encapsulated water-soluble corticosteroid derivatives for sustained release and targeting to inflammatory sites. Nanoparticles were prepared with PLGA (or PLA), zinc, betamethasone phosphate and surfactant by an oil-in-water solvent diffusion method. With this method, the efficiency of encapsulating betamethasone phosphate in the nanoparticles and the particle size were significantly affected by various factors, such as the concentration of PLGA (or PLA) and the amount of zinc added. Nanoparticles ranging from 80 to 250 nm in diameter could be prepared, with a maximum betamethasone phosphate content of 8% (w/w). Betamethasone phosphate was gradually released from the nanoparticles in diluted serum, and the release rate depended on the glycolic/lactic acid ratio and on the molecular weight of PLGA or PLA. Betamethasone was gradually released over at least 8 days from murine macrophages that had internalized betamethasone phosphate-encapsulated nanoparticles in vitro, and the rate of release was slower than from nanoparticles prepared without zinc. These results suggest that zinc increases the efficiency of encapsulating betamethasone phosphate in nanoparticles and also promotes sustained release of betamethasone phosphate from the nanoparticles.

Drug delivery to the cochlea using PLGA nanoparticles.

OBJECTIVES: This study aimed to investigate the efficacy of encapsulating therapeutic molecules in poly lactic/glycolic acid (PLGA) nanoparticles for drug delivery to the cochlea. STUDY DESIGN: An experimental study. METHODS: We examined the distribution of rhodamine, a fluorescent dye, in the cochlea, liver, and kidney of guinea pigs. Intravenous injection of rhodamine or rhodamine-encapsulated PLGA nanoparticles was used to target the fluorescent dye systemically to the liver, kidney, and cochlea, and these molecules were applied locally to the round window membrane (RWM) of the cochlea. The localization of rhodamine fluorescence in each region was quantitatively analyzed. RESULTS: After systemic application of rhodamine nanoparticles, fluorescence was identified in the liver, kidney, and cochlea. The systemic application of nanoparticles had a significant effect on targeted and sustained delivery of rhodamine to the liver but not the kidney or cochlea. Rhodamine nanoparticles placed on the RWM were identified in the scala tympani as nanoparticles, indicating that the PLGA nanoparticles can permeate through the RWM. Furthermore, the local application of rhodamine nanoparticles to the RWM was more effective in targeted delivery to the cochlea than systemic application. CONCLUSIONS: These findings indicate that PLGA nanoparticles can be an useful drug carrier to the cochlea via local application.

Encapsulation of beraprost sodium in nanoparticles: analysis of sustained release properties, targeting abilities and pharmacological activities in animal models of pulmonary arterial hypertension.

Prostaglandin I2 (PGI2) and its analogues (such as beraprost sodium, BPS) are beneficial for the treatment of pulmonary arterial hypertension (PAH). The encapsulation of BPS in nanoparticles to provide sustained release and targeting abilities would improve both the therapeutic effect of BPS on PAH and the quality of life of patients treated with this drug. BPS was encapsulated into nanoparticles prepared from a poly(lactic acid) homopolymer and monomethoxy poly(ethyleneglycol)-poly(lactide) block copolymer. The accumulation of nanoparticles in damaged pulmonary arteries was examined using fluorescence-emitting rhodamine S-encapsulated nanoparticles. The monocrotaline-induced PAH rat model and the hypoxia-induced mouse model were used to examine the pharmacological activity of BPS-encapsulated nanoparticles. A nanoparticle, named BPS-NP, was selected among various types of BPS-encapsulated nanoparticles tested; this was based on the sustained release profile in vitro and blood clearance profile in vivo. Fluorescence-emitting rhodamine S-encapsulated nanoparticles were prepared in a similar manner to that of BPS-NP, and showed accumulation and prolonged residence in monocrotaline-damaged pulmonary peripheral arteries. Intravenous administration of BPS-NP (once per week, 20µg/kg) protected against monocrotaline-induced pulmonary arterial remodeling and right ventricular hypertrophy. The extent of this protection was similar to that observed with oral administration (once per day, 100µg/kg) of BPS alone. The once per week intravenous administration of BPS-NP (20µg/kg) also exhibited an ameliorative effect on hypoxia-induced pulmonary arterial remodeling and right ventricular hypertrophy. The beneficial effects of BPS-NP on PAH animal models seem to be mediated by its sustained release and tissue targeting profiles. BPS-NP may be useful for the treatment of PAH patients due to reduced dosages and frequency of BPS administration.

Development of biodegradable nanoparticles for liver-specific ribavirin delivery.

Ribavirin is an antiviral drug used for the treatment of chronic hepatitis C. However, ribavirin induces severe side effects such as hemolytic anemia. In this study, we prepared biodegradable nanoparticles as ribavirin carriers to modulate the pharmacokinetics of the drug. The nanoparticles encapsulating ribavirin monophosphate (RMP) were prepared from the blend of poly(d,l-lactic acid) homopolymer and arabinogalactan (AG)-poly(l-lysine) conjugate by using the solvent diffusion method in the presence of iron (III). RMP was efficiently and stably embedded in the nanoparticles and gradually released for 37 days in phosphate-buffered saline at 37°C. The coating of AG on the nanoparticles surfaces was verified by measuring the zeta potentials and performing an aggregation test of the nanoparticles using galactose-binding lectin. Moreover, the nanoparticles were efficiently internalized in cultured HepG2 cells. Ribavirin was drastically accumulated to the liver of mice after intravenous administration of the RMP-loaded nanoparticles, after which the ribavirin content gradually decreased for at least 7 days. Our results indicated successful development of nanoparticles with dual functions, targeting to the liver and sustained release of ribavirin, and suggested that the present strategy could help to advance the clinical application of ribavirin as a therapeutic agent for chronic hepatitis C.

Poly (N-isopropylacrylamide)-PLA and PLA blend nanoparticles for temperature-controllable drug release and intracellular uptake.

We designed a temperature-responsive and biodegradable novel drug-delivery carrier. A block copolymer, poly (N-isopropylacrylamide-dl-lactide) (PNIPAAm-PLA), was synthesized by the ring-opening polymerization of dl-lactide, and used as a carrier for a drug-delivery system. In this study, temperature-responsive nanoparticles (NPs) encapsulating betamethasone disodium 21-phosphate (BP) were prepared from a blend of PLA homopolymer and block copolymers by an oil-in-water solvent-diffusion method in the presence of zinc ion (PLA/PNIPAAm-PLA (NPs)). The resulting NP size was around 140 nm. The drug release from temperature-responsive NP could be controllable by changing the temperature. Moreover, a murine macrophage-like cell line, RAW 264.7 cells, was used to measure and image the cell uptake of fluorescent PLA/PNIPAAm-PLA NPs at 30 °C and 37 °C on the boundary of LCST (34 °C). Below the LCST, cellular uptake was not observed, but contrary to cellular uptake it was clearly observed above the LCST. Moreover, we found this effect to be useful for controlling the stealthiness by changing the temperature. Present temperature-responsive NPs have successfully exhibited thermo-responsive drug release and intracellular uptake while possessing a biodegradable character.

Therapeutic effect of stealth-type polymeric nanoparticles with encapsulated betamethasone phosphate on experimental autoimmune uveoretinitis.

PURPOSE: The therapeutic effects of betamethasone phosphate (BP) encapsulated in biocompatible and biodegradable blended nanoparticles of poly(lactic acid) (PLA) homopolymers and PEG-block-PLA copolymers (stealth nanosteroids) were examined in an experimental autoimmune uveoretinitis (EAU) model in Lewis rats. METHODS: EAU was induced by S-antigen peptide in Lewis rats. Accumulation of systemically administered Cy7-labeled stealth nanoparticles in inflamed eyes of rats with EAU was assessed using in vivo fluorescence imaging, and the therapeutic effect of stealth nanosteroids, nonstealth nanosteroids, or saline on EAU was examined. The eyes were obtained 7 days after the treatment, and the histologic score was determined using pathologic findings. The expression of inflammatory cytokines including IL-6, IL-17, and VEGF was determined immunohistochemically. RESULTS: Cy7-stealth nanoparticles accumulated in inflamed eyes of rats with EAU and remained in situ for a 3-day period. Systemically administered stealth nanosteroids (100 µg of BP) reduced the clinical scores of rats with EAU within 1 day and maintained the effect for 2 weeks. This treatment also decreased the histologic scores and the expression of inflammatory cytokines in the retina of EAU. CONCLUSIONS: The strong therapeutic benefit on EAU obtained with the stealth nanosteroids may have been due to prolonged blood circulation and targeting to the inflamed uvea and retina, in addition to sustained release in situ.

Techniques for efficient entrapment of pharmaceuticals in biodegradable solid micro/nanoparticles.

IMPORTANCE OF THE FIELD: Biodegradable solid particles are potential carriers for both hydrophobic and hydrophilic drugs and have been marketed for prolongation of pharmaceutical activity. In developing such particles, it is important to achieve stable encapsulation of the drugs in the particles and a controlled rate of drug release. AREAS COVERED IN THIS REVIEW: In this paper, the principles and techniques for preparing such particles are reviewed. WHAT THE READER WILL GAIN: Overall, it remains difficult to identify a general approach for achieving effective entrapment and controlled release, because these qualities are determined by multiple complex factors. The encapsulation efficiency of drugs in particles can be improved through various techniques, including hydrophobic interaction, covalent bonding, ionic interaction and physical isolation. In addition, the release behaviors of drugs are strongly influenced by environmental conditions as well as the physicochemical properties of the polymers and drugs. TAKE HOME MESSAGE: Solid particles with targeting ability in addition to prolongation of biological activity may have potential for development of a new type of pharmaceutical in the clinical field.

Preparation and characterization of a nanoparticulate formulation composed of PEG-PLA and PLA as anti-inflammatory agents.

We have prepared polymeric nanoparticles using a blend of poly(lactic acid) and monomethoxy-polyethyleneglycol(PEG)-polylactide block copolymer along with betamethasone disodium phosphate (BP). Nanoparticles have been screened for anti-inflammatory activity using experimental rat models of inflammation. In the present study, we examined the degradation of nanoparticles in vitro during incubation. We found that the nanoparticles lost the PEG chains present on their surfaces within a few days, and subsequently gradually released BP. Furthermore, we found that these nanoparticles preferentially accumulated in the inflammatory lesion in adjuvant arthritis rat models, and that the amount of BP gradually depleted from the lesion over 14 days. These results suggested the mechanism underlying the anti-inflammatory effect of the nanoparticles in vivo: the initial accumulation of BP in the lesion due to the enhanced permeability and retention effect, the subsequent internalization in inflammatory macrophages due to the loss of PEG, and the release of BP in cells during the hydrolysis of polymers. The nanoparticles were successfully prepared on a large-scale and stably stored in the form of a freeze-dried formulation for at least 69 weeks below 25 degrees C. These results suggest that the nanoparticles can be used as an anti-inflammatory pharmaceutical formulation in a clinical setting.

Stealth-nanoparticle strategy for enhancing the efficacy of steroids in mice with noise-induced hearing loss.

AIMS: This study aimed to investigate the efficacy of encapsulating steroids, which is a primary choice for the treatment of sensorineural hearing loss, in polyethylene glycol-coated polylactic acid nanoparticles for drug delivery to the cochlea. MATERIALS & METHODS: We prepared polyethylene glycol-coated polylactic acid nanoparticles encapsulating rhodamine or betamethasone phosphate (BP), and administered them systemically to CBA/N mice previously exposed to intense noise. We assessed nanoparticle distribution using rhodamine fluorescence, BP concentrations in tissues, nuclear translocation of glucocorticoid receptors and the function and histology of the mouse cochleae. RESULTS & CONCLUSION: Polyethylene glycol-coated polylactic acid nanoparticles delivered BP to cochleae over a sustained period, resulting in significant reductions in histological and functional damage to cochleae and indicating the potential therapeutic benefits of these nanoparticles for enhancing the delivery of BP in acute sensorineural hearing loss.

Efficient entrapment of poorly water-soluble pharmaceuticals in hybrid nanoparticles.

Polymeric micelles consisting of amphiphilic block copolymers have emerged as a promising carrier of various drugs, but unfortunately show a limited potential for encapsulating (solubilizing) such drugs. In this study, hybrid nanoparticles consisting of monomethoxypolyethyleneglycol-polylactide block copolymer (PEG-PLA) and oleic acid calcium salt were prepared to enhance the solubilization of poorly water-soluble drugs. Micelles made of a mixture of sodium oleate and PEG-PLA at various ratios were used as the template for preparation of the nanoparticles. These mixed micelles could efficiently solubilize poorly water-soluble drugs in aqueous media, when compared with polymeric micelles made of PEG-PLA alone. Addition of calcium to the mixed micelles induced the formation of oleic acid calcium salt, resulting in hybrid nanoparticles. These hybrid nanoparticles had a high colloidal stability, neutral zeta potential, and high drug entrapment efficiency. Drugs entrapped in nanoparticles made at a high PEG-PLA ratio were protected from enzymatic degradation in serum, while drugs entrapped in the mixed micelles were not, indicating that the hybrid nanoparticles show good drug retention. These results suggested that such hybrid nanoparticles may be used to expand the availability of poorly water-soluble drugs for various therapeutic applications.

Polymeric nanoparticles encapsulating betamethasone phosphate with different release profiles and stealthiness.

The purpose of this study was to engineer nanoparticles with various sustained profiles of drug release and prolonged circulation by blending poly(D,L-lactic acid)/poly(D,L-lactic/glycolic acid) (PLA/PLGA) homopolymers and poly(ethylene glycol) (PEG)-block-PLA/PLGA copolymers encapsulating betamethasone disodium 21-phosphate (BP). Nanoparticles of different sizes, drug encapsulation/release profiles, and cellular uptake levels were obtained by mixing homopolymers and block copolymers with different compositions/molecular weights at various blend ratios by an oil-in-water solvent diffusion method. The in vitro release of BP increased with nanoparticles of smaller size or of PLGA homopolymers instead of PLA homopolymers. Furthermore, the uptake of nanoparticles by macrophage-like cells decreased with nanoparticles of higher PEG content, and nanoparticles of PEG-PLGA block copolymers were taken up earlier than those of PEG-PLA block copolymers after incubation with serum. In addition, prolonged blood circulation was observed with nanoparticles of smaller size with higher PEG content, and nanoparticles of PEG-PLA block copolymers remained longer in circulation than those of PEG-PLGA block copolymers. Analysis of BP concentration in organs revealed reduced liver distribution of blended nanoparticles compared with PLA nanoparticles. This is the first study to systematically design and characterize biodegradable PLA/PLGA and PEG-PLA/PLGA-blended nanoparticles encapsulating BP with different release profiles and stealthiness.

Prolonging the in vivo residence time of prostaglandin E(1) with biodegradable nanoparticles.

PURPOSE: Prostaglandins have potent and diverse biologic activities, but their clinical application is severely restricted, mainly due to rapid inactivation in vivo. In order to modulate the pharmacokinetics of prostaglandin E(1) (PGE(1)), we prepared biodegradable nanoparticles as a drug carrier. METHODS: Nanoparticles encapsulating PGE(1) were prepared from a blend of poly(lactic acid) homopolymer and poly(ethylene glycol)-poly(lactide) block copolymer by the solvent diffusion method in the presence of iron. RESULTS: PGE(1) was efficiently and stably embedded in the nanoparticles through interaction with iron, despite being relatively hydrophilic and having unstable chemical properties. Depending on the isomers and molecular weight of poly(lactic acid) selected, PGE(1) was gradually released from the nanoparticles at various rates into diluted serum in vitro. Both stable retention of PGE(1) in the nanoparticles and coating of the nanoparticles with poly(ethylene glycol) led to an extremely extended blood residence time of PGE(1), as well as preferential accumulation in vascular lesions. CONCLUSIONS: These results suggest that the present strategy is useful to advance the clinical application of PGE(1) as a therapeutic agent for vascular disorders.