Core-modified chitosan-based polymeric micelles for controlled release of doxorubicin

Amphiphilic stearic acid-grafted chitosan oligosaccharide (CSO-SA) micelles have been shown a good drug delivery system by incorporating hydrophobic drugs into the core of the micelles. One of the problems associated with the use of CSO-SA micelles is disassociation or the initial burst drug release during the dilution of drug delivery system by body fluid. Herein, the core of CSO-SA micelles was modified by the physical solubilization of stearic acid (SA) to reduce the burst drug release and enhance the physical stability of CSO-SA micelles. The CSO-SA micelles had 27.4+/-2.4 nm number average diameter, and indicated pH-sensitive properties. The micelle size and drug release rate from micelles increased with the decrease of pH value. After the incorporation of SA into CSO-SA micelles, the micelle size was increased, and the zeta potential was decreased. The extents of the increase in micelle size and the decrease of zeta potential related with the incorporated amount of SA. The in vitro drug release tests displayed the incorporation of SA into CSO-SA micelles could reduce the drug release from the micelles due to the enhanced hydrophobic interaction among SA, hydrophobic drug and hydrophobic segments of CSO-SA.     

Preparation,characterization, and drug release behaviors of drug nimodipine-loaded poly(epsilon-caprolactone)-poly(ethylene oxide)-poly(epsilon-caprolactone) amphiphilic triblock copolymer micelles

Amphiphilic triblock copolymers, poly(epsilon-caprolactone)-poly(ethylene oxide)-poly(epsilon-caprolactone) (PCL-PEO-PCL), were synthesized by ring opening polymerization of epsilon-caprolactone initiated with the hydroxyl functional groups of poly(ethylene glycol) at both ends of the chain. The micelles composed of this type of copolymer had such a structure that both ends of the PEO chain were anchored to the micelle. The critical micelle concentration of the block copolymer in distilled water was determined by a fluorescence probe technique using pyrene. As the hydrophobic components of the block copolymer increased, the critical micelle concentration value decreased. To estimate the feasibility as novel drug carriers, the block copolymer micelles were prepared by precipitation of polymer from acetone solution into water. From the observation of transmission electron microscopy, the micelles exhibited a spherical shape. Nimodipine was incorporated into the hydrophobic inner core of micelles as a lipophilic model drug to investigate the drug release behavior. The PEO/PCL ratio of copolymer was a main factor in controlling micelle size, drug-loading content, and drug release behavior. As PCL weight ratio increased, the micelle size and drug-loading content increased, and the drug release rate decreased.     

A polymeric micellar carrier for the solubilization of biphenyl dimethyl dicarboxylate

A polymeric micelle drug delivery system was developed to enhance the solubility of poorly-water soluble drug, biphenyl dimethyl dicarboxylate, DDB. The block copolymers consisting of poly(D,L-lactide) (PLA) as the hydrophobic segment and methoxy poly(ethylene glycol) (mPEG) as the hydrophilic segment were synthesized and characterized by NMR, DSC and MALDI-TOF mass spectroscopy. The size of the polymeric micelles measured by dynamic light scattering showed a narrow monodisperse size distribution with the average diameter less than 50 nm. The MW of mPEG-PLA, 3000 (MW of mPEG, 2 K; MW of PLA, 1 K), and the presence of hydrophilic and hydrophobic segments on the polymeric micelles were confirmed by MALDI-TOF mass spectroscopy and NMR, respectively. Polymeric micelle solutions of DDB were prepared by three different methods, i.e. the matrix method, emulsion method and dialy-sis method. In the matrix method, DDB solubility was reached to 13.29 mg/mL. The mPEG-PLA 2K-1 K micelle system was compared with the poloxamer 407 micelle system for their critical micelle concentration, micelle size, solubilizing capacity, stability in dilution and physical state. DDB loaded-polymeric micelles prepared by the matrix method showed a significantly increased aqueous solubility (>5000 fold over intrinsic solubility) and were found to be superior to the poloxamer 407 micelles as a drug carrier.     

Thermosensitive mPEG-b-PA-g-PNIPAM Comb Block Copolymer Micelles: Effect of Hydrophilic Chain Length and Camptothecin Release Behavior

Purpose

Block copolymer micelles are extensively used as drug controlled release carriers, showing promising application prospects. The comb or brush copolymers are especially of great interest, whose densely-grafted side chains may be important for tuning the physicochemical properties and conformation in selective solvents, even in vitro drug release. The purpose of this work was to synthesize novel block copolymer combs via atom transfer radical polymerization, to evaluate its physicochemical features in solution, to improve drug release behavior and to enhance the bioavailablity, and to decrease cytotoxicity.

Methods

The physicochemical properties of the copolymer micelles were examined by modulating the composition and the molecular weights of the building blocks. A dialysis method was used to load hydrophobic camptothecin (CPT), and the CPT release and stability were detected by UV–vis spectroscopy and high-performance liquid chromatography, and the cytotoxicity was evaluated by MTT assays.

Results

The copolymers could self-assemble into well-defined spherical core-shell micelle aggregates in aqueous solution, and showed thermo-induced micellization behavior, and the critical micelle concentration was 2.96–27.64 mg L^?1. The micelles were narrow-size-distribution, with hydrodynamic diameters about 128–193 nm, depending on the chain length of methoxy polyethylene glycol (mPEG) blocks and poly(N-isopropylacrylamide) (PNIPAM) graft chains or/and compositional ratios of mPEG to PNIPAM. The copolymer micelles could stably and effectively load CPT but avoid toxicity and side-effects, and exhibited thermo-dependent controlled and targeted drug release behavior.

Conclusions

The copolymer micelles were safe, stable and effective, and could potentially be employed as CPT controlled release carriers.     

Synthesis of Novel Biodegradable Methoxy Poly(ethylene glycol)-Zein Micelles for Effective Delivery of Curcumin

Novel biodegradable micelles were synthesized by conjugating methoxy poly(ethylene glycol) (mPEG) to zein, a biodegradable hydrophobic plant protein. The mPEG-zein micelles were in the size range of 95-125 nm with a low CMC (5.5 × 10(-2) g/L). The micelles were nonimmunogenic and were stable upon dilution with buffer as well as 10% serum. Curcumin, an anticancer agent with multiple delivery challenges, was encapsulated in mPEG-zein micelles. The micelles significantly enhanced the aqueous solubility (by 1000-2000-fold) and stability (by 6-fold) of curcumin. PEG-zein micelles sustained the release of curcumin up to 24 h in vitro. Curcumin-loaded mPEG-zein micelles showed significantly higher cell uptake than free curcumin in drug-resistant NCI/ADR-RES cancer cells in vitro. Micellar curcumin formulation was more potent than free curcumin in NCI/ADR-RES cancer cells, as evidenced from the 3-fold reduction in IC(50) value of curcumin. Overall, this study for the first time reports a natural protein core based polymeric micelle and demonstrates its application for the delivery of hydrophobic anticancer drugs such as curcumin.     

仿穿膜肽型壳聚糖衍生物N-辛基-N-精氨酸壳聚糖的合成和表征

以壳聚糖为母体,在其侧链氨基上引入亲水基精氨酸以及疏水基辛基,合成了一种新型的具有仿穿膜肽结构的壳聚糖衍生物——N-辛基-N-精氨酸壳聚糖(OACS)。同时通过FT-IR、1H NMR、元素分析和精氨酸显色法确证了OACS的化学结构以及其辛基和精氨酸的取代度。荧光光谱法测得系列OACS的临界胶束浓度为0.12～0.27 mg.mL/1;溶解度实验表明其在pH 1～12溶液中均易溶,并可自组装形成淡蓝色略带乳光的胶束溶液;马尔文粒径测定仪显示系列OACS形成的聚合物胶束平均粒径为158.4～224.6 nm,多分散系数为0.038～0.309,ζ电位为+19.16～+30.80 mV;原子力显微镜图谱显示所得胶束粒子分散均匀、大小规则圆整;MTT实验证实所得OACS在50～1 000μmol.L?1内安全性能良好。细胞实验结果表明,随着精氨酸取代度的升高,OACS胶束进入细胞的荧光量也随之增加,与壳聚糖相比,最大增加倍数可达40倍。因此,OACS有望作为一种兼具促吸收和载药功能的新型纳米载体。     

Spray-dried casein-based micelles as a vehicle for solubilization and controlled delivery of flutamide: Formulation,characterization, and in vivo pharmacokinetics

Novel casein (CAS)-based micelles loaded with the poorly soluble anti-cancer drug, flutamide (FLT), were successfully developed in a powdered form via spray-drying technique. Genipin (GNP) was used to crosslink CAS micelles as demonstrated by color variation of the micelles. Drug solubilization was enhanced by incorporation within the hydrophobic micellar core which was confirmed by solubility study and UV spectra. Spherical core–shell micelles were obtained with a particle size below 100 nm and zeta potential around −30 mV. At low drug loading, FLT was totally incorporated within micellar core as revealed by thermal analysis. However, at higher loading, excess non-incorporated drug at micelle surface caused a significant reduction in the surface charge density. Turbidity measurements demonstrated the high physical stability of micelles for 2 weeks dependent on GNP-crosslinking degree. In a dry powdered form, the micelles were stable for 6 months with no significant changes in drug content or particle size. A sustained drug release from CAS micelles up to 5 days was observed. After i.v. administration into rats, CAS micelles exhibited a prolonged plasma circulation of FLT compared to drug solution. Furthermore, a more prolonged drug systemic circulation was observed for GNP-crosslinked micelles. Overall, this study reports the application of spray-dried natural protein-based micelles for i.v. delivery of hydrophobic anti-cancer drugs such as FLT.     

SDS-aided immobilization and controlled release of camptothecin from agarose hydrogel.

Camptothecin (CPT), known to be an effective anticancer drug, has a limited therapeutic utility because of its poor water solubility. In this work, an approach has been made to overcome the limitation. CPT was first incorporated into the micelles formed from an ionic surfactant, sodium dodecyl sulfate (SDS) and the micellar drug aqueous solution was then used in preparation of the agarose hydrogel. It has been found that the presence of SDS greatly increased the solubility of CPT in water. For example, in 1 ml of 1.0 wt.% SDS water solution, 0.11 mg CPT could be solubilized (0.318 mM), which was 83 times the solubility in pure water. It was the hydrophobic cores of the SDS micelles that were able to accept the lipophilic drug to form stable drug-immobilized micelles. The formulation of a hydrogel using the drug-immobilized micelles has allowed us to obtain a unique and novel drug release system where the drug molecules are encapsulated by the micelles and the drug-containing micelles are dispersed in the gel network. The release of CPT from the so deliberately fabricated agarose hydrogel system has been studied as a function of surfactant concentration at 37 degrees C. The diffusion coefficients of CPT obtained by fitting to Fick's law ranged from 2.12 to 7.36 x 10(-7)cm(2)s(-1). The results showed that SDS prolonged the drug release by reducing the diffusion coefficient of CPT in the gel.     

Controlled dual release of basic fibroblast growth factor and indomethacin from heparin-conjugated polymeric micelle

This work describes the development of heparinized polymeric micelle as a novel injectable carrier for the dual drug delivery that can simultaneously release basic fibroblast growth factor (bFGF) and indomethacin (IMC), which can promote the regeneration of damaged tissue and prevent the inflammatory response after implantation. Tetronic-PCL-heparin for the preparation of heparinized polymeric micelle was synthesized by introducing PCL as a biodegradable linkage on Tetronic, following the conjugation of heparin. The mean diameter of the formed TCH micelle was around 114 nm and increases in the micelle size after single and dual drug loading were observed. Loading efficiencies of IMC and bFGF were 30.9% and 70.5%, respectively. In vitro dual drug release profiles from TCH micelles were investigated. IMC was more slowly released from dual drug-loaded micelle over 3 weeks as compared with single drug-loaded one. bFGF was released over 2 months in a controlled manner. Therefore, the release profile results support that TCH micelle could not only incorporate a hydrophobic drug into the core but also bind with bFGF to heparin that exists on its outer shell. The TCH micelle will have enhanced therapeutic effects on the target site which may be required the multi-function of drugs to use.     

Drug release from thermo-responsive self-assembled polymeric micelles composed of cholic acid and poly(N-isopropylacrylamide)

Cholic acid, conjugated with amine-terminated poly(N-isopropylacrylamide) (abbreviated as CA/ATPNIPAAm), was synthesized by a N, N'-dicyclohexyl carbodiimide (DCC)-mediated coupling reaction. Self-assembled CA/ATPNIPAAm micelles were prepared by a diafiltration method in aqueous media. The CA/ATPNIPAAm micelles exhibited a lower critical solution temperature (LCST) at 31.5 degrees C. Micelle sizes measured by photon correlation spectroscopy (PCS) were approximately 31.6+/-5.8 nm. The CA/ATPNIPAAm micelles were spherical and their thermal size transition was observed by transmission electron microscope (TEM). A fluorescence probe technique was used for determining the micelle formation behavior of CA/ATPNIPAAm in aqueous solutions using pyrene as a hydrophobic probe. The critical micelle concentration (CMC) was evaluated as 8.9 x 10(-2) g/L. A drug release study was performed using indomethacin (IN) as a hydrophobic model drug. The release kinetics of IN from the CA/ATPNIPAAm micelles revealed a thermo-sensitivity by the unique character of poly(N-isopropylacrylamide) i.e. the release rate was higher at 25 degrees C than at 37 degrees C.     

Oxidized phospholipid based pH sensitive micelles for delivery of anthracyclines to resistant leukemia cells in vitro

A self-assembled micelle drug delivery system was constructed with an oxidized phospholipid for anthracycline anti-cancer drug delivery. An oxidized phospholipid, 1-palmitoyl-2-azelaoyl-sn-glycero-3-phosphocholine (PazPC), was chosen to fabricate micelles via both electrostatic and hydrophobic interactions for delivery of doxorubicin (DOX) and idarubicin (IDA). The formation of ion-pair complexes between PazPC and DOX was first investigated under different pH conditions. Drug-loaded PazPC micelles at a 5:1 molar ratio of lipid/drug at pH 7.0 were then prepared by the solvent evaporation method. The empty and drug-loaded PazPC micelles exhibited a small particle size (～10 nm) and high encapsulation efficiency. In vitro stability and release profile indicated that the micelles were stable at physiological conditions, but exhibited pH-sensitive behavior with accelerated release of DOX or IDA in an acidic endosome environment. Finally, in vitro uptake and cytotoxicity were evaluated for leukemia P388 and its resistant subline P388/ADR. The drug-loaded PazPC micelles enhanced drug uptake and exhibited higher cytotoxicity in both leukemia cells in comparison to free drugs. In conclusion, we developed a novel pH sensitive oxidized phospholipid-based micellar formulation which could potentially be useful in delivering anthracycline anti-cancer drugs and provide a novel strategy for increasing the therapeutic index while overcoming multidrug resistance for leukemia treatment.     

Redox-sensitive micelles for targeted intracellular delivery and combination chemotherapy of paclitaxel and all-trans-retinoid acid

The application of paclitaxel (PTX) in clinic has been restricted due to its poor solubility. Several traditional nano-medicines have been developed to improve this defect, while they are still lack of tumor targeting ability and rapid drug release. In this work, an amphiphilic polymeric micelle of hyaluronic acid (HA) – all-trans-retinoid acid (ATRA) with a disulfide bond, was developed successfully for the co-delivery of PTX and ATRA. The combination chemotherapy of PTX and ATRA can strengthen the anti-tumor activity. Along with self-assembling to micelles in water, the delivery system displayed satisfying drug loading capacities for both PTX (32.62% ± 1.39%) and ATRA, due to directly using ATRA as the hydrophobic group. Rapid drug release properties of the PTX-loaded redox-sensitive micelles (HA-SS-ATRA) in vitro were confirmed under reducing condition containing GSH. Besides, HA-CD44 mediated endocytosis promoted the uptake of HA-SS-ATRA micelles by B16F10 cells. Due to these properties, cytotoxicity assay verified that PTX-loaded HA-SS-ATRA micelles showed concentration-dependent cytotoxicity and displayed obvious combination therapy of PTX and ATRA. Importantly, HA-SS-ATRA micelles could remarkably prolong plasma circulation time after intravenously administration. Therefore, redox-sensitive HA-SS-ATRA micelles could be utilized and explored as a promising drug delivery system for cancer combination chemotherapy.     

Improving the topical ocular pharmacokinetics of lyophilized cyclosporine A-loaded micelles: formulation,in vitro and in vivo studies

Dry eye syndrome (DES) is one of the most common disorders of the eye for which combined treatment includes modification of the ocular environment and pathogenic therapies. Cyclosporine A (CsA), a immunosuppressive agent, has been demonstrated to be effective for the treatment of DES but is limited clinically by its low ocular bioavailability due to poor water solubility. In this paper, methoxy poly (ethylene glycol)-poly (lactide) polymer (mPEG-PLA) micelles were investigated as alternative vehicles for the solubilization and delivery of CsA to the eye. The in vitro stability indicated that CsA-loaded micellar lyophilized powder was stable for at least 3?months and the release profile showed a sustained release manner of CsA from micelles physically. In vivo ocular distribution studies demonstrated that the micellar formulations exhibited a 4.5-fold increase in retention effect at eyes compared with 0.05% CsA emulsion. In addition, the in vivo pharmacokinetics profile showed that the CsA-loaded micelles could enhance the retention time, achieving longer effect toward the DES. These studies proposed an effective micelle formulation as a novel ocular drug delivery system to improve solubility and bioavailability of ophthalmic CsA-controlled delivery.     

9-nitrocamptothecin polymeric nanoparticles: cytotoxicity and pharmacokinetic studies of lactone and total forms of drug in rats

The objective of this study was to evaluate the cytotoxicity and pharmacokinetics of total and lactone forms of 9-nitrocamptothecin (9-NC), an effective antineoplastic drug, after intravenous injection of drug incorporated into poly (DL-lactic-glycolic acid) nanoparticles (NPs). Drug-loaded NPs (9-NC.NP) were prepared by the nanoprecipitation method and examined for particle characteristics and in-vitro release in phosphate buffered saline. The best formulation showed a narrow size with an average diameter of 207+/-26 nm and a drug loading of more than 33.5%. The drug release profile showed a sustained 9-NC release up to 160 h. For a pharmacokinetic study, the concentration of 9-NC as the lactone form (9-NC.lac) and as the total of the lactone and carboxylate forms (9-NC.tot) in plasma was determined by using reverse-phase high performance liquid chromatography after intravenous administration of 9-NC.NP and a control solution to cannulated Wistar rats. In-vitro cytotoxic activity of 9-NC.NP and control solution was evaluated on the human ovarian cancer cell line (A2780sn) by MTT cell cytotoxicity assay. Results of in-vivo studies showed that NP encapsulation markedly increased the plasma concentration of both lactone and total forms of 9-NC compared with free drug. In comparison with free drug, NPs resulted in 3.63-fold and 5.40-fold increases in area under the plasma concentration-versus-time curve (AUC(0-infinity)) for lactone and total forms of 9-NC, respectively. The values of mean residence time and elimination half-life (T(1/2)) were also significantly higher for NPs than for free drug. The in-vitro cytotoxicity study revealed that the IC50 value of NPs decreased 10-fold compared with the drug solution. Prepared NPs described here were considered potentially useful in both stabilizing and delivering 9-NC and enhancing the efficacy of this drug for cancer treatment for which high drug retention in the body, protection from the drug-active lactone form, and gradual drug release appeared to be related.     

Formulation of drugs in block copolymer micelles: drug loading and release

Block copolymer micelles have become accepted as a viable strategy for drug formulation and delivery. Block copolymer micelles may serve as solubilizers and/or true drug carriers depending on their drug retention properties in vivo. Indeed the formulation of hydrophobic drugs in these micelle systems has been shown to provide up to a 30,000 fold increase in the water solubility of some compounds. In addition, the administration of drugs in copolymer micelles has been shown to reduce their toxicity and improve their therapeutic efficacy. The present review is focused on the drug loading and release properties of block copolymer micelles. Specifically, the properties of the drug, properties of the micelle core and the presence of interactions between the drug and the core-forming block are discussed in terms of their influence on the drug loading and release properties of the micelles. The various methods employed to prepare drug-loaded micelles are reviewed and the in vitro release assays used to predict the in vivo release characteristics of the formulations are discussed. The balance between drug loading and micelle stability is highlighted as a critical factor in the optimization of micelle-based formulations. The in vivo performance of micelles as delivery systems is evaluated by comparing the pharmacokinetics of free drug and drug administered in micelle-based formulations. Overall, the composition-property and property-performance relationships outlined in this review may aid in guiding the rational design of block copolymer micelles for drug delivery. In addition, suggestions for future research in this area are provided as a means to assist in furthering block copolymer micelles as one of the leading advanced drug delivery technologies for the systemic administration of drugs.     

Amphiphilic polyaspartamide copolymer-based micelles for rivastigmine delivery to neuronal cells

A novel polysorbate-80 (PS(80))-attached amphiphilic copolymer comprising a hydrophilic α,β-poly(N-2-hydroxyethyl)-d,l-aspartamide (PHEA) backbone and hydrophobic squalenyl-C(17) (Sq(17)) portions was synthesized and characterized; the formation of polymeric micelles was also evaluated. Rivastigmine free-base (Riv), a hydrophobic drug employed to treat Alzheimer's disease, was chosen as model drug to investigate micelle's ability to incorporate hydrophobic molecules and target them to neuronal cells. Micelle formation was studied through analyses including fluorescence spectroscopy and 2D (1)H-NMR NOESY experiments. Finally, the capacity of Riv-loaded micelles, versus free drug, to penetrate mouse neuroblastoma cells (Neuro2a) was evaluated. 2D (1)H-NMR NOESY experiments demonstrated that the PHEA-EDA-Sq(17)-PS(80) copolymer self-assembles into micelle structures in water, with a micelle core formed by hydrophobic interaction between Sq(17) alkyl chains. Fluorescence probe studies revealed the CAC of PHEA-EDA-Sq(17)-PS(80) micelles, which was 0.25?mg mL(-1). The micelles obtained had a nanometric hydrodynamic diameter with narrow size distribution and negative surface charge. The PHEA-EDA-Sq(17)-PS(80) micelles incorporated a large amount of Riv, and the system maintained the stability of Riv after incubation in human plasma. An in vitro biological assay evidenced no cytotoxic effects of either empty or loaded micelles on the neuronal cell lines tested. Moreover, the micelles are internalized by neuroblastoma cell lines with drug uptake depending on the micelles concentration.     

Preparation and <Emphasis Type="Italic">in vitro</Emphasis> evaluation of povidone-sodium cholate-phospholipid mixed micelles for the solubilization of poorly soluble drugs

Mixed micelles made of polyvinylpyrrolidone (PVP), sodium cholate, and phospholipids were prepared to improve the solubility of poorly water-soluble drugs. Sylibin, a drug used in treating liver diseases, was incorporated into the mixed micelles. The formulation of sylibin containing PVP-sodium cholate-phospholipid mixed micelles with an optimized composition (PVP/sodium cholate/phospholipid/silybin = 3:3:4:1∼2 by weight) was obtained based on the study of pseudoternary phase diagrams. The critical micelle concentration was used to evaluate the micellar stability towards dilution. The results showed that addition of PVP to sodium-cholate-phospholipid mixed micelles increased stability. The solubility of sylibin in PVP-sodium cholate-phospholipid mixed micelles was higher than that in pure water or in sodium cholate-phospholipid mixed micelles. In a stability study, we found that PVP-sodium cholate-phospholipid mixed micelles showed good stability. After 3 months storage at 40°C, just 2.6% sylibin was lost with only minor changes of the particle size when compared to a reference formulation containing sodium cholate and phospholipid mixed micelles. In addition, the developed formulation significantly improved in vitro drug release. The time required to release 50% sylibin (t50%) from sodium cholate and phospholipid mixed micelles was 326 h, while the t50% from PVP-sodium cholate-phospholipid mixed micelles was only 51.1 h. Our results suggest that these mixed micelles might have significant potential application to the biomedical field.     

A comparative study on the effects of amphiphilic and hydrophilic polymers on the release profiles of a poorly water-soluble drug

This paper reports the use of two crystalline polymers, an amphiphilic Pluronic® F-127 (PF-127) and a hydrophilic poly(ethylene glycol) (PEG6000) as drug delivery carriers for improving the drug release of a poorly water-soluble drug, fenofibrate (FEN), via micelle formation and formation of a solid dispersion (SD). In 10% PF-127 (aq.), FEN showed an equilibrium solubility of ca. 0.6?mg/mL, due to micelle formation. In contrast, in 10% PEG6000 (aq.), FEN only exhibited an equilibrium solubility of 0.0037?mg/mL. FEN-loaded micelles in PF-127 were prepared by direct dissolution and membrane dialysis. Both methods only yielded a highest drug loading (DL) of 0.5%. SDs of FEN in PF-127 and PEG6000, at DLs of 5–80%, were prepared by solvent evaporation. In-vitro dissolution testing showed that both micelles and SDs significantly improved FEN’s release rate. The SDs of FEN in PF-127 showed significantly faster release than crystalline FEN, when the DL was as high as 50%, whereas SDs of PEG6000 showed similar enhancement in the release rate when the DL was not more than 20%. The DSC thermograms of SDs of PF-127 exhibited a single phase transition peak at ca. 55–57?°C when the DL was not more than 50%, whereas those in PEG6000 exhibited a similar peak at ca. 61–63?°C when the DL was not more than 35%. When the DL exceeded 50% for SDs of PF-127 and 35% for SDs of PEG6000, DSC thermograms showed two melting peaks for the carrier polymer and FEN, respectively. FT-IR studies revealed that PF-127 has a stronger hydrophobic–hydrophobic interaction with FEN than PEG6000. It is likely that both dispersion and micelle formation contributed to the stronger effect of PF-127 on enhancing the release rate of FEN in its SDs.     

Preparation and characterization of polymeric micelles for solubilization of poorly soluble anticancer drugs.

The objective of this study is to investigate the solubilization of poorly water-soluble anticancer drugs, octaethylporphine (OEP), meso-tetraphenyl porphine (mTPP) and camptothecin (CPT), in Pluronic and polyethylene glycol-distearoylphosphatidylethanolamine (PEG-DSPE) polymeric micelles. Three different Pluronic and PEG-DSPE polymers with various chain lengths were chosen and micelle formulations were prepared by using various drug:polymer ratios. Formulations were characterized by critical micellization concentration (CMC) values of copolymers, micelle particle size and distribution, zeta potential, loading efficiency and stability. Polymers formed very stable, low CMC micelles with smaller sizes than 100 nm. It was shown that drug loading efficiency highly depends on the polymer type, drug type and their ratios. The most efficient drug loading was obtained by loading mTPP in PEG2000-DSPE and Pluronic F127 micelles. This result is attributed to phenyl groups in mTPP might lead to attraction between alkyl groups in the polymer and increase drug incorporation. PEG-DSPE formulations had higher zeta potential values indicating that they would be more stable against aggregation than Pluronic micelles. From the drug assay aspect Pluronic micelles remained more stable in 3-month long stability test. These results showed that besides their solubilizing effects, polymeric micelles could be useful as novel drug carriers for hydrophobic drugs.     

9-硝基喜树碱在大鼠组织中的分布及内酯稳定性

考察9-硝基喜树碱(9-NC)静脉注射后在人鼠组织中的分布及内酯稳定性.建立了HPLC法间时测定组织和血浆中9-NC内酯浓度和总浓度.大鼠静脉注射9-NC溶液后测定各时间点组织中内酯浓度、总浓度和内酯比例.大多数组织中的9-NC内酯比例明显高于血浆;肝中的内酯比例最低,甚至低于血浆;血浆、肾和小肠中的内酯比例随时问延长而下降.9-NC在肝以外的组织中内酯稳定性显著优于血浆.