PCL Block Length Research Articles

Synthesis, Characterization and Evaluation of Segmented Polycaprolactone for Development of Dura Substitute

Molecular design and modification allow the properties of degradable materials to be suited for specific requirement of biomedical applications. For example, the dura substitute requires both mechanically and biologically suitable for repairing loss of dura mater. Here in this paper, a novel urethane linkage containing poly(ɛ-caprolactone) (PCL) for use as dura substitute was synthesized by solution polymerization. By using ɛ-caprolactone precursors with different molecular weights and ratios, a series of segmented poly(ɛ-caprolactone) (sPCL) were obtained via ring opening polymerization with diisocynate as coupling agent. The chemical structures of sPCL were characterized by means of GPC, IR, and 1H NMR. The effect of PCL block length on thermal behavior has been investigated using differential scanning calorimeter (DSC). Physical properties such as mechanical properties and invitro degradation rate were evaluated and the results also suggest that urethane linked PCL exhibit tunable degradation rate that is controlled by the PCL block length. sPCL membrane were fabricated and evaluated in vitro and in vivo as dura substitute.

Synthesis, Characterization and Crystallization of Poly(Ethylene Glycol)-b-Poly(ε-Caprolactone)

A family of poly(ethylene glycol)-b-poly(ε-caprolactone) (PEG-PCL) were synthesized in high yields by the ring-opening polymerization of monomethoxy-terminated poly(ethylene glycol) (mPEG) with ε-caprolactone in the presence of stannous octoate (Sn(Oct)2). Their crystallization behaviors were studied by DSC, XRD. The results illustrated that crystallization behaviors of the copolymers depended on the copolymer composition and the relative length of each block in copolymers. The melting peak of PCL block appeared gradually in the XRD patterns and DSC curves in copolymers, with increasing of the length of PCL blocks.

Microencapsulation of cytarabine using poly(ethylene glycol)–poly(ε-caprolactone) diblock copolymers as surfactant agents

Background: The high water solubility and the low molecular weight of cytarabine (Ara-C) are major obstacles against its particulate formulation as a result of its low affinity to the commonly used hydrophobic polymers. Methods: Biodegradable cytarabine loaded-microparticles (Ara-C MPs) were elaborated using poly(ϵ-caprolactone) (PCL) and monomethoxy polyethylene glycol (mPEG)–PCL diblock copolymer in order to increase the hydrophilicity of the polymeric matrix. For this purpose, a series of mPEG–PCL diblock copolymers with different PCL block lengths were synthesized. Compositions and molecular weights of obtained copolymers were characterized by Fourier transform infrared spectroscopy, nuclear magnetic resonance, size exclusion chromatography, and size exclusion chromatography–multi-angle laser light scattering. Ara-C MPs were prepared by double emulsion-solvent evaporation method. The effects of varying PCL block lengths on microparticle encapsulation efficiency, size, and zeta potential were evaluated. Results: Increasing the PCL block lengths of copolymers substantially increased the Ara-C encapsulation efficiency and the microparticle size but it decreased their zeta potential. Microparticles were spherical in shape, with a smooth surface and composed of homogenously distributed Ara-C-containing aqueous domains in the polymer matrix. The in vitro drug release kinetics of the optimized microparticles showed a hyperbolic profile with an initial burst release. Conclusion: These results showed the important role of the amphiphilic diblock copolymers as stabilizing agent in the encapsulation of Ara-C in PCL microparticles, suggesting their potential use for the microparticulate formulations of other small hydrophilic bioactive molecules.

Magnetic core-bilayer shell nanoparticle: A novel vehicle for entrapmentof poorly water-soluble drugs

We are herein reporting a synthesis of indomethacin-loaded bilayer-surface magnetite nanoparticles and their releasing behavior. The particles were first stabilized with oleic acid as a primary surfactant, followed by poly(ethylene glycol) methyl ether-poly(3-caprolactone) (mPEG–PCL) amphiphilic block copolymer as a secondary surfactant to form nanoparticles with hydrophobic inner shell and hydrophilic corona. mPEG–PCL copolymers with systematically varied molecular weights of each block (2000–2000, 2000–10,000, 5000–5000 and 5000–10,000 g/mol, respectively) were synthesized via a ring-opening polymerization of 3-caprolactone using mPEG as a macroinitiator. The particles were 9 nm in diameter and exhibited superparamagnetic behavior at room temperature with saturation magnetization (Ms) about 35 emu/g magnetite. Percent of magnetite and the copolymers in the complexes were determined via thermogravimetric analysis (TGA). The effect of mPEG and PCL block lengths in the copolymer– magnetite complex on the properties of the particles, e.g. particle size, magnetic properties, stability in water, drug entrapping and loading efficiency and its releasing behavior were investigated. This novel magnetic nanocomplex might be suitable for use as an efficient drug delivery vehicle with tunable drugreleased properties.

In vivo implantation of 2,2′-bis(oxazoline)-linked poly-ɛ-caprolactone: Proof for enzyme sensitive surface erosion and biocompatibility

Previously, we have demonstrated that 2,2-bis(2-oxazoline) linked poly-ɛ-caprolactone (PCL-O) is degraded in vitro enzymatically by surface erosion which could enable the novel use of this material for drug delivery and other biomedical applications. In this study, degradation, erosion (weight loss) and toxicity of PCL-O poly(ester-amide)s were evaluated in vivo. PCL and three PCL-O polymers with different PCL block lengths (Mn: 1500, 3900, 7500g/mol) were melt-pressed in the form of discs and implanted subcutaneously in Wistar rats (dose ∼340mg/kg) for 1, 4 and 12 weeks. With implantation for 12 weeks, up to 16.5% weight loss of polymer discs was measured for the most extensively linked PCL-O polymer (block length 1500g/mol) whereas practically no weight loss was observed with the other polymers. NMR, DSC and SEC studies as well as SEM micrographs before and after implantation and in vitro hydrolysis studies indicate that enzyme based surface erosion of PCL-O polymers occurred in vivo. The in vivo evaluation based on results from hematology, clinical chemistry and histology of the implantation area and main organs (i.e. heart, lung, liver, kidney, spleen and brain) demonstrated that PCL-O polymers are biocompatible and safe, enzyme sensitive biomaterials.

Synthesis and characterization of poly(ε‐caprolactone)‐b‐poly(ethylene glycol)‐b‐poly(ε‐caprolactone) triblock copolymers with dibutylmagnesium as catalyst

AbstractTwo series of poly(ε‐caprolactone)‐b‐poly(ethylene glycol)‐b‐poly(ε‐caprolactone) triblock copolymers were prepared by the ring opening polymerization of ε‐caprolactone in the presence of poly(ethylene glycol) and dibutylmagnesium in 1,4‐dioxane solution at 70°C. The triblock structure and molecular weight of the copolymers were analyzed and confirmed by 1H NMR, 13C NMR, FTIR, and gel permeation chromatography. The crystallization and thermal properties of the copolymers were investigated by wide‐angle X‐ray diffraction (WAXD) and differential scanning calorimetry (DSC). The results illustrated that the crystallization and melting behaviors of the copolymers were depended on the copolymer composition and the relative length of each block in copolymers. Crystallization exothermal peaks (Tc) and melting endothermic peaks (Tm) of PEG block were significantly influenced by the relative length of PCL blocks, due to the hindrance of the lateral PCL blocks. With increasing of the length of PCL blocks, the diffraction and the melting peak of PEG block disappeared gradually in the WAXD patterns and DSC curves, respectively. In contrast, the crystallization of PCL blocks was not suppressed by the middle PEG block. © 2008 Wiley Periodicals, Inc. J Appl Polym Sci, 2009

In vitro human plasma distribution of nanoparticulate paclitaxel is dependent on the physicochemical properties of poly(ethylene glycol)-block-poly(caprolactone) nanoparticles

In this study, we synthesized and characterized two methoxy poly(ethylene glycol)-block-poly(caprolactone) (MePEG-b-PCL) amphiphilic diblock copolymers, both based on MePEG with a molecular weight of 5000 g/mol (114 repeat units) and PCL block lengths of either 19 or 104 repeat units. Nanoparticles were formed from these copolymers by a nanoprecipitation and dialysis technique. The MePEG 114-b-PCL 19 copolymer was water soluble and formed micelles that had a hydrodynamic diameter of 40 nm at all copolymer concentrations tested, and displayed a relatively low core microviscosity. The practically water insoluble MePEG 114-b-PCL 104 copolymer formed nanoparticles with a larger hydrodynamic diameter, which was dependent on copolymer concentration, and possessed a higher core microviscosity than the MePEG 114-b-PCL 19 micelles, characteristic of nanospheres. The micelles solubilized a maximum of 1.6% w/w of the hydrophobic anticancer agent, paclitaxel (PTX), and released 92% of their drug payload over 7 days, as compared to the nanospheres, which solubilized a maximum of 3% w/w of PTX and released 60% over the same period of time. Both types of nanoparticles were found to be hemocompatible, causing only minimal hemolysis and no changes in plasma coagulation times as compared to control. Upon in vitro incubation in human plasma, PTX solubilized by micelles had a plasma distribution similar to free drug. The majority of PTX was associated with the lipoprotein deficient plasma (LPDP) fraction, which primarily consists of albumin and alpha-1-acid glycoprotein. In contrast, nanospheres were capable of retaining more of the encapsulated drug with significantly less PTX partitioning into the LPDP fraction.

Temperature sensitivity and drug encapsulation of star‐shaped amphiphilic block copolymer based on dendritic poly(ether‐amide)

The star-shaped amphiphilic block copolymer (DPEA-PCL-PNIPAAms) with different PCL block lengths was prepared through ring opening polymerization of epsilon-caprolactone (CL) initiated by hydroxyl end-capped dendritic poly(ether-amide) (DPEA-OH), and then coupling with carboxyl end-capped linear poly(N-isopropylacrylamide) (PNIPAAm-COOH) via an esterification process. The molecular structure was characterized by FT-IR, (1)H NMR, and GPC analysis. As the copolymer dissolved in water, the core-shell structural nanoparticle was formed as a micelle. The fluorescence, (1)H NMR, and dynamic light scattering (DLS) techniques were utilized to confirm the formation of micelles. The optical transmittance and US-DSC measurements demonstrated that the micelles performed the reversible dispersion/aggregation behavior in response to temperature through the outer PNIPAAm polymer shell. The micelles loaded with daidzein showed a very rapid drug release speed at temperatures above the lower critical solution temperature (LCST) due to the temperature-induced structural change of the polymeric micelles.

Self-Assembled Micelles of Biodegradable Triblock Copolymers Based on Poly(ethyl ethylene phosphate) and Poly(ϵ-caprolactone) as Drug Carriers

A series of novel amphiphilic triblock copolymers of poly(ethyl ethylene phosphate) and poly(-caprolactone) (PEEP-PCL-PEEP) with various PEEP and PCL block lengths were synthesized and characterized. These triblock copolymers formed micelles composed of a hydrophobic core of poly(-caprolactone) (PCL) and a hydrophilic shell of poly(ethyl ethylene phosphate) (PEEP) in aqueous solution. The micelle morphology was spherical, determined by transmission electron microscopy. It was found that the size and critical micelle concentration values of the micelles depended on both hydrophobic PCL block length and PEEP hydrophilic block length. The in vitro degradation characteristics of the triblock copolymers were investigated in micellar form, showing that these copolymers were completely biodegradable under enzymatic catalysis of Pseudomonas lipase and phosphodiesterase I. These triblock copolymers were used for paclitaxel (PTX) encapsulation to demonstrate the potential in drug delivery. PTX was successfully loaded into the micelles, and the in vitro release profile was found to be correlative to the polymer composition. These biodegradable triblock copolymer micelles are potential as novel carriers for hydrophobic drug delivery.

Synthesis, isothermal crystallization and micellization of mPEG–PCL diblock copolymers catalyzed by yttrium complex

Amphiphilic biodegradable mPEG–PCL diblock copolymers have been synthesized using rare earth catalyst: yttrium tris(2,6-di-tert-butyl-4-methylphenolate) [Y(DBMP)3] in the presence of monomethoxy poly(ethylene glycol) (mPEG, Mn=5000) as macro-initiator. The diblock architecture of the copolymers was thoroughly characterized by 1H NMR, 13C NMR and SEC. The molecular weights of mPEG–PCLs can be well controlled by adjusting the feeding molar ratio of ɛ-CL to mPEG. Thermal and crystallization behaviors of the diblock copolymers were investigated by DSC and POM (polarized optical microscope). The crystallization property of mPEG–PCL block copolymers depends on the length of PCL blocks. As the molecular weight of PCL block increased, the crystallization ability of mPEG block was visibly restrained. Aqueous micelles were prepared by dialysis method. The critical micelle concentration of the copolymers, which was determined to be 0.9–6.9mg/L by fluorescence technique, increased with the decreasing of PCL block length. The particle sizes determined by DLS were 30–80nm increasing with the PCL block length. TEM images showed that these micelles were regularly spherical in shape.

Synthesis and Characterization of Random and Triblock Copolymers of ε-Caprolactone and (Benzylated)hydroxymethyl glycolide

The aim of this study was to develop new polyesters with pendant functional hydrophilic groups suitable for biomedical applications. Therefore, ε-caprolactone (CL) was copolymerized with benzyl protected hydroxymethyl glycolide (BHMG) to introduce, after deprotection, hydroxyl groups into the polyester. Random and triblock copolymers were synthesized in the melt using benzyl alcohol and tin(II) 2-ethylhexanoate as initiator and catalyst, respectively, and deprotected by hydrogenation. The synthesized polyesters before and after deprotection were characterized by NMR, GPC, and DSC measurements. Mixtures of CL and BHMG were polymerized at 110, 130, and 150 °C. A polymerization kinetics study revealed that BHMG was far more reactive than CL at the three reaction temperatures investigated. However, due to transesterification reactions, random copolymers were formed at 150 °C, whereas at 110 °C, the copolymers had a more blocky structure. Taking advantage of this knowledge, ABA triblock copolymers of poly(ε-caprolactone) (PCL, block B) and poly(benzyl protected hydroxymethyl glycolide) (PBHMG, block A) were synthesized. To this end, α,ω PCL-diols were first synthesized at 130 °C by melt polymerization of CL initiated with 1,4-butanediol, which were subsequently chain extended with BHMG at 130 °C. Four triblock copolymers with different PCL (from 2.3 to 4.8 kg/mol) and PBHMG (from 2.0 to 4.3 kg/mol) block lengths were synthesized. The random copolymers (before and after deprotection) were fully amorphous and had their Tg ranging from −29 to −16 °C. Before deprotection, the blocks of the triblock copolymers were fully miscible, while triblock copolymers showed phase separation and were semicrystalline materials after deprotection. The PCL segments crystallize with a Tm ranging from 39 to 46 °C. The latter polymers are interesting for tissue engineering applications because they enable the formation of porous dimensionally stable materials at body temperature.

Degradation behaviors of monomethoxy poly(ethylene glycol)‐b‐poly(ε‐caprolactone) nanoparticles in aqueous solution

AbstractMonomethoxy poly(ethylene glycol)‐b‐poly(ε‐caprolactone)(MPEG‐b‐PCL) diblock copolymers were synthesized via a ring‐opening polymerization. The polymeric nanoparticles prepared by precipitation/solvent evaporation exhibit a core–shell structure, characterized by dynamic light scattering (DLS), nuclear magnetic resonance (NMR), and atomic force microscopy (AFM). The hydrolytic degradation of those nanoparticles was studied by DLS, NMR, and gel permeation chromatography (GPC). It was found that the molecular weight of PCL block in a copolymer significantly affects the stability of nanoparticles in aqueous solution and nanoparticles with shorter PCL block length degraded faster. The degradation behaviors could be divided into two stages with slow degradation at the interface region via swelling effect and fast degradation at inner core via caves and channels formed by cleavage of ester bonds. Copyright © 2007 John Wiley & Sons, Ltd.

Degradation behaviors of star-shaped poly(ethylene glycol)–poly(ɛ-caprolactone) nanoparticles in aqueous solution

Star-shaped poly(ethylene glycol) (PEG)–poly(ɛ-caprolactone) (ɛ-PCL) block copolymers were synthesized via a ring-opening polymerization. Nanoparticles prepared by the precipitation/solvent evaporation technique exhibit a core-shell structure. The hydrolytic degradation of 3-arm PEG–PCL copolymeric nanoparticles was studied by dynamic light scattering (DLS), nuclear magnetic resonance (NMR) and gel permeation chromatography (GPC). It was found that copolymers with shorter PCL block length degraded faster. The sizes of nanoparticles fluctuated during the initial degradation period, and then increased slightly before finally dropping off. The degradation mainly occurred at CL–CL linkages firstly then at the EO–CL linkages. The CL/EO molar ratios and the molecular weights of copolymers decreased as degradation time and a zero-order degradation behavior was observed.

Amphiphilic biodegradable poly(CL- b-PEG- b-CL) triblock copolymers prepared by novel rare earth complex: Synthesis and crystallization properties

Amphiphilic biodegradable poly(CL- b-PEG- b-CL) triblock copolymers have been successfully prepared by the ring-opening polymerization of ε-caprolactone (CL) employing yttrium tris(2,6-di-tert-butyl-4-methylphenolate) [Y(DBMP) 3] as catalyst and double-hydroxyl capped PEGs (DHPEG) as macro-initiator. The triblock architecture, molecular weight, thermal and crystallization properties of the copolymers were characterized by NMR spectra, SEC, DSC and WAXD analyses. The isothermal crystallization behavior of the copolymers was investigated by POM analysis in detail, which is greatly influenced by the length of PCL and PEG blocks. On the POM micrograph of PEG 10,000–(PCL 8600) 2, a unique morphology of concentric spherulites was observed due to the sequent crystallization of the PCL and PEG blocks.

Effects of block length on the enzymatic degradation and erosion of oxazoline linked poly-ɛ-caprolactone

The aim of the study was to develop enzyme sensitive polymers for pharmaceutical applications. Thus, 2,2′-bis(2-oxazoline)-linked poly-ɛ-caprolactone (PCL-O) polymers were synthesized by using ɛ-caprolactone precursors with different molecular weights ( M n: 1500, 3900, 7500 and 12,000 g/mol), and the effects of PCL block length on enzymatic degradation and erosion (weight loss) of PCL-O films were studied. Solvent cast PCL and PCL-O films were incubated (22 days) in the presence of pancreatin (1%, pH 7.5), with and without enzyme inhibitors. In the absence of enzyme inhibitors, surface erosion of the PCL-O films occurred during incubation, and the erosion of the PCL-O films increased in parallel with a decrease in the PCL block length. The presence of the lipase inhibitors, paraoxon-ethyl and tetrahydrolipstatin delayed the weight loss of the PCL-O films. These results indicate that lipase was mainly responsible for the enzymatic erosion of the PCL-O films. In comparison, practically no weight loss of the PCL or the PCL-O films was observed in phosphate buffer (pH 7.4) (28 days incubation). The results demonstrate that the studied ɛ-caprolactone based poly(ester-amide)s are enzyme sensitive polymers whose erosion rate can be controlled by the PCL block length.

Micellization and gelation of aqueous solutions of star-shaped PEG–PCL block copolymers consisting of branched 4-arm poly(ethylene glycol) and polycaprolactone blocks

Star-shaped block copolymers consisting of non-toxic poly(ethylene glycol) and biodegradable polycaprolactone ((PEG5K–PCL) 4) were synthesized by ring-opening polymerization of the ε-caprolactone monomer with hydroxyl-terminated 4-armed PEG as initiator. These biodegradable, amphiphilic star block copolymers showed micellization and sol–gel transition behaviors in aqueous solution with varying concentration and temperature. In the dilute aqueous solutions of star block copolymers, micellization behavior occurred over specific concentration. The 1,6-diphenyl-1,3,5-hexatriene (DPH) solubilization method was used to determine the critical micellization concentration (CMC) of star block copolymers. The obtained micelle size increased with increasing hydrophobic PCL block length. In high-concentration solutions, the star block copolymers showed temperature-sensitive sol–gel transition behavior. The morphology of the micelle and gel was investigated by atomic force microscopy (AFM). As a result, the micelles showed a core-corona spherical structure at concentration near CMC, while the gel showed a mountain-chain-like morphology picture. It was proposed that with increasing the micelle concentration the worm-like micelle clusters formed firstly and the gel was constructed by the packing of micelle clusters.

In vivo fate of unimers and micelles of a poly(ethylene glycol)-block-poly(caprolactone) copolymer in mice following intravenous administration

Methoxy poly(ethylene glycol)- b-poly(caprolactone) (MePEG- b-PCL) copolymers with varying PEG block lengths and a constant PCL block length were synthesized by cationic ring-opening polymerization and used to form nano-sized micelles. Due to their small size and superior in vitro stability, the MePEG 5000- b-PCL 5000 micelles were selected for further in vitro characterization and an in vivo evaluation of their fate and stability following intravenous (i.v.) administration. Specifically, 3H-labelled MePEG 5000- b-PCL 5000 micelles were i.v. administered to Balb/C mice at copolymer doses of 250, 2 and 0.2 mg/kg in order to examine the distribution kinetics of (1) copolymer assembled as thermodynamically stable micelles, (2) copolymer assembled as thermodynamically unstable micelles and (3) copolymer unimers, respectively. Overall, it was found that when the copolymer is assembled as thermodynamically stable micelles the material is effectively restricted to the plasma compartment. Interestingly, the copolymer was found to have a relatively long circulation half-life even when administered at a dose that would likely fall to concentrations below the CMC following distribution. Analysis of plasma samples from this group revealed that even 24 h post-administration a significant portion of the copolymer remained assembled as intact micelles. In this way, this study demonstrates that the hydrophobic and semi-crystalline nature of the PCL core imparts a high degree of kinetic stability to this micelle system.

Composition Dependence of the Crystallization Behavior and Morphology of the Poly(ethylene oxide)-poly(ε-caprolactone) Diblock Copolymer

The crystallization behavior and morphology of the crystalline-crystalline poly(ethylene oxide)-poly(epsilon-caprolactone) diblock copolymer (PEO-b-PCL) was studied by differential scanning calorimetry (DSC), wide-angle X-ray diffraction (WAXD), Fourier transform infrared spectroscopy (FTIR), small-angle X-ray scattering (SAXS), and hot-stage polarized optical microscope (POM). The mutual effects between the PEO and PCL blocks were significant, leading to the obvious composition dependence of the crystallization behavior and morphology of PEO-b-PCL. In this study, the PEO block length was fixed (Mn = 5000) and the weight ratio of PCL/PEO was tailored by changing the PCL block length. Both blocks could crystallize in PEO-b-PCL with the PCL weight fraction (WFPCL) of 0.23-0.87. For the sample with the WFPCL of 0.36 or less, the PEO block crystallized first, resulting in the obvious confinement of the PCL block and vice versa for the sample with WFPCL of 0.43 or more. With increasing WFPCL, the crystallinity of PEO reduced continuously while the variation of the PCL crystallinity exhibited a maximum. The long period of PEO-b-PCL increased with increasing WFPCL from 0.16 to 0.50 but then decreased with the further increase of WFPCL due to the interaction of the respective variation of the thicknesses of the PEO and PCL crystalline lamellae. Only the PEO spherulites were observed in samples with WFPCL of 0.16-0.36 by POM, in contrast to only the PCL spherulites in samples with WFPCL of 0.56-0.87. For samples with WFPCL of 0.43 and 0.50, a unique concentric spherulite was observed. The morphology of the inner and outer portions of the concentric spherulites was determined by the PCL and PEO spherulites, respectively. The growth rate of the PEO spherulites reduced rapidly with increasing WFPCL from 0 to 0.50. However, when increasing WFPCL from 0.43 to 0.87, the variation of the growth rate of the PCL spherulites exhibited a maximum rather than a monotonic change.

Aggregation behavior of MPEG‐PCL diblock copolymers in aqueous solutions and morphologies of the aggregates

AbstractPoly(ethylene glycol)‐b‐polycaprolactone (MPEG‐PCL) diblock copolymers were synthesized via a ring‐opening polymerization of ε‐CL monomers with MPEG as an initiator. Their solubilities and apparent critical micelle concentrations (CMC) in aqueous solution were investigated as well as the determination of the micellar hydrodynamic diameter using dynamic light scattering (DLS). As PCL block length increased, the solubility and CMC decreased while diameters of micelles increased. The gel–sol transition behaviors were investigated using a vial tilting method. Aqueous solutions of copolymers undergo a gel to sol transition with increase in temperature when their polymer concentrations are above a critical gel concentration (CGC). The CGC of the copolymers and gel–sol transition temperature are influenced by the PCL chain length. The tapping mode AFM was performed by imaging the freeze‐dried deposits from the copolymer solutions on mica to investigate a process from free chains to micelles and to gel. © 2006 Wiley Periodicals, Inc. J Polym Sci Part B: Polym Phys 44: 3406–3417, 2006

Encapsulation of hydrophobic drugs in polymeric micelles through co-solvent evaporation: The effect of solvent composition on micellar properties and drug loading

This study was designed to develop an optimized co-solvent evaporation procedure for the efficient encapsulation of hydrophobic drugs in polymeric micelles of methoxy poly(ethylene oxide)- block-poly(ɛ-caprolactone) (MePEO- b-PCL). MePEO- b-PCL block copolymers having varied MePEO and PCL molecular weights were synthesized, assembled to polymeric micelles, and used for the encapsulation of cyclosporine A (CyA) by a co-solvent evaporation method. The co-solvent composition was varied by changing the type of organic co-solvent (using acetone, acetonitrile and tetrahydrofuran), the ratio of organic to aqueous phase, and their order of addition. Carrier size, morphology and encapsulated CyA levels were defined by dynamic light scattering (DLS), transmission electron microscopy (TEM) and HPLC, respectively, and the effect of co-solvent composition on micellar properties and loaded CyA levels was evaluated. Application of acetone and acetonitrile as the selective co-solvent for the core-forming block led to a decrease in the average diameter of self-assembled structures. When acetone was added to water, a decrease in the ratio of organic to aqueous phase led to an increase in the loading efficiency of CyA in MePEO- b-PCL micelles. A similar trend in CyA loading was observed for MePEO- b-PCL micelles of varied MePEO and PCL block lengths. The ratio of organic to aqueous phase did not affect CyA loading when water was added to acetone. Irrespective of the order of addition, the decrease in the organic to aqueous phase ratio caused a reduction in the average diameter of the empty and CyA loaded micelles. We conclude that the co-solvent evaporation method may be optimized to improve the efficiency of drug encapsulation in polymeric micelles. For CyA encapsulation in MePEO- b-PCL micelles, addition of acetone to water at lower organic to aqueous phase ratio is shown to be the optimum procedure leading to higher drug encapsulation and smaller average diameter for the self-assembled structures.