Size Control in Production and Freeze-Drying of Poly-ε-Caprolactone Nanoparticles

This work is focused on the control of poly-ε-caprolactone nanoparticle characteristics, notably size and size distribution, in both the production and preservation (by using freeze-drying) stages. Nanoparticles were obtained by employing the solvent displacement method in a confined impinging jets mixer. The effect of several operating conditions, namely, initial polymer concentration and solvent-to-antisolvent flow rate ratio, and the influence of postprocessing conditions, such as final dilution and solvent evaporation, on nanoparticle characteristics was investigated. Further addition of antisolvent (water) after preparation was demonstrated to be effective in obtaining stable nanoparticles, that is, avoiding aggregation that would result in larger particles. On the contrary, solvent (acetone) evaporation was shown to have a small effect on the final nanoparticle characteristics. Eventually, freeze-drying of the solutions containing nanoparticles, after solvent evaporation, was also investigated. To ensure maximum nanoparticles stability, lyoprotectants (e.g., sucrose and mannitol) and steric stabilizers (e.g., Cremophor EL and Poloxamer 388) had to be added to the suspensions. The efficacy of the selected lyoprotectants, in the presence (or absence) of steric stabilizers, and in various concentrations, to avoid particle aggregation during the freeze-drying process was investigated, thus pointing to the optimal formulation. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 103:1839–1850, 2014     

Poly(ε-Caprolactone) Nanocapsules in Carteolol Ophthalmic Delivery

In order to increase the ocular absorption of carteolol, this antiglaucomatous drug was incorporated into either nanoparticles (NP) or nanocapsules (NC). The polymer used was poly(-caprolactone) (PCL). The dosage forms were tested on intraocular hypertensive-induced rabbits. Results are presented as the chronological variations of the intraocular pressure (IOP) in comparison with the commercial aqueous solution (Carteol eye drops). The therapeutic results (decrease in IOP) were much more pronounced with carteolol incorporated into the colloidal carriers than with the commercial eye drops. Further, NC displayed a better effect than NP because the drug was entrapped in the oily core of the carrier, thus more readily available to the eye. The incorporation of the drug into nanocapsules produced a decline in the cardiovascular side effects in comparison with aqueous eye drops, thus showing that the undesired noncorneal absorption was reduced. In conclusion, colloidal suspension made of poly(-caprolactone) could offer a good opportunity for ophthalmic delivery of drugs.     

In Vitro and In Vivo Safety Evaluation of Biodegradable Self-Assembled Monomethyl Poly (Ethylene Glycol)–Poly(ε-Caprolactone)–Poly (Trimethylene Carbonate) Micelles

Safety evaluation of self-assembled polymeric micelles is important for biomedical involvement in drug delivery systems in the future. In this study, biodegradable monomethyl poly (ethylene glycol)–poly (ε-caprolactone)–poly (trimethylene carbonate) [MPEG–P(CL-co-TMC)] copolymer was synthesized and characterized by Fourier transform infrared spectroscopy, nuclear magnetic resonance analysis, and gel permeation chromatography. MPEG–P(CL-co-TMC) micelles were prepared by self-assembly without any organic solvent. The present study was conducted to assess the safety of blank MPEG–P(CL-co-TMC) micelles both in vitro and in vivo. Particle size (30.09 ± 0.06 nm) and zeta potential (0.067 ± 0.027 mV) of obtained micelles were determined by Malvern laser particle size analyzer. The results of in vitro toxicity evaluation implied that the prepared micelles did not cause hemolysis or severely cell toxicity. Meanwhile, we did not observe any toxic response or histopathological changes in the study of in vivo acute toxicity evaluation and histopathological study of MPEG–P(CL-co-TMC) micelles. In conclusion, the maximal tolerance dose of MPEG–P(CL-co-TMC) micelles (100 mg/mL) by intravenous injection was supposed to be greater than 10 g/kg body weight. Therefore, it might have potential applications in biomedical field. © 2013 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 103:305–313, 2014     

Comparative Study of Poly (ε-Caprolactone) and Poly(Lactic-co-Glycolic Acid) -Based Nanofiber Scaffolds for pH-Sensing

Purpose

This study aims to develop biodegradable and biocompatible polymer-based nanofibers that continuously monitor pH within microenvironments of cultured cells in real-time. In the future, these fibers will provide a scaffold for tissue growth while simultaneously monitoring the extracellular environment.

Methods

Sensors to monitor pH were created by directly electrospinning the sensor components within a polymeric matrix. Specifically, the entire fiber structure is composed of the optical equivalent of an electrode, a pH-sensitive fluorophore, an ionic additive, a plasticizer, and a polymer to impart mechanical stability. The resulting poly(ε-caprolactone) (PCL) and poly(lactic-co-glycolic acid) (PLGA) based sensors were characterized by morphology, dynamic range, reversibility and stability. Since PCL-based nanofibers delivered the most desirable analytical response, this matrix was used for cellular studies.

Results

Electrospun nanofiber scaffolds (NFSs) were created directly out of optode material. The resulting NFS sensors respond to pH changes with a dynamic range centered at 7.8?±?0.1 and 9.6?±?0.2, for PCL and PLGA respectively. NFSs exhibited multiple cycles of reversibility with a lifetime of at least 15 days with preservation of response characteristics. By comparing the two NFSs, we found PCL-NFSs are more suitable for pH sensing due to their dynamic range and superior reversibility.

Conclusion

The proposed sensing platform successfully exhibits a response to pH and compatibility with cultured cells. NSFs will be a useful tool for creating 3D cellular scaffolds that can monitor the cellular environment with applications in fields such as drug discovery and tissue engineering.

     

Nanoparticles Based on Linear and Star-Shaped Poly(Ethylene Glycol)-Poly(ε-Caprolactone) Copolymers for the Delivery of Antitubulin Drug

Purpose

Biodegradable polymeric nanoparticles of different architectures based on polyethylene glycol-co-poly(ε-caprolactone) block copolymers have been loaded with noscapine (NOS) to study their effect on its anticancer activity. It was intended to use solubility of NOS in an acidic environment and ability of the nanoparticles to passively target drugs into cancer tissue to modify the NOS pharmacokinetic properties and reduce the requirement for frequent injections.

Methods

Linear and star-shaped copolymers were synthetized and used to formulate NOS loaded nanoparticles. Cytotoxicity was performed using a sulforhodamine B method on MCF-7 cells, while biocompatibility was determined on rats followed by hematological and histopathological investigations.

Results

Formulae with the smallest particle sizes and adequate entrapment efficiency revealed that NOS loaded nanoparticles showed higher extent of release at pH 4.5. Colloidal stability suggested that nanoparticles would be stable in blood when injected into the systemic circulation. Loaded nanoparticles had IC₅₀ values lower than free drug. Hematological and histopathological studies showed no difference between treated and control groups. Pharmacokinetic analysis revealed that formulation P1 had a prolonged half-life and better bioavailability compared to drug solution.

Conclusions

Formulation of NOS into biodegradable polymeric nanoparticles has increased its efficacy and residence on cancer cells while passively avoiding normal body tissues.

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Graphical Abstract ?

     

Poly(butylcyanoacrylate) and Poly(ε-caprolactone) Nanoparticles Loaded with 5-Fluorouracil Increase the Cytotoxic Effect of the Drug in Experimental Colon Cancer

The clinical use of 5-fluorouracil, one of the drugs of choice in colon cancer therapy, is limited by a nonuniform oral absorption, a short plasma half-life, and by the development of drug resistances by malignant cells. We hypothesized that the formulation of biodegradable nanocarriers for the efficient delivery of this antitumor drug may improve its therapeutic effect against advanced or recurrent colon cancer. Hence, we have engineered two 5-fluorouracil-loaded nanoparticulate systems based on the biodegradable polymers poly(butylcyanoacrylate) and poly(ε-caprolactone). Drug incorporation to the nanosystems was accomplished by entrapment (encapsulation/dispersion) within the polymeric network during nanoparticle synthesis, i.e., by anionic polymerization of the monomer and interfacial polymer disposition, respectively. Main factors determining 5-fluorouracil incorporation within the polymeric nanomatrices were investigated. These nanocarriers were characterized by high drug entrapment efficiencies and sustained drug-release profiles. In vitro studies using human and murine colon cancer cell lines demonstrated that both types of nanocarriers significantly increased the antiproliferative effect of the encapsulated drug. In addition, both nanoformulations produced in vivo an intense tumor growth inhibition and increased the mice survival rate, being the greater tumor volume reduction obtained when using the poly(ε-caprolactone)-based formulation. These results suggest that these nanocarriers may improve the antitumor activity of 5-fluorouracil and could be used against advanced or recurrent colon cancer.KEY WORDS: 5-fluorouracil, colon cancer, poly(butylcyanoacrylate), poly(ε-caprolactone), polymeric nanoparticles     

Cilostazol-Loaded Poly(ε-Caprolactone) Electrospun Drug Delivery System for Cardiovascular Applications

Purpose

The study discusses the value of electrospun cilostazol-loaded (CIL) polymer structures for potential vascular implant applications.

Methods

Biodegradable polycaprolactone (PCL) fibers were produced by electrospinning on a rotating drum collector. Three different concentrations of CIL: 6.25%, 12.50% and 18.75% based on the amount of polymer, were incorporated into the fibers. The fibers were characterized by their size, shape and orientation. Materials characterization was carried out by Fourier Transformed Infrared spectroscopy (FTIR), Raman spectroscopy, differential scanning calorimetry (DSC) and X-ray diffraction (XRD). In vitro drug release study was conducted using flow-through cell apparatus (USP 4).

Results

Three-dimensional structures characterized by fibers diameter ranging from 0.81 to 2.48 μm were in the range required for cardiovascular application. DSC and XRD confirmed the presence of CIL in the electrospun fibers. FTIR and Raman spectra confirmed CIL polymorphic form. Elastic modulus values for PCL and the CIL-loaded PCL fibers were in the range from 0.6 to 1.1 GPa. The in vitro release studies were conducted and revealed drug dissolution in combination with diffusion and polymer relaxation as mechanisms for CIL release from the polymer matrix.

Conclusions

The release profile of CIL and nanomechanical properties of all formulations of PCL fibers demonstrate that the cilostazol loaded PCL fibers are an efficient delivery system for vascular implant application.

     

Preparation and Drug Loading of Poly(Ethylene Glycol)-block-Poly(ε-Caprolactone) Micelles Through the Evaporation of a Cosolvent Azeotrope

PURPOSE: The aim of this work was to study the assembly, drug loading, and stability of poly(ethylene glycol)-block-poly(epsilon-caprolactone) (PEG-b-PCL) micelles. METHODS: Three PEG-b-PCL compositions with PCL number average molecular weights of 1000, 2500, and 4000 g/mol were used. The assembly of PEG-b-PCL micelles, induced by the addition of water to acetonitrile (ACN), was characterized with 1H nuclear magnetic resonance spectroscopy (1H-NMR) and dynamic light scattering (DLS) with and without the presence of fenofibrate, a poorly water-soluble drug. PEG-b-PCL micelles with encapsulated fenofibrate were prepared through the removal of a negative ACN-water azeotrope under reduced pressure. Fenofibrate content was measured using reverse-phase high-performance liquid chromatography (HPLC), whereas the kinetic stability of PEG-b-PCL micelles with and without encapsulated fenofibrate was evaluated using size exclusion chromatography (SEC). RESULTS: The critical water content (CWC), the water content at which amphiphilic block copolymer (ABC) micelle assembly begins, was determined using DLS and ranged from 10% to 30% water, depending on both PCL molecular weight and PEG-b-PCL concentration. As the water content was increased, the PEG-b-PCL unimers assembled into swollen structures with hydrodynamic diameters ranging from 200 to 800 nm. The 1H-NMR peaks associated with the PCL block exhibited line-broadening, following the addition of D2O, indicating that the PCL blocks reside in the core of the PEG-b-PCL micelle. With further addition of water, the PCL cores collapsed to form fairly monodisperse PEG-b-PCL micelles (20-60 nm). In the presence of fenofibrate, the CWC value was lowered, perhaps due to hydrophobic interactions of fenofibrate and the PCL block. Further addition of water and subsequent evaporation of the negative ACN-water azeotrope resulted in fenofibrate-loaded PEG-b-PCL micelles of under 50 nm. The extent of fenofibrate encapsulation was dependent on PCL block size. At a polymer concentration of 1.0 mg/ml, PEG-b-PCL (5000:4000) and (5000:2500) micelles could encapsulate more than 90% of the initial loading level of fenofibrate, whereas PEG-b-PCL (5000:1000) micelles encapsulate only 28%. SEC experiments revealed that PEG-b-PCL (5000:4000) and (5000:2500) micelles eluted intact, indicating kinetic stability, whereas PEG-b-PCL (5000:1000) micelles eluted primarily as unimers. CONCLUSIONS: PEG-b-PCL in ACN assembles with fenofibrate into drug-loaded polymeric micelles with the addition of water and the subsequent removal of a negative ACN-water azeotrope.     

Microencapsulation of Superoxide Dismutase into Poly(ε-Caprolactone) Microparticles by Reverse Micelle Solvent Evaporation

The aim of this work was to encapsulate superoxide dismutase (SOD) in poly(ε-caprolactone) (PCL) microparticles by reverse micelle solvent evaporation. The concentration of PCL, the hydrophile-lipophile balance (HLB), and concentration of the sucrose ester used as surfactant in the organic phase were investigated as formulation variables. Relatively higher encapsulation efficiency (～48%) and retained enzymatic activity (>90%) were obtained with microparticle formulation made from the 20% (w/v) PCL and 0.05% (w/v) sucrose ester of HLB = 6. This formulation allowed the in vitro release of SOD for at least 72 hr. These results showed that reverse micelle solvent evaporation can be used to efficiently encapsulate SOD in PCL microparticles. Such formulations may improve the bioavailability of SOD.     

Coupling of Naltrexone to Biodegradable Poly(α-Amino Acids)

The narcotic antagonist naltrexone (I) was modified at the 3 and 14 hydroxyl positions and covalently coupled to a biodegradable poly(-amino acid) backbone through a labile bond. Selective acetylation of I with acetic anhydride gave naltrexone-3-acetate (II), which was subsequently succinoylated to naltrexone-3-acetate-14-hemisuccinate (III) with succinic anhydride. The polymeric backbone chosen for initial coupling experiments was poly-N ⁵-(3-hydroxypropyl)-L-glutamine (PHPG). The side-chain hydroxyl functionality permitted covalent bonding of III through an ester linkage. Hydrolysis of covalently bound drug to give naltrexone or its derivatives (II and III) should be much slower than diffusion of drug through the polymer matrix. While hydrolysis of naltrexone from the polymer side chain is first order, release of drug from the matrix can be zero order due to the geometry of the device and the physical and chemical interactions between naltrexone and the polymer matrix. In vitro studies of PHPG–naltrexone conjugate in disk form did not show constant release because of the hydrophilic nature of the polymer backbone and the changing local chemical environment upon hydrolysis of drug–polymer linkages. The conjugated system was made more hydrophobic by coupling drug to copolymers of hydroxypropyl-L-glutamine (HPG) and L-leucine. Conjugates of III coupled with copoly(HPG-70/Leu-30) demonstrated a nearly constant, but slightly declining release rate of naltrexone and its derivatives for 28 days in vitro.     

Stability of Interleukin 1β (IL-1β) in Aqueous Solution: Analytical Methods,Kinetics, Products,and Solution Formulation Implications

The thermal stability of IL-1 in aqueous solution as a function of temperature (5–60°C), pH (2–9), buffer (acetate, citrate, tris, and phosphate), and cyroprotectants (sugars, HSA) was investigated in this study. The analytical methodologies included RP-HPLC, SEC, ELISA, IEF-PAGE, SDS-PAGE, and bioassay. The degradation and inactivation of IL-1 at or above 39°C were attributed to autoxidation of the two cysteine residues in the denatured protein, followed by hydrophobic/covalent aggregation and precipitation. At or below 30°C, IEF- and SDS-PAGE results suggest a possible deamidation reaction. The difference in mechanism of degradation precludes the prediction of formulation shelf life from accelerated temperature data. Nonetheless, the good stability observed at 5°C suggests that a solution formulation may be feasible for IL-1.     

Poly (ε-caprolactone) nanocapsules for oral delivery of raloxifene: process optimization by hybrid design approach,in vitro and in vivo evaluation

Abstract

Raloxifene HCl (RLX), a selective oestrogen receptor modulator, has low oral bioavailability (<2%) in humans due to its poor aqueous solubility and extensive first-pass metabolism in gut. In this study, we optimised the method of preparation for poly (ε-caprolactone) (PCL) based nanocapsules of RLX by double emulsion method (w/o/w). A hybrid design approach, Plackett–Burman design followed by rotatable central composite design, was used to arrive at the optimised formulation. The optimised formulation was subjected to in vitro and in vivo evaluation. RLX loaded nanocapsules were spherical in shape with particle size less than 200?nm and high encapsulation efficiency (>80%). RLX-loaded nanocapsules showed 2.1-fold increase in oral bioavailability compared to free RLX. IV pharmacokinetic studies indicated that RLX loaded into nanocapsule had significantly low clearance in comparison with free RLX. Designed nanocapsules showed promise as delivery systems to enhance oral bioavailability and in reducing clearance of raloxifene.     

Complement Activation by Core–Shell Poly(isobutylcyanoacrylate)–Polysaccharide Nanoparticles: Influences of Surface Morphology, Length, and Type of Polysaccharide

Purpose Biodistribution of intravenously administered nanoparticles depends on opsonization. The aim of this study was the evaluation of complement activation induced by nanoparticles coated with different polysaccharides. Influences of size and configuration of dextran, dextran sulfate, or chitosan bound onto nanoparticles were investigated. Method Core–shell nanoparticles were prepared by redox radical or anionic polymerization of isobutylcyanoacrylate in the presence of polysaccharides. Conversion of C3 into C3b in serum incubated with nanoparticles was evaluated. Results Cleavage of C3 increased with size of dextran bound in “loops” configuration, whereas it decreased when dextran was bound in “brush.” It was explained by an increasing steric repulsive effect of the brush, inducing poor accessibility to OH groups. The same trend was observed for chitosan-coated nanoparticles. Nanoparticles coated with a brush of chitosan activated the complement system lesser than nanoparticles coated with a brush of dextran. This was explained by an improved repelling effect. Dextran-sulfate-coated nanoparticles induced a low cleavage of C3 whereas it strongly enhanced protein adsorption. Conclusion Complement activation was highly sensitive to surface features of the nanoparticles. Type of polysaccharide, configuration on the surface, and accessibility to reactive functions along chains are critical parameters for complement activation.     

Accelerated Degradation of Poly(ε-caprolactone) by Organic Amines

The solid-state degradation of poly(-caprolactone) catalyzed by primary, secondary and tertiary alkylamines was investigated. The degradation process was monitored by weight loss and molecular weight change measured by gel permeation chromatography. Degradation studies were conducted at 37°C in methanol solutions of the alkylamines. Primary alkylamines caused rapid weight loss (i.e., ~90% weight loss in 30 days) that depended on alkylamine concentration, molar ratio of alkylamine to poly(-caprolactone) monomer and alkyl chain length. The secondary alkylamines caused less rapid polymer weight loss (i.e., ~90%) weight loss within 80 days). One tertiary alkylamine (N,N-diisopropylethylamine) showed little catalytic effect while a bicyclic tertiary alkylamine (quinuclidine) was about as catalytic as the primary alkylamines. The degradation products isolated when primary alkylamines were used include both esters and amides indicating that nucleophilic attack by the alkylamines competed with the amine-catalyzed methanolysis reaction. Only ester moieties could be identified in the products from reactions containing secondary and tertiary alkylamines, which indicated that they acted as nucleophilic catalysts. All of the primary alkylamines reduced poly(-caprolactone) molecular weight from about 25,000 to 10,000 within 10 days after which the molecular weight of the remaining solid leveled off even though weight loss continued.     

Paclitaxel Prodrugs with Sustained Release and High Solubility in Poly(ethylene glycol)-b-poly(ε-caprolactone) Micelle Nanocarriers: Pharmacokinetic Disposition, Tolerability, and Cytotoxicity

Purpose

Develop a Cremophor® and solvent free formulation of paclitaxel using amphiphilic block co-polymer micelles of poly(ethylene glycol)-b-poly(?-caprolactone) (PEG-b-PCL) and characterize their release, solubility, cytotoxicity, tolerability, and disposition.

Methods

Hydrophobic prodrugs of paclitaxel were synthesized via DCC/DMAP or anhydride chemistry to overcome the poor loading (<1% w/w) of paclitaxel in micelles of PEG-b-PCL. Micelles were prepared by a co-solvent extraction technique. A micellar formulation of paclitaxel prodrug (PAX7′C₆) was dosed intravenously to rats (10 mg/kg) and compared to Taxol® (paclitaxel in CrEL:EtOH) and PAX7′C₆ in CrEL:EtOH as controls at the same dose. Pharmacokinetic parameters and tissue distribution were assessed.

Results

Paclitaxel prodrugs had solubilities >5 mg/ml in PEG-b-PCL micelles. Resulting PEG-b-PCL micelles contained 17-22% w/w prodrug and were less than 50 nm in diameter. PEG-b-PCL micelles released paclitaxel prodrugs over several days, t_1/2>3 d. Only the 7′derivative of paclitaxel with the shortest acylchain 7′hexonoate (PAX7′C₆) maintained cytotoxic activity similar to unmodified paclitaxel. PAX7′C₆ micelles demonstrated an increase in area under the curve, half-life, and mean residence time while total clearance and volume of distribution decreased.

Conclusions

Paclitaxel prodrugs in PEG-b-PCL micelle nanocarriers augment the disposition and increase tolerability making further studies on tumor efficacy warranted.     

Overcoming Multidrug Resistance in 2D and 3D Culture Models by Controlled Drug Chitosan‐Graft Poly(Caprolactone)‐Based Nanoparticles

The principal limitations of chemotherapy are dose‐limiting systemic toxicity and the development of multidrug‐resistant phenotypes. The aim of this study was to investigate the efficiency of a new sustained drug delivery system based on chitosan and ε‐caprolactone to overcome multidrug resistance in monolayer and drug resistance associated with the three‐dimensional (3D) tumor microenvironment in our established 3D models. The 5‐fluorouracil (5‐FU)‐loaded nanoparticles (NPs) were characterized by transmission electron microscope and dynamic light scattering, and its released property was determined at different pH values. 5‐FU/NPs exhibited well‐sustained release properties and markedly enhanced the cytotoxicity of 5‐FU against HCT116/L‐OHP or HCT8/VCR MDR cells in two‐dimensional (2D) and its parental cells in 3D collagen gel culture with twofold to threefold decrease in the IC₅₀ values, as demonstrated by 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide assay, Hoechst/propidium iodide staining and flow cytometry analysis. Furthermore, the possible mechanism was explored by high‐performance liquid chromatography and rhodamine 123 accumulation experiment. Overall, the results demonstrated that 5‐FU/NPs increase intracellular concentration of 5‐FU and enhance its anticancer efficiency by inducing apoptosis. It was suggested that this novel NPs are a promising carrier to decrease toxic of 5‐FU and has the potential to reverse the forms of both intrinsic and acquired drug resistance in 2D and 3D cultures. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 103:1064–1074, 2014     

The Effect of Salts on the Stability of β-Galactosidase in Aqueous Solution,as Related to the Water Mobility

The effect of salts (KI, KBr, NaCl, KC1, KF, phosphate, and Na₂SO₄) on the stability of -galactosidase in aqueous solution was studied from the aspect of changes in water mobility. At salt concentrations up to 200 mM, the inactivation rate of -galactosidase in all the salt solutions studied increased with increasing salt concentration. At higher concentrations, those salts which had little effect on the spin-lattice relaxation time, T ₁, of water (KI, KBr, and KC1) continued to increase the inactivation rate of -galactosidase with increasing concentration, while those salts which decreased the T _l of water (KF, phosphate, and Na₂SO₄) decreased the inactivation rate. It appeared that the decrease in water mobility caused by KF, phosphate, and Na₂SO₄ resulted in stabilization of -galactosidase. The results indicate that water mobility is an important factor in the denaturation rate of proteins.     

Comparative studies of poly(ε-caprolactone) and poly(D,L-lactide) as core materials of polymeric micelles

Polymeric micelles have been successfully used to deliver a variety of therapeutic agents. Nonetheless, several limitations and considerations must be clarified and well-studied to achieve the highest therapeutic effect. In this study, a series of methoxy poly(ethylene glycol)-block-poly(ε-caprolactone) (PEG-b-PCL) and methoxy poly(ethylene glycol)-block-poly(D,L-lactide) (PEG-b-PLA) with varying molecular weight (MW) of hydrophobic core segment were synthesized. These block copolymers can form micelle with PCL or PLA as core-forming blocks and PEG as a coronal material. The effect of MW on micelle size and critical micelle concentration (CMC) was studied. DOX (DOX) was encapsulated inside the micelle core. Drug-loading content and size of micelles were studied. Drug release studies inside cells were evaluated by confocal laser scanning microscopy. In summary, the PLA core which is less hydrophobic than PCL showed higher CMC, smaller micelle size and faster DOX release inside nucleus.     

Reversion of Multidrug Resistance by Co-Encapsulation of Doxorubicin and Metformin in Poly(lactide-co-glycolide)-d-α-tocopheryl Polyethylene Glycol 1000 Succinate Nanoparticles

Purpose

P-glycoprotein (P-gp) mediated multidrug resistance (MDR) has been recognized as the main obstacle against successful cancer treatment. To address this problem, co-encapsulated doxorubicin (DOX) and metformin (Met) in a biodegradable polymer composed of poly(lactide-co-glycolide) (PLGA) and D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) was prepared. We reported in our previous study that Met inhibits P-gp in DOX resistant breast cancer (MCF-7/DOX) cells. TPGS is a bioactive compound which has also been shown to inhibit P-gp, further to its pharmaceutical advantages.

Methods

The DOX/Met loaded PLGA-TPGS nanoparticles (NPs) were prepared by double emulsion method and characterized for their surface morphology, size and size distribution, and encapsulation efficiencies of drugs in NPs.

Results

All NPs were found to be spherical-shaped with the size distribution below 100 nm and encapsulation efficiencies were 42.26?±?2.14% for DOX and 7.04?±?0.52% for Met. Dual drug loaded NPs showed higher cytotoxicity and apoptosis in MCF-7/DOX cells in comparison to corresponding free drugs. The higher cytotoxicity of dual drug loaded NPs was attributed to the enhanced intracellular drug accumulation due to enhanced cellular uptake and reduced drug efflux which was obtained by combined effects of Met and TPGS in reducing cellular ATP content and inhibiting P-gp.

Conclusion

Simultaneous delivery of DOX and Met via PLGA-TPGS NPs would be a promising approach to overcome MDR in breast cancer chemotherapy.

     

Biochar as a sustainable and renewable additive for the production of Poly(ε-caprolactone) composites

Sustainable poly(ε-caprolactone) (PCL) composites can be produced via initiation of polymerization using the surface hydroxyl groups of oxidized biochar nanostructures obtained after liquid-phase exfoliation of biochar. Biochars are stable, renewable, and sustainable carbon-based materials, which in large-scale applications have the potential to mitigate climate change. The biochar used herein is produced by pyrolysis of hardwood waste biomass (e.g. sawdust, branches, bark) and then converted using nitric acid to oxidized biochar (oxbc). Oxbc is directly sonicated in ε-caprolactone to produce the exfoliated analogue (Eoxbc), which is used to promote the ring-opening polymerization of ε-caprolactone. Eoxbc is highly dispersible in this monomer, and thus reactions can be performed under neat conditions. Eoxbc presents sufficient surface hydroxyl groups (?OH) to initiate and facilitate the ring-opening polymerization of ε-caprolactone using tin octoate, organic bases or lipase enzymes as catalysts. The PCL/Eoxbc composites produced present higher crystallinity and increased stiffness when compared to pure PCL. In preliminary studies, Eoxbc also shows a positive effect upon the degradation of PCL under various conditions.