Encapsulation of docetaxel in oily core polyester nanocapsules intended for breast cancer therapy
© Youm et al; licensee Springer. 2011
Received: 19 September 2011
Accepted: 14 December 2011
Published: 14 December 2011
This study is designed to test the hypothesis that docetaxel [Doc] containing oily core nanocapsules [NCs] could be successfully prepared with a high percentage encapsulation efficiency [EE%] and high drug loading. The oily core NCs were generated according to the emulsion solvent diffusion method using neutral Labrafac CC and poly(d, l-lactide) [PLA] as oily core and shell, respectively. The engineered NCs were characterized for particle mean diameter, zeta potential, EE%, drug release kinetics, morphology, crystallinity, and cytotoxicity on the SUM 225 breast cancer cell line by dynamic light scattering, high performance liquid chromatography, electron microscopies, powder X-ray diffraction, and lactate dehydrogenase bioassay. Typically, the formation of Doc-loaded, oily core, polyester-based NCs was evidenced by spherical nanometric particles (115 to 582 nm) with a low polydispersity index (< 0.05), high EE% (65% to 93%), high drug loading (up to 68.3%), and a smooth surface. Powder X-ray diffraction analysis revealed that Doc was not present in a crystalline state because it was dissolved within the NCs' oily core and the PLA shell. The drug/polymer interaction has been indeed thermodynamically explained using the Flory-Huggins interaction parameters. Doc release kinetic data over 144 h fitted very well with the Higuchi model (R 2 > 0.93), indicating that drug release occurred mainly by controlled diffusion. At the highest drug concentration (5 μM), the Doc-loaded oily core NCs (as a reservoir nanosystem) enhanced the native drug cytotoxicity. These data suggest that the oily core NCs are promising templates for controlled delivery of poorly water soluble chemotherapeutic agents, such as Doc.
In cancer therapy, most of the proposed formulations present certain drawbacks related to the formulation properties including low drug loading, toxicity, and unsuitable release pattern. An ideal formulation should provide biocompatible nanosized particles and high drug loading with sustained-release characteristics. This allows releasing the drug in the target site in its therapeutic concentration and preventing drug inefficiency and side effects. The current research was aimed to prepare highly loaded docetaxel [Doc] oily core nanocapsules [NCs].
Doc, a semisynthetic analog of paclitaxel, is an extract from the needles of the European yew tree Taxus baccata. It is prepared by chemical modification of 10-deacetylbacattin III, an inactive precursor compound, and then isolated . Doc is a highly potent, cytotoxic, and antimitotic agent used in the treatment of various types of cancers, including metastatic breast, ovarian, prostate, advanced non-small-cell lung, head/neck, and advanced gastric cancers by inhibiting the microtubule depolymerization of free tubulin [3, 4]. Due to its poor water solubility (10 to 20 μg/l), polysorbate 80 has been markedly used to improve the aqueous solubility of Doc [5–7]. This currently available, marketed formulation has been associated with the absence of selectivity for target tissues, serious dose limiting toxicities, and hypersensitivity reactions, as well as sensory and motor neuropathies that are sometimes severe and irreversible. Previously, various alternative formulations, including NCs, pegylated liposomes, targeted immunoliposomes, Doc-fibrinogen-coated olive oil droplets, and cyclodextrins [8–15] have been intensively developed for the delivery of Doc. However, the nanosized polymeric nanoparticles represent promising drug-delivery systems which have some advantages such as biodegradability, good biocompatibility, non-toxicity, higher stability, and controlled drug delivery. Polymeric nanoparticles (nanospheres and NCs) not only maintain a prolonged circulation time in the body (especially when pegylated) by avoiding the reticuloendothelial system, but also can extravagate and accumulate into the tumor tissue. This is likely due to the reliance of these nanoparticles on passive accumulation through enhanced permeability and retention, which is highly dependent on adequate blood flow to the tumor .
According to the literature, the NCs correspond to nanostructures with polymeric wall enveloping an oily core, whereas the nanospheres consist of a polymeric matrix . There is increasing scientific evidence supporting the notion that certain lipids are able to inhibit both presystemic drug metabolism and P-glycoprotein-mediated drug efflux . Several polymers have been proposed as nanocarriers for drug delivery systems. For example, poly(d, l-lactic acid) and poly(ε-caprolactone) [PCL] have been extensively used as nanocarriers because of their excellent biocompatibility and biodegradability. These polyesters have been approved by the US Food and Drug Administration and are the most widely used commercial polymers for drug delivery [19, 20]. Presently, the only available Doc formulations for clinical use consists of intravenous [IV] solutions containing Tween 80® (Sanofi-aventis, Bridgewater, NJ, USA). These solutions namely Taxotere® and Docetaxel®, 10 to 20 mg/ml, are administered IV at a dose ranging from 60 to 100 mg/m2 over 1 h every 3 weeks ). However, such high doses and a long term medication schedule may produce more severe side effects . One of the reasons could be ascribed to the composition of the formulation and the poor control of the drug release rate. Therefore, the development of compatible polymer-based nanocarriers with high drug loading might be a helpful subject in cancer research.
The current research was aimed to prepare highly loaded Doc oily core NCs. However, the relationship between drug and formulation excipients has also been investigated to better control the encapsulation process.
Materials and methods
Poly(d, l-lactide) [PLA], Resomer® R206, Mw 125 kDa, with an inherent viscosity of 1.0 dl/g; PLA, Resomer® R207, Mw 209 kDa, with an inherent viscosity of 1.5 dl/g; and PLA, Resomer® R208, Mw 250 kDa, with an inherent viscosity of 1.8 dl/g were purchased from Boehringer Inc. (Ridgefield, CT, USA). PCL (Mw = 72 kDa) was kindly provided by Union Carbide (Danbury, CT, USA). Polyvinyl alcohol [PVA] (9 to 10 kDa and 30 to 70 kDa) and ethyl acetate were obtained from Sigma-Aldrich (St. Louis, MO, USA). Docetaxel or Doc was purchased from LC Laboratories (Woburn, MA, USA). Labrafac CC (caprylic/capric triglyceride, d = 0.945 g/cm3) was kindly supplied by Gattefosse Corporation (St-Priest, France) as a gift. For the high-performance liquid chromatography [HPLC] analysis, acetonitrile and methanol were supplied from Fisher (Thermo Fisher Scientific, Fair Lawn, NJ, USA). All the other reagents were of analytical grade and used without further purification.
Preparation of the nanocapsules
Experimental design and general procedure for Doc-loaded nanocapsules
Fifteen formulations of Doc-loaded NCs were prepared by emulsion-diffusion method as previously described . Briefly, the polyester (40 to 360 mg) was solubilized in water-saturated ethyl acetate (10 ml); then, the neutral oil (0.1 to 0.9 ml) containing Doc (2 to 18 mg) was further added to the organic mixture. The resulting solution was emulsified in 40 ml of PVA 2.5% to 5% (w/v) aqueous phase solution by homogenization (homogenizer, IKA ULTRA-TURRAX T-25, IKA Labortechnik, Staufen, Germany) at 8,000 rpm for 10 min. A large volume (200 ml) of deionized water was added dropwise into the previous solution to promote the diffusion of ethyl acetate into the aqueous phase. To remove the organic solvent, the nanosuspension was stirred under vacuum at 40°C Rotavapor® RII (BUCHI Labortechnik AG, Flawil, Switzerland) for 30 min. NCs were recovered by ultracentrifugation at 12,000 rpm at 5°C for 30 min, washed twice with deionized water to remove the excess of PVA, and freeze-dried for 12 h (Labconco Corp. Kansas City, MO, USA). Blank NCs were prepared without Doc using the above method. The composition of the 15 formulations is listed in the first four columns of Table S1 in Additional file 1.
Screening for polyester selection based on the blank particle mean diameter
For the first screening test, a set of four biodegradable polymers, including PLA R206, PLA R207, PLA R208, and PCL, was used to obtain a suitable formulation based on the mean diameter of the obtained blank NCs. An amount of 200 mg of polyesters was solubilized in an organic phase containing 10 ml of water-saturated ethyl acetate and 0.5 ml of neutral oil. Each experiment was performed in triplicate.
Screening for stabilizer selection based on the blank particle mean diameter
Since PVA could be used as an emulsion stabilizer in the NCs' formulation process, it was important to first investigate the effect of PVA molecular weight (9 to 10 kDa and 30 to 70 kDa) on the blank NCs' mean diameter. Secondly, the influence of the PVA concentration (2.5% to 5%) on the particle mean diameter and polydispersity index [PDI] was studied.
Physicochemical characterization of docetaxel-loaded nanocapsules
Particles' mean diameter and zeta potential analysis
The particle mean diameter and PDI of the Doc-loaded NCs were measured by dynamic light scattering [DLS] (Zetasizer Nano ZS series from Malvern Instruments Ltd., Worcestershire, UK) as recently reported . The sample to be measured was appropriately diluted with water and briefly sonicated for 2 min. The measurement of each sample was completed at a scattering angle of 175°. Each measurement was done in triplicate, and the average effective diameter and polydispersity were recorded.
Drug loading and percent encapsulation efficiency of docetaxel-loaded nanocapsules
Scanning electron microscopy analysis
Scanning electron microscopy [SEM] was used to assess the NCs' morphology. A droplet of NCs' suspension was put into a grid. The excess of the fluid was removed by wicking it off with an adsorbent paper, and then, it was visualized under a Hitachi S4700 cold-cathode field emission SEM [FESEM] (Hitachi High-Technologies Corporation, Minato-ku, Tokyo, Japan). The particles were sprinkled onto a stub covered with an adhesive conductive carbon tab, then sputter-coated with a fine layer of platinum metal. Then, the particles were imaged in the FESEM at 2 to 5 kV.
Transmission electron microscopy analysis
The selected samples were examined with a JEOL 1400 transmission electron microscope [TEM] (JEOL Ltd., Tokyo, Japan) and photographed digitally on a Gatan axis-mount 2 k × 2 k digital camera (Gatan, Inc., Pleasanton, CA, USA). The freeze-dried samples were put into a small mold, referred to as a BEEM capsule, and then imbedded in liquid epoxy resin (Epon-Araldite, Sigma-Aldrich Corporation, St. Louis, MO, USA). The resin was polymerized at 60°C for 2 days, and then, ultrathin 80-nm sections were cut on a Leica UCT ultramicrotome (Leica Microsystems Ltd., Milton Keynes, UK) with a Diatome diamond knife (Diatome, Hatfield, PA, USA). The sections were collected on 200-mesh copper grids and put into the TEM for imaging on a Gatan digital camera.
Powder X-ray diffraction pattern analysis
Powder X-ray diffraction [PXRD] analysis of the freeze-dried NCs was performed using a MiniFlex automated X-ray diffractometer (Rigaku, The Woodlands, TX, USA) at room temperature. Ni-filtered Cu Kα radiation was used at 30 kV and 15 mA. The diffraction angle covered from 2θ = 5° to 2θ = 60°, with a step size of 0.05°/step and a count time of 3 s/step (effectively 1°/min). The diffraction patterns were processed using Jade 8+ software (Materials Data, Inc., Livermore, CA, USA).
Refractive index measurement
The oil, water-saturated ethyl acetate, and ethyl acetate-saturated water refractive index values were measured experimentally at 25°C (Auto Abbe 10500 Refractometer; Reichert Analytical Instruments, Depew, NY, USA) using Milli-Q water (Millipore Co., Billerica, MA, USA) as a reference. A droplet of liquid was deposited on the prism surface. The obtained values are the average of five measurements.
In vitro drug release kinetics
This experiment was performed using the equilibrium dialysis method for 144 h. Specifically, a known amount of Doc-loaded oily core NCs (1 mg) was suspended in a dialysis bag (Spectra/Float-A-Lyzer, MWCO 3.5-5 kDa, Spectrum Laboratories Inc. Rancho Dominguez, CA, USA) containing 5 ml of phosphate buffer saline [PBS] (Sigma-Aldrich, St. Louis, MO, USA). The bag containing the NCs' suspension was placed in 40 ml of PBS. The system was placed in a shaking water bath (BS-06, Lab. Companion, Des Plaines, IL, USA) at 37°C with an agitation speed of 50 rpm. At predetermined time intervals, 500 μl of PBS solution was withdrawn from the immersion medium and replaced by the same volume of fresh medium. The cumulative percentage of drug released for each time point was calculated as a percentage of the total drug loading of the NCs tested. The quantitative analysis of the data obtained from the study was confirmed using Higuchi's kinetic model  to elucidate the mechanism of the drug release.
Solubility parameter determination
where V m is the molar volume of the drug, R is the ideal gas constant (8.314 J·K-1·mol-1), and T is the temperature in Kelvin (293.15 K) .
In vitro evaluation of Doc-loaded nanocapsules' cytotoxicity
where, experimental, background, and positive represent the fluorescence intensity of NC-treated wells, background wells (wells without cells), and positive control wells (cells treated with 1% of Triton X-100), respectively. The fluorescence intensity was detected by using a microplate reader (DTX 800 multimode microplate reader, Beckman Coulter, Brea, CA, USA) at an excitation wavelength of 560 nm and emission wavelength of 590 nm.
Results and discussion
Polymer selection based on the mean diameter of blank nanocapsules
Stabilizer concentration and molecular weight effects on the blank particle mean diameter
Preparation and characterization of docetaxel-loaded nanocapsules
For optimization purposes, 15 batches of PLA R208 Doc-loaded oily core NCs were prepared using the above method. As shown in Table S1 in Additional file 1, the lowest value of the NCs' diameter was obtained with F6 (115.6 nm), while the largest particle diameter was obtained with F9 (582.8 nm). The PDI ranged from 0.004 to 0.318 (F14 and F9, respectively). It was found that the particle mean diameter is strongly dependent to the polymer amount. Indeed, at a low PLA amount (40 mg), the particle mean diameter increases with increasing drug amount (see F9 versus F10, P < 0.0001). This might be explained by the fact that the lipophilic feature tends to decrease the leakage of the drug into the external aqueous medium, leading to improved drug content in the nanoparticles (which is consistent with the previous report) . However, at a high PLA amount (360 mg), the particle mean diameter decreases with increasing drug amount (see F4 versus F5, P < 0.0001). The latter was not consistent with the commonly published report and might be a result of drug solubilization in the polymer matrix, leading to decrease the particle mean diameter. Thus, the solubilization capacity of PLA has a great importance in the preparation of the Doc-loaded NCs.
From Table S1 in Additional file 1, the data suggest that the NCs' mean diameter decreases with increasing oil content from 189 nm to 133 nm (see F3 versus F13, P < 0.0001). The results also show that at a low oil content, the drug level did not have any effect on the NCs' mean diameter, which is consistent with the previous study .
From Table S1 in Additional file 1, it appears that for most of the formulations, the PDI value was less than 0.05, indicating a monodispersity according to the National Institute of Standard . However, the polydispersity seems to be increased with decreasing PLA amount (see F13 versus F1, from 0.005 to 0.296, P = 0.0078). This suggests that the PLA amount may contribute to ensure the NCs' monodispersity.
Table S1 in Additional file 1 lists also the EE% of the Doc-loaded NCs. Interestingly enough, the results showed that the EE% was mainly governed by the PLA content. A high PLA content led to a high EE% (see pairwise comparison: F1 to F13, F3 to F9, F4 to F11, F5 to F10, respectively). At a low PLA content, the EE% was decreasing regardless of the oil content (comparing F9 to F10, P = 0.0006). At a high oil content, a medium content of PLA is at least required to obtain a high EE% (see F7 and F13, P = 0.9038). The lowest EE% (F9, 65.3%) was obtained when the PLA and oil contents were both at the lowest level (40 mg and 0.1 ml, respectively). This is because the encapsulation process of hydrophobic drugs into these particles results from the interaction between the drug, polymers, and oil. Thus, the drug loading and EE% were found to depend on its solubility in the polymeric material, which is strongly related to the polymer composition, its molecular weight, the drug and polymer interaction, and the presence of end-functional ester or carboxyl groups . These findings were consistent with a previous report . Once the NCs' physicochemical properties have been analyzed, their size and morphology can be most directly monitored by various forms of electron microscopy.
Physicochemical characterization of docetaxel-loaded nanocapsules
Powder X-ray diffraction analysis
In vitro drug release study
Solubility parameter determination
where Δγ is the surface tension difference between ethyl acetate and oil, respectively.
The surface tensions of pure oil and ethyl acetate are 30.00 mN/m  and 6.80 mN/m , respectively. The Δγ resulting from mixing these two substances is 23.20 mN/m, which is estimated to be γ A. From Equation 8, α was found to be 4.10 mN/m. However, the obtained value of γ AB from Equation 7 was 7.94 mN/m.
where γ is the interfacial tension (A, B, and C refer to the three phases). Based on these conventions, complete engulfing of phase A by phase C will occur if only if S A < 0, S B < 0 and S c > 0. In this study, oil-ethyl acetate mixture is the phase A, water is phase B, and the polymeric phase (PLA) is phase C. The calculation of the spreading coefficients of a specific phase A/phase C system allows predicting the possible formation of oily core NCs.
The corresponding interfacial tension values were obtained as follows: γ BC was obtained from the literature (γ BC = +6.83 mN/m , γ AC = +0.06 mN/m was obtained from Table S4 in Additional file 1[46, 47], and γ AB calculated from Equation 7 was 7.94 mN/m, which is comparable to the literature value of 8.42 mN/m . The positive sign of the water-PLA interfacial tension (γ BC = +6.83 mN/m) implies that it tries to reduce its energy by reducing its surface area, and therefore, a spherical shape might be maintained. Based on these data, the obtained spreading coefficients were S A = -1.17 mN/m (< 0), S B = -14.71 mN/m (< 0), and S C = +1.05 mN/m (> 0). Thermodynamically, the driving forces allowed the formation of a PLA layer between the water and oily phase, thus engulfing the oily phase. These data fundamentally explain why the oily core was surrounded by a polymer layer as visually evidenced by the TEM analysis.
In vitro evaluation of Doc-loaded NC cytotoxicity
In this work, we developed PLA-based Doc-loaded oily NCs by solvent diffusion method. The results confirmed the formation of Doc-loaded oily core polyester-shell NCs in the nanosize range (115 to 582 nm) and high EE% (65% to 93%). Most of the NCs were monodisperse in size (PDI = 0.005) with smooth surface. The PXRD data suggested that Doc was dissolved in the NCs. The Doc release data over 144 h fitted well with the Higuchi model (R 2 > 0.93), indicating that the drug mainly diffused out of the NCs in this timeframe. Consistent with the analysis of the spreading coefficients and visual evidence from EM, the NCs' oily core was indeed formed. The results from the cytotoxicity study suggested that at a high concentration (5 μM), the enhanced toxicity of the encapsulated drug on the examined cancerous cell line might be due to both the particle's uptake by the SUM 225 cells and the sustained drug release profile from the NCs. In a future work, we plan to investigate the cancer cell targeting capability of pegylated Doc-loaded NCs conjugated to specific ligands for drug delivery applications.
IY has a Ph.D. degree in Pharmaceutical Sciences and is a post doctoral research associate in the Division of Pharmaceutical Sciences, School of Pharmacy, University of Missouri-Kansas City. XY is a graduate student in the Division of Pharmaceutical Sciences, School of Pharmacy, University of Missouri-Kansas City. JM has BS, MS, and Ph.D. degrees in Geochemistry and Mineralogy. He is an associate professor in the Department of Geosciences, University of Missouri-Kansas City. BBCY has PharmD and Ph.D. degrees in Pharmaceutical Sciences. He is also an associate professor in the Division of Pharmaceutical Sciences, School of Pharmacy, University of Missouri-Kansas City.
The authors are thankful to Gattefosse Corporation for providing a gift sample of Labrafac CC, to Dr. Elizabet Kostoryz (Division of Pharmacology, University of Missouri-Kansas City) for assistance with the DLS measurement, and to Randy Tindall (Electron Microscopy Center, University of Missouri-Columbia) for the electron microscopy studies. We are also grateful to Fariba Behbod, PharmD, PhD, Assistant Professor, Pathology and Laboratory Medicine, University of Kansas Medical Center for kindly providing the SUM 225 cell line.
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