A Novel Docetaxel-Loaded Poly (ε-Caprolactone)/Pluronic F68 Nanoparticle Overcoming Multidrug Resistance for Breast Cancer Treatment
© to the authors 2009
Received: 12 June 2009
Accepted: 1 September 2009
Published: 16 September 2009
Multidrug resistance (MDR) in tumor cells is a significant obstacle to the success of chemotherapy in many cancers. The purpose of this research is to test the possibility of docetaxel-loaded poly (ε-caprolactone)/Pluronic F68 (PCL/Pluronic F68) nanoparticles to overcome MDR in docetaxel-resistance human breast cancer cell line. Docetaxel-loaded nanoparticles were prepared by modified solvent displacement method using commercial PCL and self-synthesized PCL/Pluronic F68, respectively. PCL/Pluronic F68 nanoparticles were found to be of spherical shape with a rough and porous surface. The nanoparticles had an average size of around 200 nm with a narrow size distribution. The in vitro drug release profile of both nanoparticle formulations showed a biphasic release pattern. There was an increased level of uptake of PCL/Pluronic F68 nanoparticles in docetaxel-resistance human breast cancer cell line, MCF-7 TAX30, when compared with PCL nanoparticles. The cytotoxicity of PCL nanoparticles was higher than commercial Taxotere®in the MCF-7 TAX30 cell culture, but the differences were not significant (p > 0.05). However, the PCL/Pluronic F68 nanoparticles achieved significantly higher level of cytotoxicity than both of PCL nanoparticles and Taxotere®(p < 0.05), indicating docetaxel-loaded PCL/Pluronic F68 nanoparticles could overcome multidrug resistance in human breast cancer cells and therefore have considerable potential for treatment of breast cancer.
Cancer remains the leading cause of death worldwide. The global incidence and mortality of breast cancer remains high despite extraordinary progress in understanding the molecular mechanisms underlying carcinogenesis, tumor promotion, and the establishment of molecular targeted therapies . Although early detection and screening of breast cancer is associated with less invasive surgical procedures and may increase survival, the 5-year survival rate of metastatic breast cancer (stage IV) is still below 15%. Multidrug resistance (MDR) to anticancer agents remains a major barrier to successful cancer treatment. Thus, the development of effective therapies overcoming MDR against invasive breast cancer and particularly highly metastatic disease still remains a significant priority. Nanoparticulate delivery systems in cancer therapies provide better penetration of therapeutic and diagnostic substances within the body at a reduced risk in comparison with conventional cancer therapies. Nanoparticles could reduce the multidrug resistance (MDR) that characterizes many anticancer drugs, including docetaxel, by a mechanism of internalization of the drug , reducing its efflux from cells mediated by the P-glycoprotein . Nanoparticle distribution within the body is based on various parameters such as their relatively small size resulting in longer circulation times and their ability to take advantage of tumor characteristics. In comparison to conventional cancer treatments, the nanoscale of these particulate systems also minimizes the irritant reactions at the injection site. Nanoparticles and their use in drug delivery is a far more effective cancer treatment method than conventional chemotherapy, which is typically limited by the toxicity of drugs to normal tissues, short circulation half-life in plasma, limited aqueous solubility, and nonselectivity restricting therapeutic efficacy .
Docetaxel is a poorly water-soluble, semi-synthetic taxane analog commonly used in the treatment of breast cancer, oval cancer, small and nonsmall cell lung cancer, prostate cancer, etc. Its commercial formulation Taxotere® is formulated in high concentration of Tween 80, which has been found associated with severe side effects including hypersensitivity reactions, cumulative fluid retention, nausea, mouth sores, hair loss, peripheral neuropathy, fatigue, and anemia [5, 6] and has shown incompatibility with the common PVC intravenous administration sets . In order to eliminate the Tween 80-based adjuvant and in the attempt to increase the drug solubility, alternative formulations have been attempted, such as liposomes , nanoparticles [8–10], docetaxel-fibrinogen-coated olive oil droplets . Among them, the nanoparticle formulation holds greatest promise for this purpose. The nanoparticles showed advantages such as more stable during storage over others. Moreover, such a colloidal system is able to extravasate solid tumors into the inflamed or infected site, where the capillary endothelium is defective [3, 4].
Nanoparticles serving in anticancer therapies may be comprised, in whole or in part, of various lipids and natural and synthetic polymers. Most commonly used synthetic polymers to prepare nanoparticles for drug delivery are biodegradable. Among the various biodegradable polymers approved by the US Food and Drug Administration (FDA), poly(lactide) (PLA), poly(d,l-lactide-co-glycolide) (PLGA), and poly (caprolactone) (PCL) are used most often in the literature. In the family of polyesters, PCL occupies a unique position: it is at the same time biodegradable and miscible with a variety of polymers, and it crystallizes very readily . A lack of toxicity and great permeability has already found wide use for PCL in medical applications . Pluronic F68 is a difunctional block copolymer surfactant terminating in primary hydroxyl groups. It is both water and organic solvent soluble. Poloxamers and poloxamine nonionic surfactants have diverse applications in various biomedical fields ranging from drug delivery and medical imaging to management of vascular diseases and disorders . In the present study, Pluronic F68 was incorporated into PCL as a pore-forming agent and drug-releasing enhancer. Previous studies by our group have demonstrated the amount of Pluronic F68 blended into PCL affected the microspheres morphology and controlled paclitaxel release . In addition, it has been demonstrated that Pluronic block copolymers interact with multidrug-resistant (MDR) tumors resulting in drastic sensitization of these tumors with respect to various anticancer agents [13, 14]. The key attribute for the biological activity of Pluronics is their ability to incorporate into membranes followed by subsequent translocation into the cells and affecting various cellular functions, such as mitochondrial respiration, ATP synthesis, activity of drug efflux transporters, apoptotic signal transduction, and gene expression. As a result, Pluronics cause drastic sensitization of MDR tumors to various anticancer agents including docetaxel, enhance drug transport across the blood–brain barriers (BBB) and intestinal barriers and cause transcriptional activation of gene expression both in vitro and in vivo [14, 15]. Furthermore, recent studies indicated that Pluronic F68 is a potent in vitro inhibitor of both P-gp and CYP3A4 . Thus, in this research we investigate the hypothesis that a novel docetaxel-loaded PCL/Pluronic F68 nanopaticles overcoming multidrug resistance (MDR) will achieve better therapeutic effects in docetaxel-resistance human breast adenocarcinoma MCF-7 cell line.
Materials and Methods
In brief, docetaxel of purity 99% was purchased from Shanghai Jinhe Bio-Technology Co. Ltd, Shanghai, China. Polycaprolactone (Mn ~ 42,500) was obtained from Sigma–Aldrich (St. Louis, MO, USA). Cell Counting Kit-8 (CCK-8) was from Dojindo Molecular Technologies Inc., Kumamoto, Japan. ε–Caprolactone monomer with 99.9% purity was from Aldrich Chemical Co., USA. The monomer was further purified by vacuum distillation over CaH2. Pluronic F68 with molecular weight (Mw) around 8,300 containing about 80% poly (ethyl oxide) (PEO) segment and 20% of poly (propyl oxide) (PPO) segment was purchased from BASF, Germany. The Pluronic F68 was incorporated into PCL matrix in 10% of weight ratio as a molecular distribution, which would leach out in aqueous medium to leave microporous structure in the PCL matrix (Sun et al., 2006). Polyvinyl alcohol (PVA) (MW 30 000–70 000) was obtained from Sigma, Chemical Co (St Louis, MO). Acetonitrile and methanol used as mobile phase in high performance liquid chromatography (HPLC) were purchased from EM Science (ChromAR, HPLC grade, Mallinckrodt Baker, USA). All other chemicals were HPLC grade and were used without further purification. Millipore water was prepared by a Milli-Q Plus System (Millipore Corporation, Breford, USA).
Synthesis of PCL/Pluronic F68 Compound
Preparation of Nanoparticles
The nanoparticles were prepared by modified solvent displacement method as described previously . Briefly, 100 mg of PCL/Pluronic F68 compound and 17.65 mg of docetaxel were dissolved in 100 mL of acetone by mild heating and sonication. The mixed solution was gently poured into 50 mL of deionized water containing 1,000 mg of PVA under magnetic stirring. The emulsion was then evaporated overnight under reduced pressure to remove the organic solvent. The resulting suspension of nanoparticles was centrifuged at 23,000 rpm for 30 min. The pellet was washed twice with distilled water to remove free drug and PVA. The resulted particles were freeze-dried for 2 days. Docetaxel-loaded PCL nanoparticles and empty PCL/Pluronic F68 nanoparticles were prepared by the same method. In addition, the fluorescent coumarin-6-loaded nanoparticles were prepared in the same way except 0.05% (w/v) coumarin-6 was encapsulated instead of docetaxel.
Characterization of Nanoparticles
The nanoparticles were imaged by a field emission scanning electron microscopy (FESEM) system at an accelerating voltage of 5 kV. To prepare samples for FESEM, the particles were fixed on the stub by a double-sided sticky tape and then coated with platinum layer by JFC-1300 automatic fine platinum coater (JEOL, Tokyo, Japan) for 80 s.
Size Analysis and Zeta Potential
The particle size and size distribution were measured by laser light scattering (Brookhaven Instruments. Corporation, Holtsville, NY 90-PLUS analyzer). Before measurement, the freshly prepared particles were appropriately diluted. Zeta potential of the docetaxel-loaded nanoparticles was detected by laser Doppler anemometry (Zeta Plus zeta potential analyzer, Brookhaven Corporation, Holtsville, NY). The particles (about 2 mg) were suspended in deionized water before measurement. The data were obtained with the average of three measurements.
Drug Loading and Encapsulation Efficiency
Drug content in the nanoparticles was assayed by HPLC (Agilent LC 1100, Santa Clara, CA, USA). A reverse-phase Inertsils ODS-3 column (150 μm × 4.6 μm, pore size 5 μm, GL science Inc, Tokyo, Japan) was used. Briefly, 5 mg particles were dissolved in 1 mL DCM under vigorous vortexing. This solution was transferred to 5 mL of mobile phase consisting of deionized water, methanol, and acetonitrile (50:45:5, v/v). DCM was evaporated in nitrogen atmosphere and the clear solution was obtained for HPLC analysis. The solution was transferred into HPLC vial after filtered through 0.22 mm syringe filter. The flow rate of mobile phase was 1 mL/min. The column effluent was detected at 230 nm with a UV/VIS detector. The measurement was performed triplicate. The encapsulation efficiency (EE) was expressed as the percentage of the drug loaded in the final product.
Differential Scanning Calorimetry (DSC)
The physical status of docetaxel inside the nanoparticles was investigated by differential scanning calorimetry (DSC 822e, Mettler Toledo, Switzerland). The samples were purged with dry nitrogen at a flow rate of 20 mL/min. The temperature was raised at 10 °C/min.
In Vitro Drug Release
Dialysis method was selected to examine the drug release in vitro. Briefly, 15 mg nanoparticles were dispersed in 5 mL release medium (phosphate buffer solution (PBS) of pH 7.4 containing 0.1% w/v Tween 80) to form a suspension. Tween 80 was used to increase the solubility of docetaxel in the buffer solution and avoid the binding of docetaxel to the tube wall. The suspension was put into a standard grade regenerated cellulose dialysis membrane (Spectra/Por®6, MWCO = 1,000, Spectrum, Houston, TX, USA). Then, the closed bag was put into a centrifuge tube and immersed in 15 mL release medium. The tube was put in an orbital water bath shaking at 120 rpm at 37.0 °C. At given time intervals, 10 mL samples was sucked out for analysis and replaced with fresh medium. In this research, the sink condition was maintained by the addition of Tween 80 and frequent replacement of fresh buffer during the in vitro release experiment. The newly collected samples were extracted with 2 mL DCM and reconstituted in 5 mL mobile phase. The DCM was evaporated by nitrogen stream. The analysis procedure was similar as for the measurement of EE.
In this research, human breast cancer cell lines MCF-7 cells of passages between 26 and 31 (American Type Culture Collection, VA) were cultured in Dubelco’s modified essential medium (DMEM) supplemented with 10% FBS, 100 mM sodium pyruvate, 1.5 g/L of sodium bicarbonate, and 1% penicillin–streptomycin and incubated in SANYO CO2 incubator at 37 °C in a humidified-environment of 5% carbon dioxide. Then, docetaxel-resistance human breast cancer cells (MCF-7 TAX30) were created as described previously . Briefly, the cells were made resistant to docetaxel by short-term in vitro exposure to docetaxel for 1 h, which was immediately followed by washing of the cells several times with culture media, trypsinization, and splitting the cells for subsequent cell growth recovery. The cells were initially exposed to 10 nmol/L docetaxel increasing to 500 nmol/L for 1 h. After this point, the cells were exposed to 1 μmol/L docetaxel increasing to 30 μmol/L docetaxel for 24 h.
Cellular Uptake of Nanoparticles
For quantitative study, docetaxel-resistance human breast cancer cells (MCF-7 TAX30) were seeded into 96-well black plates (Costar, IL, USA) of 1.3 × 104cells/well, and after the cells reached confluence, the cells were equilibrated with HBSS at 37 °C for 1 h and then incubated with coumarin-6-loaded PCL/Pluronic F68 nanoparticle suspension. The nanoparticles were dispersed in the medium at a concentration of 100, 250, and 500 μg/mL. The wells with nanoparticles were incubated at 37 °C for 2 h. After incubation, the suspension was removed, and the wells were washed three times with 50 μL cold PBS to eliminate traces of nanoparticles left in the wells. After that, 50 μL of 0.5% Triton X-100 in 0.2N NaOH was introduced into each sample wells to lyse the cells. The fluorescence intensity of each sample well was measured by microplate reader (GENios, Tecan, Switzerland) with excitation wave length at 430 nm and emission wavelength at 485 nm. Cell uptake efficiency was expressed as the percentage of cells-associated fluorescence versus the fluorescence present in the feed solution.
For the qualitative study, cells were reseeded in the chambered-cover glass system (LABTEK®, Nagle Nunc, IL). After the cells were incubated with 250 μg/mL coumarin-6-loaded nanoparticles at 37 °C for 2 h, they were rinsed with cold PBS for three times and then fixed by ethanol for 20 min. The cells were further washed twice with PBS, and the nuclei were counterstained with propidium iodide (PI) for 30 min. The cell monolayer was washed twice with PBS and mounted in Dako®fluorescent mounting medium (Glostrup, Denmark) to be observed by confocal laser scanning microscope (CLSM) (LSM 410, Zeiss, Jena, Germany) with an imaging software, Fluoview FV500.
In Vitro Cytotoxicity
where Abssis the fluorescence absorbance of the cells incubated with the nanoparticle suspension, and Abscontrolis the fluorescence absorbance of the cells incubated with the culture medium only (positive control). IC50, the drug concentration at which inhibition of 50% cell growth was observed, in comparison with that of the control sample, was calculated by curve fitting of the cell viability data.
The results are expressed as mean ± SD. The significance of differences was assessed using Student’st test and was termed significance whenp = 0.05.
Results and Discussion
Characterization of Nanoparticles
Characterization of nanoparticles
Size (nm)(n = 3)
Polydispersion (n = 3)
Drug loading (%)
Encapsulation efficiency (%)
Zeta potential (mV)(n = 3)
293.2 ± 3.6
−48.70 ± 3.11
201.7 ± 10.1
−12.50 ± 0.86
281.2 ± 5.5
−35.70 ± 2.99
222.7 ± 5.4
−20.50 ± 1.34
Zeta potential, i.e., surface charge can greatly influence the particles stability in suspension through the electrostatic repulsion between the particles. It is also an important factor to determine their interaction in vivo with the cell membrane, which is usually negatively charged. In addition, from the zeta potential measurement, we can roughly know the dominated component on the particles surface. The detection of laser Doppler anemometry showed that zeta potential of docetaxel-loaded PCL/Pluronic F68 nanoparticles was −12.5 mV, a great increase compared with that of PCL nanoparticles, with zeta potential around −48.7 mV. Since Pluronic F68 is nonionic, this surface charge increase demonstrated the presence of Pluronic F68 layer on the surface, which shifted the shear plane of the diffusive layer to a larger distance . However, high absolute value of zeta potential is necessary to ensure stability and avoid aggregation of particles. It thus could be concluded that PCL/Pluronic F68 nanoparticles were electrically less stable than PCL nanoparticles.
In Vitro Drug Release
Uptake of Coumarin-6-Loaded Nanoparticles by MCF-7 TAX30 Cells
In Vitro Cell Viability of Nanoparticles
IC50of MCF-7 TAX30 cells after 24-, 48-, and 72-h incubation with docetaxel formulated in Taxotere®, PCL, and PCL/Pluronic F68 nanoparticles at various drug concentrations
Incubation time (h)
PCL/Pluronic F68 NPs
For the first time, a novel docetaxel-loaded PCL/Pluronic F68 nanoparticle formulation was prepared to overcome multidrug resistance in human breast cancer cells. The results revealed that there was an increased level of uptake of PCL/Pluronic F68 nanoparticles in docetaxel-resistance human breast cancer cell line, MCF-7 TAX30, when compared with PCL nanoparticles. The cytotoxicity of PCL nanoparticles was higher than commercial Taxotere®in the MCF-7 TAX30 cell culture, but the differences were not significant (p > 0.05). However, the PCL/Pluronic F68 nanoparticles achieved significantly higher level of cytotoxicity than both of PCL nanoparticles and Taxotere®(p < 0.05), indicating docetaxel-loaded PCL/Pluronic F68 nanoparticles could overcome multidrug resistance in human breast cancer cells and therefore have considerable potential for treatment of breast cancer.
The authors are grateful for financial support from the National Natural Science Foundation of China (NSFC) under Grant No 30500239 and the Shenzhen Municipal Government and Bureau of Science, Technology & Information for providing funding supports (to LQH) through the programs of Shenzhen National Key Lab of Health Science and Technology and the Key Lab of Gene and Antibody Therapy.
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