Curcumin loaded mixed micelles composed of Pluronic P123 and F68: Preparation, optimization and in vitro characterization
Introduction
Curcumin (Cur), bis(4-hydroxy-3-methoxyphenyl)-1,6-diene-3,5-dione, is a low molecular weight polyphenol compound derived from the rhizome of the plant Curcuma longa [1]. Curcumin as an effective ingredient has been used in traditional medicine for many centuries in countries such as India and China [2]. Recently, it is reported that curcumin has a wide range of pharmacological applications such as anti-inflammation, anti-human immuno-deficiency virus, anti-microbial, anti-oxidant, anti-parasitic, anti-mutagenic and anti-cancer with low or no intrinsic toxicity [3], [4], [5], [6], [7], [8]. In spite of this wide spectrum of pharmacological properties, the application of curcumin in clinic has been hampered due to low solubility in aqueous solution (the solubility was reported to be 11 ng/mL in plain aqueous buffer pH 5.0) and rapid degradation at physiological pH [3], [9]. And the absorption of curcumin in gastro-intestinal tract is very low, for example, the absolute oral bioavailability in rat is only about 1% [5].
Therefore, the improvement in stability, solubility and bioactivity of curcumin will be needed. In previous reports, numerous formulations of curcumin were developed, such as nanosuspension [10], β-cyclodextrin inclusion complex [3], PLGA nanoparticles [11], nanospheres [12], polymeric nanoparticles [13]. Recent studies show that inclusion of hydrophobic drugs into polymeric micelles is one of the most attractive alternatives [14]. Amphiphilic block copolymers form core–shell nano-sized aggregates which can solubilize poorly soluble drugs and thus improve their bioavailability and protect from inactivation in biological media [15]. Triblock copolymers of poly (ethylene oxide) (PEO) and poly(propylene oxide) (PPO) with the structure PEO–PPO–PEO that are known generically as poloxamers or Pluronic or Synperonic as the trade names, are highly surface-active compounds. Structural studies show that Pluronic copolymer can self-assemble into spherical micelle which is constructed with EO as a hydrophilic outer shell and PO as a hydrophobic inner core [16], [17]. As one promising nanomedicine technology, triblock copolymers as carriers for anticancer drugs are widely used in a variety of clinical applications [18], [19], [20].
Mixed micelles manifest synergistic properties, such as increased micelle stability and drug loading efficiency, superior to those of the individual components [21], [22], [23]. For example, the mixed micelles made of Pluronic P105 and TPGS provide a more stable and efficient solubilization system for camptothecin [21]. SP1049C, containing doxorubicin in the mixed micelles made from Pluronics L61 and F127, is the first anti-cancer micellar formulation to reach clinic and is undergoing Phase II clinical trials [24], [25].
Pluronic P123 (P123), composed of PEO20–PPO68–PEO20, is one of the most common representatives of Pluronic copolymer [26]. P123 demonstrates a significant cytotoxicity in the multidrug resistant (MDR) cell lines to doxorubicin due to inhibition of the P-glycoprotein (P-gp) drug efflux transport system that is over-expressed in the MDR cells [27]. Recently, the PTX-loaded polymeric micelle prepared with Pluronic P123 or P105 could effectively prolong blood circulation time and modify the biodistribution of PTX in vitro [28], [29]. However, the in vitro micelles with one Pluronic as carrier are still to be improved. As a result, the mixed micelles were developed. Moreover, a triblock copolymer with a greater number of PEO units, i.e. with higher hydrophilic/hydrophobic ratio is expected to reduce significantly the repulsions between two groups in comparison to one with lesser number of PEO units [30]. A hydrophilic chain is added to the copolymer backbone, and could significantly changed the hydrophilicity of the particles, and could provide a steric barrier to reduce particles aggregation [31], [32]. Pluronic F68 (F68) is at present approved for intravenous injection by FDA. F68 is a PEO–PPO–PEO triblock copolymer, having monomer unit ratio of 70/35/70. Owing to its high polyethylene oxide (PEO)/polypropylene oxide (PPO) ratio, F68 is rather hydrophilic compared with other Pluronic block copolymers, and thus, the critical micelle concentration (CMC) is very high [33], [34].
To increase the stability and solubility of curcumin and make it be administered by injection, curcumin loaded mixed micelles were prepared by thin-film hydration method, composed of P123 and F68. The preparation process was optimized with a central composite design (CCD). In addition, the physicochemical properties and in vitro cytotoxicity of the drug-loaded micelles were investigated.
Section snippets
Materials
Curcumin (Cur), Pluronic P123 (P123) and Pluronic F68 (F68) were purchased from Sigma–Aldrich (St. Louis, MO, USA). 3-(4,5-Dimethyl-thiazol-2-yl)-2,5-diphenyl-tetrazolium bromide (MTT), trypsin and EDTA were purchased from Amresco. Penicillin streptomycin and RPMI 1640 were purchased from Thermo Fisher (Beijing, China). Fetal bovine serum (FBS) was purchased from Tian Jin Hao Yang Biological Manufacture Co., Ltd. (Tianjin, China). Human breast carcinoma cell line MCF-7 and its
Optimization of Cur loaded micelles based on central composite design
The experimental design based on CCD is shown in Table 1 and SPSS 17.0 is employed to deal with the data to get regression equations. From the formula, all the dependent variables can be well described by quadratic polynomial with high correlation coefficient (R > 0.95, P < 0.005), and the quadratic polynomial equations were as follows:where X1 represents the amount of Cur, X2 represents ratio of
Conclusions
The mixed polymeric micelles, composed of P123 and F68 with the ratio at 2.05:1, exhibited higher EE and DL for Cur. The average size of the Cur loaded mixed micelles was 68.2 nm. Compared with the Cur propylene glycol solution, the Cur-PF showed the sustained-release property. The in vitro cytotoxicity assay showed that Cur-PF micelles presented higher cytotoxic effect on MCF-7 and MCF-7/ADR. Based on these results, it can be concluded that the mixed micelle formulation developed in this study
Acknowledgments
This work is supported by the Natural Science Foundation of Shandong Province, China (No. ZR2011HM026), the National Natural Science Foundation of China (No. 30973646) and the Independent Innovation Foundation of Shandong University (2010JC018).
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These authors contributed equally to the work.