Micelle is composed of amphiphilic molecules that could self-assemble into a hydrophilic exterior and a hydrophobic core that encapsulated with hydrophobic drugs to improve solubility. Unfortunately, traditional micelles made by an amphiphilic polymer caused that the solubilization is determined by only one polymer. To improve the limitation, additional amphiphilic polymers are added to form mixed polymeric micelle (MPM), whose volume of the hydrophobic core is increased by incorporating extra hydrophobic materials. Hence, MPM provides larger space for hydrophobic drugs to be solubilized.
In this study, a novel mixed micelle (M-DocLF) which consisted of Doc (Docetaxel), Pluronic L121, Pluronic F127 (w/w) was optimally prepared by thin-film hydration method. Briefly, Doc, PL121 and PF127 were dissolved in methanol together with different weight ratio. The solution was subsequently evaporated by rotary evaporation to obtain a thin film. The thin film formed was further dried in vacuum, and then hydrated with water and shake gently until the thin film was dissolved. The unincorporated Doc aggregates were removed by passing through a 0.22µm filter. Mean particle size (MPS), polydispersity index (PDI), encapsulation efficiency (EE), zeta potentials (ZP), and drug loading (DL) of self-assembling mixed micelles were examined for optimization. Self-assembling mixed micellar system containing Doc (M-DocLF) was optimized to consist of Doc : PL121: PF127 (w/w) =1:45:15 with high encapsulation efficacy. The sizes of M-DocLF are 215.6 nm. The polydispersity indices (PDI) are around 0.28, which indicate narrow size distribution. The results of Doc release from micelle formulation was slower than Tynen (Doc solubilized in solvent) in phosphate buffer (pH 7.0 PBS) with 0.5% Tween 80 at 37℃. M-DocLF (IC50=0.63μg/ml) shows better cytotoxicity than free Doc (IC50=0.9μg/ml) for CT26 cancer cells. Pharmacokinetics in normal and tumor bearing balb/c model in Fig 1, it demonstrated that M-DocLF has much longer blood circulation. However, comparison to M-DocLF (IV) in normal and tumor bearing balb/c model, we observed the AUC0-5 of tumor model was 0.55-fold of normal mouse but MRT of tumor model was 2.12-fold than normal mouse.
The in vivo antitumor efficacy of M-DocLF formulation was evaluated in the C26 tumor-bearing mice model. Mice were randomized into four groups when the tumor size was reach 100 mm3. The four groups of mice were intravenous injected with PBS, M-DocLF(Placebo), Tynen, M-DocLF. The size change with respective to time was measured and plotted in Fig 2. Ten days after intravenous injection, mice were sacrificed and tumors were sampled for weight measurement. The tumor inhibition rate was calculated as the % change of tumor weight using the tumor weight of PBS group as basis. The tumor inhibition rate of M-DocLF (Placebo) was -1.87%, versus 29.91%, 49.04% for Tynen, M-DocLF. It demonstrated that M-DocLF is significantly more efficacious than commercial product Tynen. The body weight of M-DocLF-treated mouse didn’t have significant difference indicating similar systemic toxicity.
In conclusion, mixed polymeric micelles of M-DocLF could be a potential carrier for delivering hydrophobic chemotherapeutic agent that could enhance the efficacy of cancer chemotherapy with minimal systemic toxicity.
Fig1.The in vivo pharmacokinetic of Docetaxel formulation after intravwnous injection (A)Normal;(B)C26 tumor bearing Balb/c mice.
Fig2. The in vivo antitumor effect of M-DocLF formulation (A) Changes in tumor volumes;(B) Changes in mice body weight
Ministry of Science and Technology of ROC (MOST 103-2320-B-038-007); Ministry of Economic Affairs, ROC (103-EC-17-A-20-S1-200)
References:
[1] Zhang, W., Y. Shi, et al. Biomaterials, 32, 2894 (2011).