Honokiol Loaded Mixed Micelles Fororal Delivery Using Novel F127 and TPGS as Carriers
doi: 10.14148/j.issn.1672-0482.2021.0376
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摘要:
目的 旨在使用普朗尼克F127(F127)和维生素E聚乙二醇1000琥珀酸酯(TPGS)制备自组装胶束，提高和厚朴酚(HK)的口服生物利用度和抗肿瘤活性。 方法 负载和厚朴酚F127/TPGS二元混合胶束(HK-M)最佳处方采用乙醇溶剂蒸发法制备，以透射电镜(TEM)、HPLC对其进行表征，用透析袋法测定HK-M中HK的累积释放量，用Caco-2测定HK-M的渗透性，并评价其生物利用度和体内抗肿瘤活性。 结果 当F127∶TPGS(4∶1)，HK-M为透明无色，粒径(23.28±2.01)nm，胶束呈球形且均匀。HK-M中HK的溶解度显著增加至4.76 mg/mL，HK-M具有较好的稳定性。HK包封于混合胶束中，可实现HK的持续释放。HK-M增强HK在Caco-2细胞单层模型中的渗透性。与游离HK相比，HK-M的相对口服生物利用度增加了1.17倍。此外，HK-M对肿瘤体积的抑制率(35.17%)高于HK组(14.86%)。 结论 HK-M能改善HK的溶解性、口服生物利用度和抗肿瘤活性。 Abstract: OBJECTIVE The purpose of this research was to develop a self-assembled micelle using biocompatible copolymers Pluronic F127 (F127) and Vitamin E d-α-Tocopheryl polyethylene glycol 1000 succinate (TPGS) to enhance the oral bioavailability and anti-cancer efficiency of honokiol (HK). METHODS The optimized prescription honokiol micelle (HK-M) was prepared by an ethanol solvent evaporation method. HK-M was characterized by transmission electron microscopy(TEM) and HPLC. The dialysis bag method was used to assesse the cumulative amount of HK released from the HK-M. Caco-2 cells were applied to measure the permeability of HK-M. The bioavailability and in vivo anti-tumor effect were also evaluated. RESULTS At the ratio of 4∶1 (F127∶TPGS), the HK-M was transparent and colourless with a small size (23.28 ± 2.01)nm and a spherical shape. The apparent solubility of HK in HK-M was dramatically increased to 4.76 mg/mL, suggesting that HK-M had good stability. Furthermore, encapsulation in micelles led to a sustained release of HK. HK-M enhances HK's permeability across Caco-2 cell monolayer. Compared with free HK, there was a 1.17-fold increase in the relative oral bioavailability for HK-M. Moreover, HK-M achieved a higher inhibition rate on tumor volume (35.17%) than HK group (14.86%). CONCLUSION-
Key words:
- honokiol /
- F127 /
- TPGS /
- micelles /
- Caco-2 cell /
- oral bioavailability /
- anti-tumor
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Figure 4. Cumulative release of HK-M and HK with phosphate- buffered saline at pH 1.2 (A) and pH 6.8 (B) in vitro (x±s, n=3)
Figure 5. The plasma drug concentration-time curve in rats after oral administration of 80 mg/kg of HK and HK-M (x±s, n=6)
Figure 6. Anti-tumor effect observed by HE staining
A.Control (×400); B. HK(×400); C. HK-M (×400). Scale bar=20μm
Figure 7. Anti-cancer effects of HK-M in the tumor xenograft model (A). Final tumor volumes after 20 completion of 2 weeks of physiological saline, free HK and HK treatment at 50 mg/kg doses (B)
Note: *P < 0.05, **P < 0.01 vs control group; #P < 0.05, vs free HK group. x±s, n=6.
Table 1. Characteristics of HK-M (x±s, n=3)
F127∶TPGS/ (mg·mL-1) Average size/nm PDI Zeta potential/mV EE/% DL/% Solubility/ (mg·mL-1) 40∶10 23.28±2.01 0.068±0.012 -2.43±0.02 91.64±0.53 8.27±0.53 4.76±0.15 
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Table 2. Permeability and efflux ratio of HK and HK-M in Caco-2 cell model (x±s, n=3)
Compound (50 μg·mL-1) Papp×10-7/(cm·s-1) Efflux ratio AP-BL BL-AP HK 3.16±0.35 2.57±0.29 0.81±0.01 HK-M 5.72±0.39* 4.33±0.31* 0.76±0.01 Note: Compared with HK group, *P < 0.05。
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Table 3. Pharmacokinetic parameters of HK and HK-M (x±s, n=6)
Parameters HK HK-M Cmax(μg/mL) 0.415±0.023 0.940±0.075** Tmax(h) 0.958±0.102 0.708±0.102** AUC0-t (μg /mL·h) 2.396±0.303 5.211±0.501** AUC0-∞ (μg /mL·h) 3.365±0.425 5.915±0.687** t1/2(h) 5.123±1.183 3.619±0.331* MRT0-∞(h) 7.824±1.352 5.887±0.371* Note: *P < 0.05, **P < 0.01。
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