Abstract：OBJECTIVE To design N dodecanol modified docetaxel(DTX) prodrug, prepare nanostructured lipid carrier(NLC) and investigate in vitro antitumor activity and in vivo pharmacodynamic. METHODS Nanostructured lipid carrier (DNLC) encapsulating n-dodecanol-modified DTX prodrug was prepared by ultrasonic method. The formulation was optimized by single-factor experiment and response surface optimization. The accumulated rates of DTX degraded from DNLC in different media was evaluated by high performance liquid chromatography (HPLC). The morphology of DNLC was observed by transmission electron microscopy (TEM). The particle size and PDI of DNLC were determined by Malvern particle size analyzer. The long-term stability of the preparations was investigated. In vitro cytotoxicity of DNLC was measured by MTT method. In vivo pharmacodynamics of DNLC were performed in 4T1 tumor xenograft balb/c mice using saline and DTX-Sol as control. RESULTS n-Dodecanol-modified DTX prodrug was synthesized and used to prepare DNLC. The optimal formulation was as following: mass ratio of emulsifier to co-emulsifier (Km) of 1∶3, solid-liquid lipid ratio of 1.43∶1, drug-lipid ratio of 1∶10, the emulsifier concentration of 60 mg·mL-1, the temperature of 70 ℃ and the stirring speed of 800 r·min-1. DNLC had a round appearance and a uniform spherical shape. And the particle size and PDI remained substantially stable within 30 d. The accumulated rates of DTX degraded from DNLC in PBS (pH 7.4), PBS (pH 7.4) containing 10 mmol·L-1 DTT and 10 mmol·L-1 H2O2 was (9.07±0.01)%, (21.52±0.35)% and (96.72±4.12)% at 24 h, respectively. After incubation of DTX-Sol and DNLC with 4T1 cells for 72 h, IC50 of DTX-Sol and DNLC were (1.2±0.2) and (13.2±4.3)nmol·L-1, respectively. The cytotoxicity of DTX-Sol group was stronger than that of DNLC group. At the end of the pharmacodynamics, the tumor volumes of the mice in saline, DTX-Sol and DNLC groups were (1 930.39±215.20), (1 013.64±138.65), and (765.16±177.43)mm3, respectively. And the change percentage of body weight in saline, DTX-Sol and DNLC groups were (-19.69±4.44)%, (-14.85±3.61)% and (-2.61±1.70)%. There were significant differences in tumor volume and body weight between the DNLC and DTX-Sol group (P<0.05). CONCLUSION The prepared DNLC shows good stability, redox sensitivity, obvious anti-tumor effect and lower toxicity . These RESULTS could provide a new experimental basis for the development of DTX prodrug loaded nano-drug delivery system.
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2020, Vol. 55 
