基于藻酸双酯钠的阿霉素/塞来昔布纳米药物晶体的制备及其抗肿瘤作用研究

Preparation and its antitumor effect of doxorubicin/celecoxib drug nanocrystals based on polysaccharide sulfate

目的制备基于藻酸双酯钠的阿霉素/塞来昔布纳米药物晶体(PPDC),并考察其体外抗肿瘤作用。方法采用纳米沉淀法制得PPDC混悬液,分别表征PPDC的形态、粒径、电位、药物晶型、药物包载情况、释药性能,通过细胞摄取、细胞毒性、细胞侵袭、细胞黏附评价PPDC对4T1细胞的抑制作用。结果PPDC混悬液呈规则球形,分散性良好,分布较窄,载药量高。塞来昔布、阿霉素以无定型稳定状态存在于PPDC中。PPDC在体外释放72 h时携载的药物能够有效释放。体外细胞实验表明,PPDC能被4T1细胞摄取,细胞毒作用具有浓度相关性,并显著抑制细胞侵袭和细胞黏附。结论PPDC有效解决塞来昔布的难溶性、稳定剂毒性大等问题,与阿霉素共载实现两药协同抑制肿瘤细胞生长和转移的作用。

Objective To prepare doxorubicin/celecoxib drug nanocrystals(polysaccharide sulfate/PVP/doxorubicin/celecoxib,PPDC) based on polysaccharide sulfate(PSS), and study its antitumor effect in vitro. Methods PPDC suspension was prepared by nano precipitation method. The morphology, particle size, potential, drug crystal form, drug loading, and drug release performance of PPDC were characterized, respectively. The inhibition of PPDC against 4T1 cells was evaluated by cell uptake, cytotoxicity, cell invasion, and cell adhesion. Results PPDC suspension was regular spherical, with good dispersion, narrow distribution, and high drug loading. Celecoxib and doxorubicin existed in PPDC in an amorphous and stable state. Drug loaded by PPDC can be effectively released after 72 h in vitro release. In vitro cell experiments showed that PPDC could be taken up by 4T1 cells, and its cytotoxicity was concentration dependent, significantly inhibiting cell invasion and cell adhesion. Conclusion PPDC can effectively solve the problems such as insolubility of celecoxib and high toxicity of stabilizer, and achieve the synergistic effect with doxorubicin in inhibiting growth and metastasis of tumor cells.