叶酸靶向修饰载新藤黄酸纳米结构脂质载体的研究

Study on folic acid-modifed nanostructured lipid carriers loaded with gambogenic acid

[目的]构建叶酸(FA)修饰的载新藤黄酸纳米结构脂质载体(FA-GNA-NLC),提高新藤黄酸(GNA)的生物利用度,增强其在肿瘤部位的蓄积,降低全身毒副作用,并对该制剂进行理化表征和体内外药效学评价。[方法]通过乳化蒸发-低温固化法构建包载GNA的纳米结构脂质载体(GNA-NLC),通过聚乙二醇(PEG)链将FA连接到NLC表面,对制剂的粒径、Zeta电位和外观形貌进行初步表征。以小鼠乳腺癌4T1细胞和人乳腺癌MDA-MB-231细胞为体外模型评价其对FA-NLC的摄取能力,以4T1细胞为体外细胞模型评价FA-GNA-NLC对肿瘤细胞的增殖抑制作用。构建乳腺癌小鼠模型,进行组织分布和体内抗肿瘤药效实验。[结果]制备得到形貌圆整、粒度均一、粒径为(16.01±0.03)nm、电位为(-6.8±0.59)mV、包封率为99%的FA-GNA-NLC。细胞毒性实验及体内抗肿瘤实验表明FA-GNA-NLC具有良好的抗肿瘤效果,细胞摄取实验及组织分布实验表明FA-NLC具有更好的靶向性,增强了药物在靶细胞、靶组织的蓄积。[结论]构建的FA-GNA-NLC增强了GNA的抗肿瘤活性,提高了GNA在肿瘤部位的蓄积,可以作为GNA的潜在载体,用于增强肿瘤靶向性,提高肿瘤治疗效果。

[Objective]To construct a folic acid(FA)modified nanostructured lipid carrier loaded with gambogenic acid(FA-GNA-NLC)to enhance the bioavailability of gambogenic acid(GNA),improve its accumulation in tumor sites,and reduce the systemic toxic side effects.Characterized the physical and chemical properties and evaluated the efficacy both in vivo and in vitro.[Methods]Nanostructured lipid carriers encapsulating GNA(GNA-NLC),modified with the FA via PEG linker,were constructed by emulsification-evaporation method.The formulations were characterized for particle size and zeta potential,morphology,encapsulation efficiency and drug loading.The cell uptake was performed on 4T1 cell and MDA-MB-231;the cytotoxicity in vitro was tested on 4T1 cell.Furthermore,the in vivo antitumor efficacy and bio-distribution assays were performed on female 4T1 tumor-bearing BALB/c mice.[Results]FA-GNA-NLC with round morphology,uniform particle size,(16.01±0.03)nm,potential(-6.8±0.59)mV,and encapsulation efficiency of 99%was prepared.The GNA-NLC modified with FA(FA-GNA-NLC)was successfully fabricated with a round morphology,a small size of(16.01±0.03)nm,a good uniformity,a potential of(-6.8±0.59)mV,and an encapsulation efficiency of 99%.Cytotoxicity and in vivo anti-tumor experiments show that FA-GNA-NLC performed higher anti-tumor efficiency,better tumor inhibition rate and lower toxicity to normal tissues than other group;cell uptake and biodistribution in vivo experiments show that FA-NLC performed better targeting,and significantly enhanced the accumulate at tumor tissues.[Conclusion]FA-GNA-NLC enhanced the anti-tumor activity of GNA,improved the accumulation in tumor sites.It can be concluded that the FA-GNA-NLC could be a potential and suitable vehicle for breast cancer.