Department of Industrial Pharmacy, Faculty of Pharmacy, Alexandria University, Alexandria 21521, Egypt.
Department of Chemical and Biochemical Engineering, Faculty of Engineering, University of Western Ontario, London, Ontario, Canada.
Int J Nanomedicine. 2019 Sep 17;14:7561-7581. doi: 10.2147/IJN.S218905. eCollection 2019.
This study was conducted to elucidate the chemopreventive potential, cytotoxic, and suppression of cellular metastatic activity of etodolac (ETD)-loaded nanocarriers.
To esteem the effect of charge and composition of the nanovectors on their performance, four types of vectors namely, negative lipid nanovesicles; phosalosomes (N-Phsoms), positive phosalosomes (P-Phsoms), nanostructured lipid carriers (NLCs) and polymeric alginate polymer (AlgNPs) were prepared and compared. ETD was used as a model cyclo-oxygenase-2 (COX-2) inhibitor to evaluate the potency of these nanovectors to increase ETD permeation and retention through human skin and cytotoxicity against squamous cell carcinoma cell line (SCC). Moreover, the chemopreventive activity of ETD nanovector on mice skin cancer model was evaluated.
Among the utilized nanovectors, ETD-loaded N-Phsoms depicted spherical vesicles with the smallest particle size (202.96±2.37 nm) and a high zeta potential of -24.8±4.16 mV. N-Phsoms exhibited 1.5, and 3.6 folds increase in the ETD amount deposited in stratum corneum, epidermis and dermis. Moreover, cytotoxicity studies revealed a significant cytotoxic potential of such nanovector with IC=181.76 compared to free ETD (IC=982.75), correlated to enhanced cellular internalization. Its efficacy extended to a reduction in the relative tumor weight with 1.70 and 1.51-fold compared to positive control and free ETD, that manifested by a 1.72-fold reduction in both COX-2 and proliferating cell nuclear antigen mRNA (PCNA-mRNA) levels and 2.63-fold elevation in caspase-3 level in skin tumors relative to the positive control group with no hepato-and nephrotoxicity.
Encapsulation of ETD in nanovector enhances its in-vitro and in-vivo anti-tumor activity and opens the door for encapsulation of more relevant drugs.
本研究旨在阐明依托度酸（ETD）载药纳米载体的化学预防潜力、细胞毒性和对细胞转移活性的抑制作用。
为了评估纳米载体的电荷和组成对其性能的影响，我们制备并比较了四种类型的载体，即负电荷脂质纳米囊泡；磷脂纳米囊泡（N-Phsoms）、正电荷磷脂纳米囊泡（P-Phsoms）、纳米结构脂质载体（NLCs）和聚合藻酸钠聚合物（AlgNPs）。以环氧化酶-2（COX-2）抑制剂依托度酸（ETD）为模型，评估这些纳米载体增加 ETD 经皮渗透和保留的能力以及对鳞状细胞癌细胞系（SCC）的细胞毒性。此外，还评估了 ETD 纳米载体对小鼠皮肤癌模型的化学预防活性。
在所使用的纳米载体中，载药 N-Phsoms 呈现出具有最小粒径（202.96±2.37nm）和高 zeta 电位（-24.8±4.16mV）的球形囊泡。N-Phsoms 使 ETD 在角质层、表皮和真皮中的沉积量分别增加了 1.5 倍和 3.6 倍。此外，细胞毒性研究表明，这种纳米载体具有显著的细胞毒性潜力，其 IC=181.76，与游离 ETD（IC=982.75）相比，细胞内吞作用增强。其疗效扩展到减少相对肿瘤重量，与阳性对照和游离 ETD 相比分别为 1.70 倍和 1.51 倍，这表现在皮肤肿瘤中 COX-2 和增殖细胞核抗原 mRNA（PCNA-mRNA）水平分别降低了 1.72 倍和 caspase-3 水平升高了 2.63 倍，与阳性对照组相比，无肝毒性和肾毒性。
将 ETD 包封在纳米载体中增强了其在体外和体内的抗肿瘤活性，并为更多相关药物的包封开辟了道路。
