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首页> 外文期刊>Biomaterials >Liposomal formulations of Etoposide and Docetaxel for p53 mediated enhanced cytotoxicity in lung cancer cell lines
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Liposomal formulations of Etoposide and Docetaxel for p53 mediated enhanced cytotoxicity in lung cancer cell lines

机译：依托泊苷和多西他赛的脂质体制剂对p53介导的肺癌细胞毒性增强

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摘要

The objective of present investigation was to develop and assess comparative enhancement in cytotoxicity of liposomal Etoposide and Docetaxel in non-small cell lung cancer cell lines after pre-treatment and co-administration of. p53 tumor suppressor gene and to assess direct lung targeting of optimized formulations by dry powder inhaler technology. Cationic liposomes with and without drug were prepared and allowed to form. p53-lipoplex for undertaking cytotoxicity studies in H-1299 (p53 null) and A-549 (p53 wt) cell lines. The optimized lipoplexes showed average size of 200-350nm, zeta potential of 25-32mV and sustained drug release up to 16-24h. The developed liposomes and lipoplexes showed significant intracellular uptake and demonstrated enhanced cytotoxicity of 13-28 % after. p53-drug co-administration and 41-63 % after. p53 pre-treatment. The. p53 mediated enhanced cytotoxicity by increased apoptosis and necrosis was also confirmed using Annexin V - FITC assay. The increased apoptosis suggested restored. p53 function and reduced anti-apoptotic drug resistance theirby causing cell sensitization and synergism towards cytotoxicity. The studies conducted above demonstrated significant cell chemo-sensitization after. p53 pre-treatment followed by Etoposide/Docetaxel liposomes administration than. p53-Etoposide or. p53-Docetaxel lipoplex co-administration; more significantly in Docetaxel and in H 1299 cell line. All the formulations when developed as dry powder inhalers showed significant. invitro lung deposition pattern in cascade impactor with fine particle faction of 33-37%. The study opens up a new strategy to treat lung cancer especially in cases of drug resistance. Moreover direct delivery to lung may provide an important role in complete remission of the disease due to target specificity.
机译：本研究的目的是开发和评估脂质体依托泊苷和多西他赛在非小细胞肺癌细胞系的预处理和共同给药后的细胞毒性比较增强。 p53抑癌基因，并通过干粉吸入器技术评估优化制剂对肺的直接靶向作用。制备具有和不具有药物的阳离子脂质体并使其形成。 p53-lipoplex用于在H-1299（p53 null）和A-549（p53 wt）细胞系中进行细胞毒性研究。优化的脂质复合物显示平均大小为200-350nm，ζ电位为25-32mV，药物持续释放长达16-24h。所开发的脂质体和脂质复合物显示出显着的细胞内摄取，并在之后显示出13-28％的增强的细胞毒性。 p53-药物共同给药和之后的41-63％。 p53预处理。的。使用膜联蛋白V-FITC测定法也证实了p53通过增加的凋亡和坏死介导的细胞毒性增强。凋亡增加提示恢复。 p53功能和降低的抗凋亡药物耐药性会引起细胞致敏作用和协同作用，从而产生细胞毒性。上面进行的研究表明，之后细胞发生了明显的化学增敏作用。 p53预处理后再用依托泊苷/多西他赛脂质体给药。 p53-依托泊苷或。 p53-多西他赛脂质复合体共同给药;在多西他赛和H 1299细胞系中更为明显。当开发为干粉吸入器时，所有制剂均表现出显着性。级联撞击器的体外肺沉积模式，细颗粒比例为33-37％。该研究开辟了一种治疗肺癌的新策略，尤其是在耐药性方面。此外，由于靶标特异性，直接递送至肺可能在疾病的完全缓解中发挥重要作用。

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