用于治疗肺癌的吸入给药的基质金属蛋白酶 2/9 触发释放胶束：制备和体外/体内研究。,International Journal of Nanomedicine

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用于治疗肺癌的吸入给药的基质金属蛋白酶 2/9 触发释放胶束：制备和体外/体内研究。
International Journal of Nanomedicine ( IF 6.6 ) Pub Date : 2018-08-13 , DOI: 10.2147/ijn.s166584
Xiaofei Wang _{1,

2} , Qinyue Chen ₁ , Xiaoyan Zhang ₁ , Xiaoqing Ren ₁ , Xiulei Zhang ₁ , Lin Meng ₁ , Huihui Liang ₁ , Xianyi Sha ₁ , Xiaoling Fang ₁

Affiliation

背景技术通过吸入给药改善药物在肺中的蓄积以及肺肿瘤中MMP2和MMP9的高表达均已被广泛报道。方法构建 MMP2/9 触发释放胶束，并进行吸入给药对抗肺肿瘤的体外和体内研究。用 GPLGIAGQ-NH2 (GQ8) 肽修饰 Pluronic P123 (P123) 以获得 P123-GQ8 (PG)。使用 PG 和琥珀酰化明胶 (SG) 和负载紫杉醇 (Ptx) 构建 MMP2/9 触发释放胶束。为了研究胶束的生物分布，在离体成像检测肺中的 DiR 量之前，通过静脉注射或吸入将封装在胶束中的 DiR 给药于大鼠。并选择B16F10肺癌裸鼠作为动物模型，评估MMP2/9触发释放胶束的体内功效。结果 PG-SG-Ptx 胶束的 Ptx 释放效率与 MMP2/9 浓度相关。对于 A549 细胞，与 P123-Ptx 相比，PG-SG-Ptx 的细胞毒性显着更大（P<0.001）。选择气溶胶吸入作为给药方法。在生物分布实验中，肺部DiR量是主要器官的5.8%±0.4%，而吸入的比率为38.8%±0.5%。对于 B16F10 肺癌裸鼠，吸入 PG-SG-Ptx 的疗效显着高于（P<0.001）紫杉醇吸入和注射 PG-SG-Ptx。吸入PG-SG-Ptx也显着抑制肺癌中Pgp的表达。

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Matrix metalloproteinase 2/9-triggered-release micelles for inhaled drug delivery to treat lung cancer: preparation and in vitro/in vivo studies.

BACKGROUND Improvement in drug accumulation in the lungs through inhalation administration and high expression of MMP2 and MMP9 in lung tumors have both been widely reported. METHODS MMP2/9-triggered-release micelles were constructed and in vitro and in vivo studies of inhalation administration against lung tumor carried out. Pluronic P123 (P123) was modified with GPLGIAGQ-NH2 (GQ8) peptide to obtain P123-GQ8 (PG). MMP2/9-triggered-release micelles were constructed using PG and succinylated gelatin (SG) and loading paclitaxel (Ptx). To study biodistribution of micelles, DiR encapsulated in micelles was dosed to rats via intravenous injection or inhalation before ex vivo imaging for detecting DiR quantity in lungs. And B16F10 lung cancer-bearing nude mice were chosen as animal models to evaluate in vivo efficacy of MMP2/9-triggered-release micelles. RESULTS Ptx-release efficiency from PG-SG-Ptx micelles was MMP2/9-concentration-dependent. For A549 cells, PG-SG-Ptx cytotoxicity was significantly greater (P<0.001) compared to P123-Ptx. Aerosol inhalation was chosen as the method of administration. In biodistribution experiment, DiR quantity in lungs was 5.8%±0.4% of that in major organs, while the ratio was 38.8%±0.5% for inhalation. For B16F10 lung cancer-bearing nude mice, the efficacy of inhalation of PG-SG-Ptx was significantly higher (P<0.001) than Taxol inhalation and injected PG-SG-Ptx. Inhaled PG-SG-Ptx also significantly inhibited the expression of Pgp in lung cancer. CONCLUSION Inhalation of MMP2/9-triggered-release micelles increased tumor sensitivity to chemotherapeutics and reduced the toxicity of chemotherapy to healthy lung cells, which has great potential in lung cancer therapy.

更新日期：2019-11-01

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