Pulmonary targeting microparticulate camptothecin delivery system: anticancer evaluation in a rat orthotopic lung cancer model.
Pulmonary targeting microparticulate camptothecin delivery system: anticancer evaluation in a rat orthotopic lung cancer model.
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DOI：
10.1097/cad.0b013e328332a322
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发表时间：
2010-01
影响因子：
2.3
通讯作者：
Sinko PJ
中科院分区：
文献类型：
--
作者：
Chao P;Deshmukh M;Kutscher HL;Gao D;Rajan SS;Hu P;Laskin DL;Stein S;Sinko PJ
大的（>6 μm）刚性微粒（MP）在静脉注射后被动地截留在肺内，使得它们成为吸入用于肺递送的有吸引力且高效的替代方案。本研究以喜树碱（CPT）的α-氨基酸前体药物Nva为模板，制备了聚乙二醇修饰的6 μm聚苯乙烯多聚体。使用扫描电子显微镜（SEM）表征表面形态。在37°C下，在大鼠血浆中，CPT在24小时内从CPT-Nva-MP中释放。与静脉注射游离CPT后的高但短暂的全身暴露相比，单次静脉注射CPT-Nva-MP后4天内体内CPT血浆浓度较低（约1 ng/mL或更低）且恒定。这表明给予MP输送系统后，肺部达到了持续的局部CPT浓度。在原位肺癌动物模型中评价抗癌功效，并与CPT的推注进行比较。发现接受游离CPT（2 mg/kg）或CPT-Nva-MP（0.22mg/kg CPT，100 mg/kg MP）的动物具有比未处理的动物统计学显著更小的肺癌面积（分别为P<0.05，P<0.01）。此外，40%接受CPT-Nva-MP的动物被发现没有癌症。使用靶向MP的CPT剂量比IV注射游离CPT后低10倍，但在减少癌区域的量方面更有效。总之，CPT-Nva-MPs能够以比全身给予的CPT低十倍的剂量获得有效的局部肺部和低全身CPT浓度，从而显着改善原位大鼠肺癌模型的抗癌功效。
Large (>6 µm) rigid microparticles (MPs) become passively entrapped within the lungs following intravenous injection making them an attractive and highly efficient alternative to inhalation for pulmonary delivery. In the current studies, PEGylated 6 μm polystyrene MPs with multiple copies of the norvaline (Nva) α-amino acid prodrug of camptothecin (CPT) were prepared. Surface morphology was characterized using a scanning electron microscope (SEM). CPT was released from the CPT-Nva-MPs over 24 hours in rat plasma at 37°C. In vivo CPT plasma concentrations were low (~1 ng/mL or less) and constant over a period of 4 days after a single intravenous injection of CPT-Nva-MPs as compared to high but short-lived systemic exposures after an IV injection of free CPT. This suggests that sustained local CPT concentrations were achieved in the lung after administration of the MP delivery system. Anti-cancer efficacy was evaluated in an orthotopic lung cancer animal model and compared to a bolus injection of CPT. Animals receiving either free CPT (2 mg/kg) or CPT-Nva-MPs (0.22 mg/kg CPT, 100 mg/kg MPs) were found to have statistically significant smaller areas of lung cancer (P<0.05, P<0.01, respectively) than untreated animals. In addition, 40% of the animals receiving CPT-Nva-MPs were found to be free of cancer. The CPT dose using targeted MPs was ten fold lower than after IV injection of free CPT but was more effective in reducing the amount of cancerous areas. In conclusion, CPT-Nva-MPs were able to achieve effective local lung and low systemic CPT concentrations at a dose that was ten times lower than systemically administered CPT resulting in a significant improvement in anticancer efficacy in an orthotopic rat model of lung cancer.