Guo Fang, Yu Meng, Wang Jinping, Tan Fengping, Li Nan
Tianjin Key Laboratory of Drug Delivery & High-Efficiency, School of Pharmaceutical Science and Technology, Tianjin University , 300072 Tianjin, People's Republic of China.
ACS Appl Mater Interfaces. 2015 Sep 23;7(37):20556-67. doi: 10.1021/acsami.5b06552. Epub 2015 Sep 9.
The therapeutic effectiveness of chemotherapy was hampered by dose-limiting toxicity and was optimal only when tumor cells were subjected to a maximum drug exposure. The purpose of this work was to design a dual-functional thermosensitive bubble-generating liposome (BTSL) combined with conjugated targeted ligand (folate, FA) and photothermal agent (IR780), to realize enhanced therapeutic and diagnostic functions. This drug carrier was proposed to target tumor cells owing to FA-specific binding, followed by triggering drug release due to the decomposition of encapsulated ammonium bicarbonate (NH4HCO3) (generated CO2 bubbles) by being subjected to near-infrared (near-IR) laser irradiation, creating permeable defects in the lipid bilayer that rapidly release drug. In vitro temperature-triggered release study indicated the BTSL system was sensitive to heat triggering, resulting in rapid drug release under hyperthermia. For in vitro cellular uptake experiments, different results were observed on human epidermoid carcinoma cells (KB cells) and human lung cancer cells (A549 cells) due to their different (positive or negative) response to FA receptor. Furthermore, in vivo biodistribution analysis and antitumor study indicated IR780-BTSL-FA could specifically target KB tumor cells, exhibiting longer circulation time than free drug. In the pharmacodynamics experiments, IR780-BTSL-FA efficiently inhibited tumor growth in nude mice with no evident side effect to normal tissues and organs. Results of this study demonstrated that the constructed smart theranostic nanocarrier IR780-BTSL-FA might contribute to establishment of tumor-selective and effective chemotherapy.
化疗的治疗效果受到剂量限制毒性的阻碍，只有当肿瘤细胞受到最大程度的药物暴露时才达到最佳效果。这项工作的目的是设计一种双功能热敏气泡生成脂质体（BTSL），它结合了共轭靶向配体（叶酸，FA）和光热剂（IR780），以实现增强的治疗和诊断功能。由于FA的特异性结合，这种药物载体被认为能够靶向肿瘤细胞，随后通过近红外（near-IR）激光照射使包封的碳酸氢铵（NH4HCO3）（产生CO2气泡）分解，从而触发药物释放，在脂质双层中产生可渗透的缺陷，使药物快速释放。体外温度触发释放研究表明，BTSL系统对热触发敏感，在热疗条件下导致药物快速释放。对于体外细胞摄取实验，由于人表皮样癌细胞（KB细胞）和人肺癌细胞（A549细胞）对FA受体的不同（阳性或阴性）反应，观察到了不同的结果。此外，体内生物分布分析和抗肿瘤研究表明，IR780-BTSL-FA可以特异性地靶向KB肿瘤细胞，其循环时间比游离药物更长。在药效学实验中，IR780-BTSL-FA有效地抑制了裸鼠体内的肿瘤生长，对正常组织和器官没有明显的副作用。本研究结果表明，构建的智能诊疗纳米载体IR780-BTSL-FA可能有助于建立肿瘤选择性和有效的化疗方法。
