目的

探讨改良羟基喜树碱纳米微球剂型对口腔鳞癌疗效提升的作用。

方法

制备闭环羟基喜树碱/聚乙二醇-聚谷氨酸苄酯（HCPT/PEG-PBLG）纳米微球，对金黄地鼠颊囊鳞癌动物模型进行干预实验：设生理氯化钠、PEG-PBLG 对照组和HCPT、HCPT/PEG-PBLG治疗组，药物腹腔注射（3 mg/kg，qd）连续5 d。计算肿瘤体积变化、肿瘤倍增时间（DT）和抑瘤率并检测药代动力学各参数。

结果

成功制备HCPT/PEG-PBLG 纳米微球，包封率56.8%；载药率7.5%。 金黄地鼠颊囊癌干预实验：HCPT 治疗组肿瘤体积于化疗第4 天缩小达到最小值后复又开始增大，DT 延长，抑瘤率：63.58%；HCPT/PEG-PBLG 治疗组肿瘤体积于化疗第4 天缩小，第8 天达到最小值，DT 与HCPT 组比较明显延长（P=0.01），抑瘤率（76.50%）提高。HCPT 体内代谢呈二室模型；HCPT/PEG-PBLG 呈缓释-突释模型，峰值浓度减少，达峰时间、消除半衰期延长；浓度-时间曲线下面积、表观分布容积增加。

结论

HCPT 对金黄地鼠颊囊癌具有较强的抑瘤作用，但开环HCPT 羧酸钠盐助溶剂型降低了抑瘤活性，体内代谢快，组织亲和力差，限制其临床应用。 HCPT/PEG-PBLG 纳米微球剂型可保留抑瘤关键结构内酯环，增加难溶性闭环HCPT 水溶性、提高内酯环稳定性，具有药物缓释、延长体内代谢时间、增加组织亲和力等优点，提高了抑癌疗效。

Objective

To explore the improvement effect of HCPT/PEG-PBLG nanoparticles on the treatment of oral squamous cell carcinoma.

Methods

PEG-PBLG nanoparticles loaded closed ring form HCPT were synthesized and measured.Intervention was performed in Golden Hamster cheek pouch squamous cell carcinoma model： normal saline， PEG-PBLG were used as blank control and HCPT & HCPT/PEG-PBLG was given through intraperitoneal injection once a day for 5 days at a dosage of 3 mg/kg.The gross volume of the tumor， the tumor's doubling time （DT）， repression rate and pharmacokinetics index were calculated.

Results

HCPT/PEGPBLG nanoparticles had been successfully synthesized， with 56.8% in encapsulation efficiency and 7.5% in loading level.Gross volume of tumor treated by HCPT decreased since 4^th day reached its minimum， tumor doubling time delayed and the tumor repression rate was 63.58%.In HCPT/PEG-PBLG group， the tumor gross volume decreased on 4^th day， reached their minimum on 8^th day， tumor doubling time was obviously longer than HCPT group （P=0.01） and tumor repression rate was 76.50%.The pharmacokinetics of HCPT carboxylic sodium salt dosage form showed two- compartment model， that of HCPT/PEG-PBLG showed a burst-and-delayed release model in vivo： T_max and t_1/2β were longer， C_max lower， AUC and Vd increased than HCPT.

Conclusions

HCPT fairly restrained tumor growth of OSCC in vivo.But in clinical， HCPT is usually converted to carboxylic sodium salt dosage form with E-lactone ring opened to make the agent solvable， which has weakened its activity of tumor-depressing， and given the agent a fast rate of metabolism as well as lower affinity to tissue in vivo， leading to the limitation of application.HCPT/PEG-PBLG nanoparticles， which has preserved the key structure of tumordepressing， E-lactone ring， increase the solubility and stabilized the lactone ring， slow down the drug release， prolong the metabolic elimination， scale up the drug affinity to tissue and make tumor-targetting possible.Compared with open ring form HCPT， it showed better therapeutic effects.