Ding Xue-Qiang, Chen Dan, Wang An-Xun, Li Su, Chen Yu, Wang Ji
Department of Oral & Maxillofacial Surgery, First Affiliated Hospital, Sun Yat-Sen University, Guangzhou City, Guangdong Province, 510080, P.R. China.
Oncol Res. 2007;16(7):313-23. doi: 10.3727/000000006783980991.
Therapeutic use of hydroxycamptothecin (HCPT), a promising antitumor agent, is limited by its poor solubility and rapid destruction. Amphiphilic block copolymer micelle carriers possess significant potential for improving drug solubility and stability. Poly[ethylene glycol]-poly[gamma-benzyl-L-glutamate] (PEG-PBLG) micelles were prepared and loaded with the active lactone form of HCPT using an uncomplicated dialysis method. HPLC and scanning electron microscopy studies revealed an encapsulation efficiency of 56.8% and a core-shell figure with a mean diameter of 200 nm. Encapsulated HCPT lactone was compared with the less active, open ring-carboxylated HCPT-Na+ soluble form generated in vivo from the free active lactone for activity against oral squamous cell carcinoma. Cytotoxicity in vitro was measured in cultured Tca8113 cells by the MTT assay and microscopy techniques. The golden hamster cheek pouch squamous cell carcinoma model was employed for in vivo studies; encapsulated lactone and open ring-carboxylated forms of HCPT were administered intraperitoneally, followed by determinations of tumor growth rate and inhibition ratio. PEG-PBLG micelles were not cytotoxic in vitro. At 48 h of treatment, open ring-carboxylated HCPT proved significantly more cytotoxic in vitro than encapsulated HCPT lactone. At 96 h, however, the open ring-carboxylated and encapsulated drugs displayed comparable in vitro cytotoxicities. In the in vivo squamous cell carcinoma model, encapsulated HCPT lactone produced greater and more prolonged tumor suppression compared to the open ring-carboxylated form. The antitumor effects of HCPT/PEG-PBLG micelles against oral squamous cell carcinoma in vivo are concluded to be superior to those exerted by open ring-carboxylated HCPT.
羟基喜树碱（HCPT）是一种很有前景的抗肿瘤药物，但其治疗应用受到其低溶解度和快速降解的限制。两亲性嵌段共聚物胶束载体在改善药物溶解度和稳定性方面具有巨大潜力。采用简单的透析法制备了聚乙二醇-聚γ-苄基-L-谷氨酸酯（PEG-PBLG）胶束，并负载了HCPT的活性内酯形式。高效液相色谱（HPLC）和扫描电子显微镜研究显示包封率为56.8%，且呈现出平均直径为200nm的核壳结构。将包封的HCPT内酯与体内由游离活性内酯生成的活性较低的开环羧化HCPT-Na+可溶形式进行比较，以研究其对口腔鳞状细胞癌的活性。通过MTT法和显微镜技术在培养的Tca8113细胞中测定体外细胞毒性。采用金黄地鼠颊囊鳞状细胞癌模型进行体内研究；将包封的内酯形式和开环羧化形式的HCPT腹腔注射给药，随后测定肿瘤生长速率和抑制率。PEG-PBLG胶束在体外无细胞毒性。在治疗48小时时，开环羧化的HCPT在体外的细胞毒性明显高于包封的HCPT内酯。然而，在96小时时，开环羧化和包封的药物在体外表现出相当的细胞毒性。在体内鳞状细胞癌模型中，与开环羧化形式相比，包封的HCPT内酯产生了更大且更持久的肿瘤抑制作用。得出结论，HCPT/PEG-PBLG胶束对口腔鳞状细胞癌的体内抗肿瘤作用优于开环羧化的HCPT。
