Rosato Antonio, Banzato Alessandra, De Luca Gilda, Renier Davide, Bettella Fabio, Pagano Claudio, Esposito Giovanni, Zanovello Paola, Bassi PierFrancesco
Department of Oncology and Surgical Sciences, Oncology Section, University of Padua, Padua, Italy.
Urol Oncol. 2006 May-Jun;24(3):207-15. doi: 10.1016/j.urolonc.2005.08.020.
To report the development of a new water-soluble paclitaxel-hyaluronic acid bioconjugate, HYTAD1-p20, for intravesical treatment of superficial bladder cancer.
HYTAD1-p20 was synthesized by carboxyl esterification of hyaluronic acid with paclitaxel, and its physicochemical and biologic properties were characterized.
Paclitaxel loading was optimized at 20% w/w; this procedure increased by 500-fold the paclitaxel concentration in the resulting water-soluble biomaterial. In vitro, HYTAD1-p20 exerted a much higher dose-dependent inhibitory effect against RT-4 and RT-112/84 bladder carcinoma cell growth than that of free drug, and directly interacted with CD44 expressed by bladder tumor cells. In vivo, results of pharmacokinetic studies performed in mice after bladder catheterization and intravesical instillation of HYTAD1-p20 disclosed that drug leakage was negligible during a 2-hour analysis. Histologic examination of drug-instilled bladders revealed that HYTAD1-p20 was extremely well tolerated, while paclitaxel alone produced mucosal disruption and submucosal infiltration of inflammatory cells. Treatment of severe combined immunodeficient mice bearing subcutaneous RT-112/84 tumors with maximum tolerated doses of bioconjugate or paclitaxel showed that HYTAD1-p20 exerted a therapeutic activity comparable to that of free drug.
These data suggest that HYTAD1-p20 significantly improved results obtained with conventional paclitaxel in terms of hydrosolubility, in vitro activity against human bladder cancer cells, and in vivo biocompatibility. This bioconjugate is a potentially useful treatment for superficial urothelial malignancy.
报告一种新型水溶性紫杉醇-透明质酸生物共轭物HYTAD1-p20用于浅表性膀胱癌膀胱内治疗的研发情况。
通过透明质酸与紫杉醇的羧基酯化反应合成HYTAD1-p20，并对其理化性质和生物学特性进行表征。
紫杉醇负载量优化为20%（w/w）；该过程使所得水溶性生物材料中的紫杉醇浓度提高了500倍。在体外，HYTAD1-p20对RT-4和RT-112/84膀胱癌细胞生长的剂量依赖性抑制作用比游离药物高得多，并与膀胱肿瘤细胞表达的CD44直接相互作用。在体内，对小鼠进行膀胱插管并膀胱内灌注HYTAD1-p20后进行的药代动力学研究结果表明，在2小时的分析过程中药物泄漏可忽略不计。对灌注药物的膀胱进行组织学检查发现，HYTAD1-p20的耐受性非常好，而单独使用紫杉醇会导致黏膜破坏和炎性细胞的黏膜下浸润。用最大耐受剂量的生物共轭物或紫杉醇治疗携带皮下RT-112/84肿瘤的严重联合免疫缺陷小鼠，结果表明HYTAD1-p20发挥了与游离药物相当的治疗活性。
这些数据表明，HYTAD1-p20在水溶性、对人膀胱癌细胞的体外活性和体内生物相容性方面显著改善了传统紫杉醇的治疗效果。这种生物共轭物是一种治疗浅表性尿路上皮恶性肿瘤的潜在有效疗法。
