Moores Cancer Center, University of California, San Diego, La Jolla, California 92093-0819, USA.
Mol Pharm. 2010 Feb 1;7(1):280-90. doi: 10.1021/mp900242f.
Intraperitoneal (ip) chemotherapy increases the survival of optimally debulked patients with ovarian cancer due to direct access of the drug to tumor nodules growing on the peritoneal surface. CD44 is overexpressed in many ovarian cancers. To further improve efficacy, we sought to develop a cisplatin-loaded microparticle that would target to CD44 on cancer cells when injected ip. Hyplat microparticles were produced by cross-linking hyaluronan via its carboxylate groups with cisplatin at a high temperature. Hyplat particles had an average diameter of 580 nm, and cisplatin was incorporated with an efficiency of approximately 50%. Drug release varied with chloride concentration but not pH. Flow cytometric analysis and confocal microscopy confirmed that CD44 positive cells (OV2008, A2780) internalized Hyplat more efficiently than CD44 negative cells (UCI101); uptake was compromised by knocking down CD44 expression. Clearance of Hyplat from the mouse peritoneum was reduced by 7-fold and tumor uptake was increased by 2- to 3-fold in CD44-positive but not CD44-negative tumor models compared to that attained with free cisplatin. Hyplat was more effective than cisplatin at slowing the growth of intraperitoneally inoculated A2780 ovarian cancer cells and improving survival thus demonstrating the potential of Hyplat to enhance the efficacy of ip chemotherapy.
腹腔内(ip)化疗通过药物直接到达腹膜表面生长的肿瘤结节,从而提高了最佳减瘤患者的生存率。CD44 在许多卵巢癌中过度表达。为了进一步提高疗效,我们试图开发一种顺铂负载的微粒,当注入腹腔时,该微粒能够靶向癌细胞上的 CD44。通过将透明质酸的羧基与顺铂在高温下交联,制备了 Hyplat 微粒。Hyplat 颗粒的平均直径为 580nm,顺铂的掺入效率约为 50%。药物释放随氯离子浓度而变化,但不受 pH 值影响。流式细胞术分析和共聚焦显微镜证实,CD44 阳性细胞(OV2008、A2780)比 CD44 阴性细胞(UCI101)更有效地内化了 Hyplat;通过敲低 CD44 表达,摄取受到了损害。与游离顺铂相比,在 CD44 阳性而不是 CD44 阴性肿瘤模型中,Hyplat 从小鼠腹膜中的清除率降低了 7 倍,肿瘤摄取增加了 2 到 3 倍。与顺铂相比,Hyplat 更能减缓腹腔内接种的 A2780 卵巢癌细胞的生长速度,提高存活率,从而证明了 Hyplat 具有增强 ip 化疗疗效的潜力。