Department of Biopharmaceutical Sciences (M/C 865) College of Pharmacy, University of Illinois at Chicago, 833 South Wood St., Chicago, Illinois 60612-7231, USA.
Pharm Res. 2011 Apr;28(4):776-87. doi: 10.1007/s11095-010-0330-4. Epub 2010 Dec 4.
Camptothecin (CPT), a potent topoisomerase I inhibitor, was originally discovered as an anticancer agent to induce programmed cell death of cancer cells. Recent evidence suggests that, similar to cancer, alterations in apoptosis and over-proliferation of key effector cells in the arthritic joint result in rheumatoid arthritis (RA) pathogenesis. Initial in vitro studies have suggested that camptothecin inhibits synoviocyte proliferation, matrix metalloproteinases expression in chrondrocytes and angiogenesis. This study is one of the first to test, in vivo, RA as a new indication for CPT.
To circumvent insolubility, instability and toxicity of CPT, we used biocompatible, biodegradable and targeted sterically stabilized micelles (SSM) as nanocarriers for CPT (CPT-SSM). We also surface-modified CPT-SSM with vasoactive intestinal peptide (VIP) for active targeting. We then determined whether this nanomedicine abrogated collagen-induced arthritis (CIA) in mice.
Based on our findings, this is the first study to report that CPT was found to be efficacious against CIA at concentrations significantly lower than usual anti-cancer dose. Furthermore, a single subcutaneous injection of CPT-SSM-VIP (0.1 mg/kg) administered to CIA mice mitigated joint inflammation for at least 32 days thereafter without systemic toxicity. CPT alone needed at least 10-fold higher dose to achieve the same effect, albeit with some vacuolization in liver histology.
We propose that CPT-SSM-VIP is a promising targeted nanomedicine and should be further developed as a safe, long-acting, disease-modifying pharmaceutical product for RA.
喜树碱（CPT）是一种有效的拓扑异构酶 I 抑制剂，最初被发现是一种抗癌药物，可诱导癌细胞程序性死亡。最近的证据表明，与癌症类似，关节炎关节中关键效应细胞的凋亡和过度增殖的改变导致类风湿关节炎（RA）发病机制。最初的体外研究表明，喜树碱抑制滑膜细胞增殖、软骨细胞中基质金属蛋白酶的表达和血管生成。这项研究是首次在体内测试喜树碱作为 RA 的新适应症之一。
为了避免 CPT 的不溶性、不稳定性和毒性，我们使用了生物相容性、可生物降解和靶向性的立体稳定胶束（SSM）作为 CPT 的纳米载体（CPT-SSM）。我们还通过表面修饰 CPT-SSM 与血管活性肠肽（VIP）进行主动靶向。然后，我们确定这种纳米药物是否能消除胶原诱导性关节炎（CIA）。
基于我们的发现，这是第一项研究报告称，喜树碱在浓度明显低于常规抗癌剂量的情况下对 CIA 有效。此外，单次皮下注射 CPT-SSM-VIP（0.1mg/kg）可减轻 CIA 小鼠的关节炎炎症，至少持续 32 天，而无全身毒性。CPT 单独使用至少需要 10 倍更高的剂量才能达到相同的效果，但肝脏组织学有一些空泡化。
我们提出 CPT-SSM-VIP 是一种很有前途的靶向纳米药物，应进一步开发为安全、长效、疾病修饰的 RA 药物。
