Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia, USA.
ACS Nano. 2011 Aug 23;5(8):6184-94. doi: 10.1021/nn200739q. Epub 2011 Jul 11.
Resistance to chemotherapy is a major obstacle in cancer therapy. The main purpose of this study is to evaluate the potential of a folate receptor-targeting nanoparticle to overcome/minimize drug resistance and to explore the underlying mechanisms. This is accomplished with enhanced cellular accumulation and retention of paclitaxel (one of the most effective anticancer drugs in use today and a well-known P-glycoprotein (P-gp) substrate) in a P-gp-overexpressing cancer model. The folate receptor-targeted nanoparticle, HFT-T, consists of a heparin-folate-paclitaxel (HFT) backbone with an additional paclitaxel (T) loaded in its hydrophobic core. In vitro analyses demonstrated that the HFT-T nanoparticle was superior to free paclitaxel or nontargeted nanoparticle (HT-T) in inhibiting proliferation of P-gp-overexpressing cancer cells (KB-8-5), partially due to its enhanced uptake and prolonged intracellular retention. In a subcutaneous KB-8-5 xenograft model, HFT-T administration enhanced the specific delivery of paclitaxel into tumor tissues and remarkably prolonged retention within tumor tissues. Importantly, HFT-T treatment markedly retarded tumor growth in a xenograft model of resistant human squamous cancer. Immunohistochemical analysis further indicated that increased in vivo efficacy of HFT-T nanoparticles was associated with a higher degree of microtubule stabilization, mitotic arrest, antiangiogenic activity, and inhibition of cell proliferation. These findings suggest that when the paclitaxel was delivered as an HFT-T nanoparticle, the drug is better retained within the P-gp-overexpressing cells than the free form of paclitaxel. These results indicated that the targeted HFT-T nanoparticle may be promising in minimizing P-gp related drug resistance and enhancing therapeutic efficacy compared with the free form of paclitaxel.
化疗耐药是癌症治疗的主要障碍。本研究的主要目的是评估叶酸受体靶向纳米粒克服/最小化耐药的潜力，并探讨其潜在机制。这是通过增强在 P-糖蛋白（P-gp）过表达的癌症模型中紫杉烷（目前使用的最有效的抗癌药物之一，也是众所周知的 P-糖蛋白（P-gp）底物）的细胞内积累和保留来实现的。叶酸受体靶向纳米粒 HFT-T 由肝素-叶酸-紫杉醇（HFT）主链和疏水性核心中额外负载的紫杉醇（T）组成。体外分析表明，HFT-T 纳米粒在抑制 P-gp 过表达癌细胞（KB-8-5）增殖方面优于游离紫杉醇或非靶向纳米粒（HT-T），部分原因是其摄取增强和细胞内滞留时间延长。在皮下 KB-8-5 异种移植模型中，HFT-T 给药增强了紫杉醇在肿瘤组织中的特异性递送，并显著延长了紫杉醇在肿瘤组织中的保留时间。重要的是，HFT-T 治疗明显延缓了耐药性人鳞状癌细胞的异种移植模型中的肿瘤生长。免疫组织化学分析进一步表明，HFT-T 纳米粒体内疗效的提高与微管稳定性、有丝分裂停滞、抗血管生成活性和细胞增殖抑制程度增加有关。这些发现表明，当紫杉醇作为 HFT-T 纳米粒给药时，与游离形式的紫杉醇相比，药物在 P-gp 过表达细胞内的保留更好。这些结果表明，与游离形式的紫杉醇相比，靶向 HFT-T 纳米粒在最小化 P-gp 相关耐药性和增强治疗效果方面可能具有前景。
