Senanayake Thulani H, Lu Yaman, Bohling Anna, Raja Srikumar, Band Hamid, Vinogradov Serguei V
Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, Nebraska, 68198-6025, USA.
Pharm Res. 2014 Jun;31(6):1605-15. doi: 10.1007/s11095-013-1265-3. Epub 2014 Jan 23.
Current cancer chemotherapy is gradually shifting to the application of drug combinations that prevent development of drug resistance. Many anticancer drugs have poor solubility and limited oral bioavailability. Using an innovative approach, we developed dual-drug nanoformulations of a polymeric nanogel conjugate with anticancer 5-FU nucleoside analog, floxuridine (FLOX), and the second anticancer drugs, paclitaxel (PCL), or a geldanamycin analog, 17-AAG, for combination therapy.
PCL or 17-AAG had been encapsulated in the cholesteryl-polyvinyl alcohol-floxuridine nanogel (CPVA-FLOX) by simple solution mixing and sonication. Dual nanodrugs formed particles with diameter 180 nm and either drug content (5-20%) that were stable and could be administered orally. Their cytotoxicity in human and mouse cancer cells was determined by MTT assay, and cellular target inhibition - by Western blot analysis. Tumor growth inhibition was evaluated using an orthotopic mouse mammary 4T1 cancer model.
CPVA-FLOX was more potent than free drug in cancer models including drug-resistant ones; while dual nanodrugs demonstrated a significant synergy (CPVA-FLOX/PCL), or showed no significant synergy (CPVA-FLOX/17-AAG) compared to free drugs (PCL or 17-AAG). Dual nanodrug CPVA-FLOX/17-AAG effect on its cellular target (HSP70) was similar to 17-AAG alone. In animal model, however, both dual nanodrugs effectively inhibited tumor growth compared to CPVA-FLOX after oral administration.
Oral dual-drug nanoformulations of poorly-soluble drugs proved to be a highly efficient combination anticancer therapy in preclinical studies.
当前癌症化疗正逐渐转向应用可预防耐药性产生的联合用药。许多抗癌药物溶解度差且口服生物利用度有限。我们采用创新方法，开发了一种聚合物纳米凝胶偶联物的双药纳米制剂，该偶联物包含抗癌5-氟尿嘧啶核苷类似物氟尿苷（FLOX）以及第二种抗癌药物紫杉醇（PCL）或格尔德霉素类似物17-烯丙基氨基-17-去甲氧基格尔德霉素（17-AAG），用于联合治疗。
通过简单的溶液混合和超声处理，将PCL或17-AAG包裹在胆固醇基聚乙烯醇-氟尿苷纳米凝胶（CPVA-FLOX）中。双纳米药物形成直径为180 nm且药物含量为5%-20%的颗粒，这些颗粒稳定且可口服给药。通过MTT法测定它们对人和小鼠癌细胞的细胞毒性，并通过蛋白质印迹分析确定细胞靶点抑制情况。使用原位小鼠乳腺4T1癌模型评估肿瘤生长抑制情况。
在包括耐药模型在内的癌症模型中，CPVA-FLOX比游离药物更有效；与游离药物（PCL或17-AAG）相比，双纳米药物显示出显著的协同作用（CPVA-FLOX/PCL），或未显示出显著的协同作用（CPVA-FLOX/17-AAG）。双纳米药物CPVA-FLOX/17-AAG对其细胞靶点（热休克蛋白70，HSP70）的作用与单独使用17-AAG相似。然而，在动物模型中，口服给药后，与CPVA-FLOX相比，两种双纳米药物均能有效抑制肿瘤生长。
在临床前研究中，难溶性药物的口服双药纳米制剂被证明是一种高效的联合抗癌疗法。
