Khan Sheema, Chauhan Neeraj, Yallapu Murali M, Ebeling Mara C, Balakrishna Swathi, Ellis Robert T, Thompson Paul A, Balabathula Pavan, Behrman Stephen W, Zafar Nadeem, Singh Man M, Halaweish Fathi T, Jaggi Meena, Chauhan Subhash C
Department of Pharmaceutical Sciences and Center for Cancer Research, University of Tennessee Health Science Center, Memphis, TN, USA.
Cancer Biology Research Center, Sanford Research/USD, Sioux Falls, SD, USA.
Biomaterials. 2015;53:731-43. doi: 10.1016/j.biomaterials.2015.02.082. Epub 2015 Mar 26.
Pancreatic cancer is the fourth most prevalent cancer with about an 85% mortality rate; thus, an utmost need exists to discover new therapeutic modalities that would enhance therapy outcomes of this disease with minimal or no side effects. Ormeloxifene (ORM), a synthetic molecule, has exhibited potent anti-cancer effects through inhibition of important oncogenic and proliferation signaling pathways. However, the anti-cancer efficacy of ORM can be further improved by developing its nanoformulation, which will also offer tumor specific targeted delivery. Therefore, we have developed a novel ORM encapsulated poly(lactic-co-glycolic acid) nanoparticle (NP) formulation (PLGA-ORM NP). This formulation was characterized for particle size, chemical composition, and drug loading efficiency, using various physico-chemical methods (TEM, FT-IR, DSC, TGA, and HPLC). Because of its facile composition, this novel formulation is compatible with antibody/aptamer conjugation to achieve tumor specific targeting. The particle size analysis of this PLGA-ORM formulation (∼100 nm) indicates that this formulation can preferentially reach and accumulate in tumors by the Enhanced Permeability and Retention (EPR) effect. Cellular uptake and internalization studies demonstrate that PLGA-ORM NPs escape lysosomal degradation, providing efficient endosomal release to cytosol. PLGA-ORM NPs showed remarkable anti-cancer potential in various pancreatic cancer cells (HPAF-II, AsPC-1, BxPC-3, Panc-1, and MiaPaca) and a BxPC-3 xenograft mice model resulting in increased animal survival. PLGA-ORM NPs suppressed pancreatic tumor growth via suppression of Akt phosphorylation and expression of MUC1, HER2, PCNA, CK19 and CD31. This study suggests that the PLGA-ORM formulation is highly efficient for the inhibition of pancreatic tumor growth and thus can be valuable for the treatment of pancreatic cancer in the future.
胰腺癌是第四大常见癌症，死亡率约为85%；因此，迫切需要发现新的治疗方法，以提高该疾病的治疗效果，同时副作用最小或无副作用。奥美昔芬（ORM）是一种合成分子，通过抑制重要的致癌和增殖信号通路，已显示出强大的抗癌作用。然而，通过开发其纳米制剂可以进一步提高ORM的抗癌疗效，这也将提供肿瘤特异性靶向递送。因此，我们开发了一种新型的包封有ORM的聚乳酸-乙醇酸共聚物纳米颗粒（NP）制剂（PLGA-ORM NP）。使用各种物理化学方法（透射电子显微镜、傅里叶变换红外光谱、差示扫描量热法、热重分析法和高效液相色谱法）对该制剂的粒径、化学成分和载药效率进行了表征。由于其组成简便，这种新型制剂与抗体/适配体偶联兼容，可实现肿瘤特异性靶向。该PLGA-ORM制剂的粒径分析（约100纳米）表明，该制剂可通过增强渗透和滞留（EPR）效应优先到达并积聚在肿瘤中。细胞摄取和内化研究表明，PLGA-ORM NPs可逃避溶酶体降解，实现向内质网的高效释放。PLGA-ORM NPs在各种胰腺癌细胞（HPAF-II、AsPC-1、BxPC-3、Panc-1和MiaPaca）以及BxPC-3异种移植小鼠模型中显示出显著的抗癌潜力，从而提高了动物存活率。PLGA-ORM NPs通过抑制Akt磷酸化以及MUC1、HER2、PCNA、CK19和CD31的表达来抑制胰腺肿瘤生长。这项研究表明，PLGA-ORM制剂对抑制胰腺肿瘤生长非常有效，因此未来对胰腺癌的治疗可能具有重要价值。
