Aslan Minela, Shahbazi Reza, Ulubayram Kezban, Ozpolat Bulent
Bioengineering Division, Institute for Graduate Studies in Science and Engineering, Hacettepe University, Ankara, Turkey.
Department of Nanotechnology and Nanomedicine, Faculty of Pharmacy, Institute for Graduate Studies in Science and Engineering, Hacettepe University, Ankara, Turkey.
Anticancer Res. 2018 Dec;38(12):6591-6606. doi: 10.21873/anticanres.13026.
Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive and lethal cancers with a median survival of 6 months after diagnosis. Intrinsic resistance to chemotherapeutics and lack of effective targeted therapies are the major factors contributing to dismal prognosis. Several important genetic alterations (i.e., mutations, deletions) have been identified to be involved in the initiation and progression of pancreatic cancer, including KRAS and inactivation of tumor suppressors, such as TP53, SMAD4 and CDKN2A. Unique tumor microenvironment with excessive stroma due to desmoplastic reaction is one of the major characteristics of PDAC, promoting tumor growth and leading to treatment failures. In addition, tumor stroma represents an important biological barrier for drug delivery and successful treatment of PDAC. Small interfering RNA (siRNA) has recently emerged as a potential and targeted therapeutic approach which is now evaluated in clinical trials. However, siRNA-based therapeutics face important challenges, including rapid serum degradation, poor tumor cell uptake and cellular uptake, leading to off-target effects. Therefore, there is a great need for the development of safe and effective nanoparticles for better tumor-specific delivery of anti-cancer therapeutics. In this article, the main challenges in the treatment of pancreatic cancer and recent advancements on nano delivery systems of chemotherapeutics and gene-targeted agents, used both in preclinical and clinical trials are reviewed.
胰腺导管腺癌（PDAC）是最具侵袭性和致命性的癌症之一，诊断后的中位生存期为6个月。对化疗药物的内在抗性和缺乏有效的靶向治疗是导致预后不佳的主要因素。已确定几种重要的基因改变（即突变、缺失）参与胰腺癌的发生和发展，包括KRAS以及肿瘤抑制因子如TP53、SMAD4和CDKN2A的失活。由于促结缔组织增生反应导致的具有过多基质的独特肿瘤微环境是PDAC的主要特征之一，促进肿瘤生长并导致治疗失败。此外，肿瘤基质是药物递送和成功治疗PDAC的重要生物学屏障。小干扰RNA（siRNA）最近已成为一种潜在的靶向治疗方法，目前正在临床试验中进行评估。然而，基于siRNA的治疗面临重要挑战，包括血清快速降解、肿瘤细胞摄取和细胞摄取不佳，导致脱靶效应。因此，迫切需要开发安全有效的纳米颗粒，以更好地实现抗癌治疗药物的肿瘤特异性递送。本文综述了胰腺癌治疗中的主要挑战以及化疗药物和基因靶向药物纳米递送系统在临床前和临床试验中的最新进展。
