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Ph-Sensitive Nanodrug Carriers for Codelivery of ERK Inhibitor and Gemcitabine Enhance the Inhibition of Tumor Growth in Pancreatic Cancer.

Molecular Pharmaceutics(2020)

Cited 36|Views35
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Abstract
Pancreatic ductal adenocarcinoma (PDAC), a metabolic disorder, remains one of the leading cancer mortality sources worldwide. An initial response to treatments, such as gemcitabine (GEM), is often followed by emergent resistance reflecting an urgent need for alternate therapies. The PDAC resistance to GEM could be due to ERK1/2 activity. However, successful ERKi therapy is hindered due to low ligand efficiency, poor drug delivery, and toxicity. In this study, to overcome these limitations, we have designed pH-responsive nanoparticles (pHNPs) with a size range of 100-150 nm for the simultaneous delivery of ERKi (SCH 772984) and GEM with tolerable doses. These pHNPs are polyethylene glycol (PEG)-containing amphiphilic polycarbonate block copolymers with tertiary amine side chains. They are systemically stable and capable of improving in vitro and in vivo drug delivery at the cellular environment's acidic pH. The functional analysis indicates that the nanomolar doses of ERKi or GEM significantly decreased the 50% growth inhibition (IC50) of PDAC cells when encapsulated in pHNPs compared to free drugs. The combination of ERKi with GEM displayed a synergistic inhibitory effect. Unexpectedly, we uncover that the minimum effective dose of ERKi significantly promotes GEM activities on PDAC cells. Furthermore, we found that pHNP-encapsulated combination therapy of ERKi with GEM was superior to unencapsulated combination drug therapy. Our findings, thus, reveal a simple, yet efficient, drug delivery approach to overcome the limitations of ERKi for clinical applications and present a new model of sensitization of GEM by ERKi with no or minimal toxicity.
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nanoparticles,pH-responsive polymers,pancreatic cancer,gemcitabine,codelivery,ERK inhibitor
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要点】:研究开发了一种pH敏感型纳米药物载体,用于同时递送ERK抑制剂和吉西他滨,有效增强胰腺癌肿瘤生长的抑制效果,并降低药物毒性。

方法】:采用pH响应型纳米颗粒((pH)NPs),尺寸范围在100-150纳米,由含有聚乙二醇(PEG)的两亲性聚碳酸酯嵌段共聚物构成,带有三级胺侧链,实现ERK抑制剂(SCH 772984)和吉西他滨的共递送。

实验】:通过体外和体内实验,在酸性细胞环境中评估了纳米颗粒的药物递送效果。实验结果表明,与游离药物相比,纳米颗粒封装的ERKi或吉西他滨在纳摩尔剂量下显著降低PDAC细胞的50%生长抑制浓度(IC50)。ERKi与吉西他滨联合使用显示出协同抑制效果。使用(NP)-N-pH封装的联合疗法效果优于未封装的联合用药。实验数据集未在文中明确提及。