pH-Sensitive Nanodrug Carriers for Codelivery of ERK Inhibitor and Gemcitabine Enhance the Inhibition of Tumor Growth in Pancreatic Cancer,Molecular Pharmaceutics

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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 ( IF 4.5 ) Pub Date : 2020-11-24 , DOI: 10.1021/acs.molpharmaceut.0c00499
Priyanka Ray ₁ , Debasmita Dutta ₁ , Inamul Haque _{2,

3} , Gauthami Nair ₄ , Jiyan Mohammed ₄ , Meredith Parmer ₁ , Narendra Kale ₁ , Megan Orr ₅ , Pooja Jain ₂ , Snigdha Banerjee _{2,

3} , Katie M Reindl ₄ , Sanku Mallik ₆ , Suman Kambhampati ₂ , Sushanta K Banerjee _{2,

3} , Mohiuddin Quadir ₁

Affiliation

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.

中文翻译：

用于 ERK 抑制剂和吉西他滨协同递送的 pH 敏感性纳米药物载体增强了对胰腺癌肿瘤生长的抑制作用

胰腺导管腺癌 (PDAC) 是一种代谢性疾病，仍然是全球主要的癌症死亡率来源之一。对吉西他滨 (GEM) 等治疗的初步反应通常会出现紧急耐药性，这反映了对替代疗法的迫切需求。PDAC 对 GEM 的抗性可能是由于 ERK1/2 活性。然而，由于配体效率低、药物递送差和毒性，ERKi 治疗的成功受到阻碍。在这项研究中，为了克服这些限制，我们设计了尺寸范围为 100-150 nm 的 pH 响应纳米粒子 ( ^pH NPs)，用于以可耐受的剂量同时递送 ERKi (SCH 772984) 和 GEM。这些^pHNPs 是含有聚乙二醇 (PEG) 的两亲聚碳酸酯嵌段共聚物，具有叔胺侧链。它们全身稳定，能够在细胞环境的酸性 pH 值下改善体外和体内药物递送。功能分析表明，与游离药物相比，当包裹在^pH NPs 中时，纳摩尔剂量的 ERKi 或 GEM 显着降低了PDAC 细胞50% 的生长抑制 (IC _{50 )。}ERKi与GEM的组合显示出协同抑制作用。出乎意料的是，我们发现 ERKi 的最小有效剂量显着促进了 PDAC 细胞上的 GEM 活性。此外，我们发现^pHNP封装的ERKi与GEM的联合治疗优于未封装的联合药物治疗。因此，我们的研究结果揭示了一种简单而有效的药物递送方法，以克服 ERKi 在临床应用中的局限性，并提出了一种新的 ERKi 致敏 GEM 模型，且无毒性或毒性最小。

更新日期：2021-01-04

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