期刊
MOLECULAR PHARMACEUTICS
卷 18, 期 1, 页码 87-100出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.molpharmaceut.0c00499
关键词
nanoparticles; pH-responsive polymers; pancreatic cancer; gemcitabine; codelivery; ERK inhibitor
资金
- NIH from the National Institute of General Medical Sciences (NIGMS) [1P20GM109024]
- NSF [0923354]
- NIH from the National Center for Research Resources [2P20 RR015566]
- NIH [1P20GM109024, 1R01 GM 114080]
- NSF from the North Dakota Established Program to Stimulate Competitive Research (ND-EPSCoR) through the Center for Sustainable Materials Science [IIA1355466]
- Department of Veterans Affairs [5I01BX001989-04, I01BX001002-05]
- KUMC Lied Basic Science Grant Program
- Grace Hortense Greenley Trust
PDAC resistance to GEM may be related to ERK1/2 activity. The use of pH-responsive nanoparticles ((pH)NPs) for simultaneous delivery of ERKi (SCH 772984) and GEM with tolerable doses displays a synergistic inhibitory effect.
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 ((pH)NPs) with a size range of 100-150 nm for the simultaneous delivery of ERKi (SCH 772984) and GEM with tolerable doses. These (pH)NPs 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 (pH)NPs 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 (NP)-N-pH-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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