Abstract
The clinical applications of platinum-based antitumor agents are still largely limited by severe side effects as well as multidrug resistance (MDR). To solve these problems, we developed an 1,2-diaminocyclohexane-platinum(II) (DACHPt)-loaded nanoparticle (NP-TPGS-Pt) by self-assembly of poly(amidoamine)-polyglutamic acid-b-D-α-tocopheryl polyethylene glycol 1000 succinate (PAM-PGlu-b-TPGS) and DACHPt. NP-TPGS-Pt showed robust stability and pH-responsive DACHPt release profile in vitro similar to the PEG-containing nanoparticle (NP-PEG-Pt). Meanwhile, in contrast with NP-PEG-Pt, NP-TPGS-Pt exhibited efficient nanoparticle-based cellular uptake by the Pt-resistant A549/DDP human lung cancer cells and caused much more cytotoxicity than free Oxaliplatin and NP-PEG-Pt. Finally, this NP-TPGS-Pt was proved to perform outstanding inhibition of Pt-resistant tumor growth, much superior than free Oxaliplatin and NP-PEG-Pt. Thus, this NP-TPGS-Pt provides a novel powerful nanomedicine platform for combatting multidrug resistant cancer.
Highlights
Up to now, platinum-based antitumor agents have been widely used to treat lung cancer, bladder cancer, gastric cancer, and ovarian cancer, etc. (Graham et al, 2000; Klein and Hambley, 2009; Wheate et al, 2010; Han and Smith, 2013; Harrach and Ciarimboli, 2015; Torre et al, 2015; Ma et al, 2017)
The mice xenografted with A549/DDP cells were injected with normal saline, Oxaliplatin, NP-PEG-Pt and NP-TPGS-Pt respectively every 4 days, five times in total
TPGS has been reported to inhibit P-glycoprotein mediated multi-drug resistance (MDR) in tumor cells, which may reduce the excretion of drugs (Collnot et al, 2007; Zeng et al, 2013)
Summary
Platinum-based antitumor agents have been widely used to treat lung cancer, bladder cancer, gastric cancer, and ovarian cancer, etc. (Graham et al, 2000; Klein and Hambley, 2009; Wheate et al, 2010; Han and Smith, 2013; Harrach and Ciarimboli, 2015; Torre et al, 2015; Ma et al, 2017). The 50% growth inhibitory concentrations (IC50) of free Oxaliplatin, NP-PEG-Pt, and NP-TPGS-Pt in the A549 and A549/DDP cells were measured by the MTT assay. Afterwards, we obtained NP-TPGS-Pt by complexing PAM-PGlu-b-TPGS with DACHPt. The NPs had a narrow monodisperse distribution and the average hydrodynamic diameter of ∼85.3 nm (Figure 4A).
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