Original ArticleNanoparticle delivery of chemotherapy combination regimen improves the therapeutic efficacy in mouse models of lung cancer
Graphical Abstract
Combinations of cisplatin and docetaxel are effective against many cancers. However, combination chemotherapy can lead to increases in toxicity and imprecise exposure of target cells to a specific drug ratio leading to treatment resistance. Co-encapsulation within nanoparticles has shown clinical success with other chemotherapies in overcoming these complications. Therefore, we developed co-formulations of cisplatin and docetaxel in PLGA–PEG nanoparticles using cisplatin prodrugs for efficient encapsulation. The combination nanoparticles show significant improvements in the therapeutic index versus the free drugs in vitro and against murine lung cancer models. Cisplatin prodrug structure also dictated therapeutic efficacy likely due to differences in co-formulation properties.
Section snippets
Methods
Additional synthesis and characterization details are available in the supplementary information.
Loading characterization of singly and dually drug loaded PLGA–PEG NPs
We prepared three different CPPs modified with butyric (C4CP), octanoic (C8CP), or decanoic (C10CP) fatty acids as previously described (Figure 1).18, 20, 23 We determined the drug loading wt% and encapsulation efficiency (%EE) in the NP formulations over a range of tested %FR for all three CPPs and DTX (Figures 2 and S2; Table S1). For singly loaded NPs, the maximal amount of drug loading was found to be 1.15 ± 0.09 wt% (14.73 ± 0.83%EE), 1.93 ± 0.10 wt% (15.23 ± 1.04%EE), 3.39 ± 0.19 wt% (22.83 ±
Discussion
The combination of CP and DTX is a proven and effective therapy treatment strategy for a variety of cancer types that may benefit from an NP co-delivery strategy.5, 10, 11, 12, 13, 14, 15, 16 Therefore, we sought to evaluate (1) the DTX/CPP combination NPs' properties, and (2) the in vivo efficacy of these combination NPs in models of lung cancer.
In combination therapy, the proper dosage and ratio of drugs are required to reach the maximum therapeutic effect.9 We determined the CPPs and DTX
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This work was supported by National Institutes of Health/National Cancer Institute (R01CA178748-01) and National Institutes of Health/National Cancer Institute (U54CA198999, Carolina Center of Cancer Nanotechnology Excellence (CCNE)-Nano Approaches to Modulate Host Cell Response for Cancer Therapy). Jing Tian is supported by the Natural Science Foundation of Tianjin (Grant No. 15JCYBJC21100) and the Science & Technology Development Fund of Tianjin Education Commission for Higher Education (No. 20110511). Zachary Rodgers is supported by the Carolina Cancer Nanotechnology T32 Training Program (C-CNTP, NIH-1T32CA196589). Andrew Wang was also supported by funding from the NIH/NCI (R21 CA182322).
The authors report no conflict of interests.
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These authors contributed equally to this work.