Original Article
Nanoparticle delivery of chemotherapy combination regimen improves the therapeutic efficacy in mouse models of lung cancer

https://doi.org/10.1016/j.nano.2016.11.007Get rights and content

Abstract

The combination chemotherapy regimen of cisplatin (CP) and docetaxel (DTX) is effective against a variety of cancers. However, combination therapies present unique challenges that can complicate clinical application, such as increases in toxicity and imprecise exposure of tumors to specific drug ratios that can produce treatment resistance. Drug co-encapsulation within a single nanoparticle (NP) formulation can overcome these challenges and further improve combinations' therapeutic index. In this report, we employ a CP prodrug (CPP) strategy to formulate poly(lactic-co-glycolic acid)–poly(ethylene glycol) (PLGA–PEG) NPs carrying both CPP and DTX. The dually loaded NPs display differences in drug release kinetics and in vitro cytotoxicity based on the structure of the chosen CPP. Furthermore, NPs containing both drugs showed a significant improvement in treatment efficacy versus the free drug combination in vivo.

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.

Image 1
  1. Download : Download high-res image (161KB)
  2. Download : Download full-size image

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

References (30)

  • N. Kolishetti et al.

    Engineering of self-assembled nanoparticle platform for precisely controlled combination drug therapy

    Proc Natl Acad Sci U S A

    (2010)
  • L. Miao et al.

    Nanoparticles with precise ratiometric co-loading and Co-delivery of gemcitabine monophosphate and cisplatin for treatment of bladder cancer

    Adv Funct Mater

    (2014)
  • S. Guo et al.

    Co-delivery of cisplatin and rapamycin for enhanced anticancer therapy through synergistic effects and microenvironment modulation

    ACS Nano

    (2014)
  • L. Raut

    Novel formulation of cytarabine and daunorubicin: a new hope in AML treatment

    South Asian J Cancer

    (2015)
  • P.A. Vasey et al.

    Docetaxel and cisplatin in combination as first-line chemotherapy for advanced epithelial ovarian cancer. Scottish Gynaecological Cancer Trials Group

    J Clin Oncol

    (1999)
  • Cited by (0)

    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.

    1

    These authors contributed equally to this work.

    View full text