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. 2021 Dec;28(1):2108-2118.
doi: 10.1080/10717544.2021.1979129.

Co-delivery of sorafenib and crizotinib encapsulated with polymeric nanoparticles for the treatment of in vivo lung cancer animal model

Tian Zhong  1 , Xingren Liu  1 , Hongmin Li  2 , Jing Zhang  1
Affiliations

Co-delivery of sorafenib and crizotinib encapsulated with polymeric nanoparticles for the treatment of in vivo lung cancer animal model

Tian Zhong et al. Drug Deliv. 2021 Dec.

Abstract

To treat various cancers, including lung cancer, chemotherapy requires the systematic administering of chemotherapy. The chemotherapeutic effectiveness of anticancer drugs has been enhanced by polymer nanoparticles (NPs), according to new findings. As an outcome, we have developed biodegradable triblock poly(ethylene glycol)-poly(ε-caprolactone)-poly(ethylene glycol) (PEG-PCL-PEG, PECE) polymeric NPs for the co-delivery of sorafenib (SORA) and crizotinib (CRIZ) and investigated their effect on lung cancer by in vitro and in vivo. There is little polydispersity in the SORA-CRIZ@NPs, an average size of 30.45 ± 2.89 nm range. A steady release of SORA and CRIZ was observed, with no burst impact. The apoptosis rate of SORA-CRIZ@NPs was greater than that of free drugs in 4T1 and A549 cells. Further, in vitro cytotoxicity of the polymeric NPs loaded with potential anticancer drugs was more quickly absorbed by cancer cells. On the other hand, compared to free drugs (SORA + CRIZ), SORA + CRIZ@NPs showed a substantial reduction of tumor development, longer survival rate, and a lowered side effect when delivered intravenously to nude mice xenograft model with 4T1 cancer cells. TUNEL positivity was also increased in tumor cells treated with SORA-CRIZ@NPs, demonstrating the therapeutic effectiveness. SORA-CRIZ@NPs might be used to treat lung cancer soon, based on the results from our new findings.

Keywords: Polymeric nanoparticles; apoptosis; co-delivery; in vivo animal model; lung cancer.

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Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Figure 1.
Figure 1.
Molecular structure of some of the potential anticancer compounds.
Figure 2.
Figure 2.
Construction of SORA–CRIZ@NPs. Triblock poly(ethylene glycol)–poly(ε-caprolactone)–poly(ethylene glycol) (PEG–PCL–PEG, PECE) polymeric nanoparticles (NPs) for the co-delivery of sorafenib (SORA) and crizotinib (CRIZ) and investigated their effect on lung cancer by in vitro and in vivo.
Figure 3.
Figure 3.
Characterization of nanoparticles. (A–C) TEM image of SORA–CRIZ@NPs with various composition (2:1, 1:1, and 1:2). The scale bar = 100 nm. (C, D) DLS analysis of respective nanoparticle composition. (G, H) Stability of the SORA–CRIZ@NPs for seven days.
Figure 4.
Figure 4.
In vitro (A) SORA release profiles from SORA–CRIZ@NPs and (B) CRIZ release manners from SORA–CRIZ@NPs in PBS (0.5%) at pH 7.4.
Figure 5.
Figure 5.
(A) In vitro cellular uptake property of SORA + CRIZ and SORA–CRIZ@NPs for 2 h incubation. (B, C) Percentage of the intensity. The scale bar = 50 µm.
Figure 6.
Figure 6.
In vitro cytotoxicity of (A) A549 and (B) 4T1 cells in the presence of SORA + CRIZ and SORA–CRIZ@NPs with various concentrations for 72 h incubation. In vitro viability of (C) A549 and (D) 4T1 cells in the presence of blank PECE-NPs for 72 h incubation. (E) Non-cancerous HUVEC cells in the presence of SORA + CRIZ and SORA–CRIZ@NPs with various concentrations for 24 h incubation (data represent mean ± SD, n = 6, Student’s t-test, ***p<.005).
Figure 7.
Figure 7.
Morphological screening of control, blank PECE, SORA + CRIZ, and SORA–CRIZ@NPs. (A, B) AO/EB staining and respective apoptosis ratio. The scale bar = 100 µm. (C, D) DAPI staining with respective apoptosis ratio. The scale bar = 100 µm.
Figure 8.
Figure 8.
(A) Apoptosis investigation of control, blank PECE, SORA + CRIZ, and SORA–CRIZ@NPs with A549 and 4T1 cells. (B) Apoptosis ratio of 4T1 and A549 cells (data represent mean ± SD, n = 6, Student’s t-test, ***p<.005).
Figure 9.
Figure 9.
In vivo evaluation of the antitumor efficacy of saline, blank PECE, SORA + CRIZ, and SORA–CRIZ@NPs. (A) Tumor growth curves of mice by various treatments. (B) The body weights of mice by various treatments. (C) Average tumor weight for each group. (D) H&E, Ki-67, and TEUNEL staining of respective treatment groups. The scale bar = 100 µm. *p<.05, **p<.01, and ***p<.005 (two-tailed Student’s t-test).
Figure 10.
Figure 10.
H&E staining of various organs of 4T1 tumor-bearing mice treated with saline, blank PECE, SORA + CRIZ, and SORA–CRIZ@NPs. The scale bar = 50 µm.
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