The application of nitric oxide delivery in nanoparticle-based tumor targeting drug delivery and treatment

Abstract

Nitric oxide (NO) shows great role in tumor biology. Recent years, more and more researches utilized NO donor in tumor targeting drug delivery and treatment. In this review, we summarized the NO donors by their endogenous and exogenous stimuli. Then the application of NO donors, which was the main aim of the review, was discussed in detailed according to their functions, including inducing tumor cell apoptosis, reversing tumor multidrug resistance, inhibiting tumor metastasis and improving drug delivery.

Keywords: Enhanced permeability and retention effect; Multidrug resistance; Nitric oxide donor; Tumor metastasis.

Graphical abstract

Fig. 1

In vivo antitumor efficiency of different treatment groups in H22 tumor-bearing mice. KM mice were injected with saline, GTN, TPGS, TNO₃, DOX, and DOX&TNO₃ on alternate days. Tumor volume (A); relative body weight of tumor-bearing mice (B); tumor weight of tumor-bearing mice (C); images of tumor tissues (D). Data was presented as mean ± SD (n = 6). *: P 〈 0.05. **: P < 0.01. ***: P 〉 0.05. (Reproduced with permission from . Copyright 2014 American Chemical Society).

Fig. 2

In vivo antitumor efficacy against MDR tumors. (A) MCF-7/ADR tumor growth profile, (B) tumor weight, (C) relative body weight, and (D) induced apoptosis of mice i.v. administrated with saline, Taxol, TSP, TN, TSP-TN0.5, TSP-TN1 and TSP-TN2 at a dose of 10 mg PTX/kg. 0.5, 1 and 2 indicated the dose ratios of TN to TSP. *P < 0.05, **P < 0.01, and ***P < 0.001 vs TSP. (E) Representative immunofluorescent images of blood vessel and tumor apoptosis. Blood vessels were stained by α-CD31 antibody (red), and nuclei were stained by DAPI (blue). Apoptotic cells were stained by TUNEL (green). (Reproduced with permission from . Copyright 2017 Elsevier).

Fig. 3

Inhibited tumor metastasis in B16F10 metastatic model. (A) Lungs were dissected for imaging. (B) Number and (C) diameter of nodules in the surface and depth of metastatic lungs, respectively. (D) Lung/body index and (E) representative H&E staining sections of lung. *P < 0.05, **P < 0.01, and ***P < 0.001 vs saline. ^#P < 0.05, ^##P < 0.01, and ^###P < 0.001 vs Taxol. (Reproduced with permission from . Copyright 2017 Elsevier).

Fig. 4

In vivo vasodilation effect after systemic administration of NO-NPs. (A) Representative power Doppler images depicting tumor vascularity. The colors indicate the flow directions toward (red) or away from (blue) the transducer. (B) Sonographic measurement of changes in vascularity upon treatment with saline and NO-NPs. The red arrow indicates the time point of intravenous administration. (C) Representative laser speckle images of changes in tumor vascularity. (D) Experimental illustrations for dual-color imaging of tumor vasculature using two-photon microscopy. (E) Representative two-photon microscopic images of tumor vasculature, labeled using TR-Dex (70 kDa) (red) or FITC-Dex (150 kDa) (green). Scale bar: 50 µm. (Reproduced with permission from . Copyright 2018 American Chemical Society).

Fig. 5

(A) In vivo fluorescence imaging of IDDHN distribution in 4T1 breast cancer-bearing mice (Ex. 780 nm; Em. 845 nm). (B) Ex vivo imaging of tumors and other tissues at 36 h post treatment. (C) ROI analysis of ICG fluorescence signals from the tumors and normal tissues (means ± SD, n = 3, *P < 0.05, ***P < 0.001). (D) Infrared thermal imaging of laser irradiation-induced temperature elevation in tumor region of 4T1 breast cancer-bearing mice post-injection of 5% glucose, IDD, IDDH or IDDHN. (E) Laser-enhanced NO release of IDDHN triggered deep tumor penetration of IDDHN, DAPI channel (blue), Cy3-tagged CD34 channel (red) and DOX channel (green), scale bars represent 50 mm. (F) Semi-quantitative intensity of DOX fluorescence signals from the tumors (means ± SD, n = 3, ***P < 0.001). (G) Extravasation of Evans blue induced by NO donor and laser irradiation of IDDHN in 4T1 tumor bearing mice (means ± SD, n = 3, *P < 0.05, ***P < 0.001). (Reproduced with permission from . Copyright 2018 Elsevier).