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. 2020 Oct 27:14:4519-4531.
doi: 10.2147/DDDT.S251749. eCollection 2020.

Lung Cancer Combination Treatment: Evaluation of the Synergistic Effect of Cisplatin Prodrug, Vinorelbine and Retinoic Acid When Co-Encapsulated in a Multi-Layered Nano-Platform

Zhen Liang  1 , Juan Li  2 , Budong Zhu  2
Affiliations

Lung Cancer Combination Treatment: Evaluation of the Synergistic Effect of Cisplatin Prodrug, Vinorelbine and Retinoic Acid When Co-Encapsulated in a Multi-Layered Nano-Platform

Zhen Liang et al. Drug Des Devel Ther. .

Abstract

Purpose: Lung cancer remains the leading cancer-associated deaths worldwide. Cisplatin (CIS) was often used in combination with other drugs for the treatment of non-small cell lung cancer (NSCLC). Prodrug is an effective strategy to improve the efficiency of drugs and reduce the toxicity. The aim of this study was to prepare and characterize CIS prodrug, vinorelbine (VNR), and all-trans retinoic acid (ATRA) co-delivered multi-layered nano-platform, evaluating their antitumor activity in vitro and in vivo.

Methods: Cisplatin prodrug (CISP) was synthesized. A multi-layered nano-platform contained CISP, VNR and ATRA were prepared and named CISP/VNR/ATRA MLNP. The physicochemical properties of CISP/VNR/ATRA MLNP were investigated. In vitro cytotoxicity against CIS-resistant NSCLC cells (A549/CIS cells) and Human normal lung epithelial cells (BEAS-2B cells) was investigated, and in vivo anti-tumor efficiency was evaluated on mice bearing A549/CIS cells xenografts.

Results: CISP/VNR/ATRA MLNP were spherical particles with particle size and zeta potential of 158 nm and 12.3 mV. CISP/VNR/ATRA MLNP (81.36%) was uptake by cancer cells in vitro. CISP/VNR/ATRA MLNP could significantly inhibit the in vivo antitumor growth and suspended the tumor volume from 1440 mm3 to 220 mm3.

Conclusion: It could be concluded that the CISP/VNR/ATRA MLNP may be used as a promising system for lung cancer combination treatment.

Keywords: cisplatin prodrug; combination treatment; lung cancer; multi-layered nano-platform; synergistic effect.

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Conflict of interest statement

The authors report no conflicts of interest for this work.

Figures

Figure 1
Figure 1
Synthesis of cisplatin prodrug. Cisplatin prodrug (CISP) was synthesized by conjugating the amino group of tryptophan (TRP) with the carboxylated CIS.
Figure 2
Figure 2
A multi-layered nano-platform contained CISP, VNR and ATRA were prepared and named CISP/VNR/ATRA MLNP. The TEM image showed that the CISP/VNR/ATRA MLNP was spherical particles with inner cores and coats on the outer surface.
Figure 3
Figure 3
Particle sizes (A), PDIs (B), and zeta potentials (C) of the particles.
Figure 4
Figure 4
The EE (A) and LE (B) of drugs loaded particles.
Figure 5
Figure 5
In vitro drug release profiles of CISP (A), VNR (B) and ATRA (C). All the three drugs showed sustained release from MLNPs. CISP and VNR exhibited similar release profiles, but ATRA were released from MLNPs in different manners compared with CISP and VNR.
Figure 6
Figure 6
The cellular uptake efficiency of CISP/VNR/ATRA MLNP and non HA coating CISP/VNR/ATRA NP were compared by the images and quantitative results.
Figure 7
Figure 7
In vitro cytotoxicity. Concentration deepened manners were found in all drugs contained formulations on both A549/CIS (A) and BEAS-2B cells (B). *P < 0.05.
Figure 8
Figure 8
The synergistic cytotoxicity was evaluated by CI values on the bases of IC50 values of different formulations. The effect of three-drug combination treatment was compared with the effect of treatment with each drug alone.
Figure 9
Figure 9
In vivo tumor inhibition ability of CISP/VNR/ATRA MLNP, CISP/VNR/ATRA NP and Free CISP/VNR/ATRA. *P < 0.05.
Figure 10
Figure 10
In vivo tissue distribution of CISP/VNR/ATRA MLNP, CISP/VNR/ATRA NP and Free CISP/VNR/ATRA. *P < 0.05.
Figure 11
Figure 11
Drugs loaded nanoparticles groups presented no significant change of body weight (A). ALT (B), LDH (C), and BUN (D) levels illustrated that drugs loaded nanoparticles groups did not change the parameters compared with control groups, while free drugs caused significant increase of these data. *P < 0.05.
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