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. 2021 Mar 8:12:632877.
doi: 10.3389/fphar.2021.632877. eCollection 2021.

Effect of Micelle-Incorporated Cisplatin With Sizes Ranging From 8 to 40 nm for the Therapy of Lewis Lung Carcinoma

Zhicheng Wang  1 , Yumin Li  1   2 , Tong Zhang  1 , Hongxia Li  1 , Zhao Yang  2 , Cheng Wang  1   3
Affiliations

Effect of Micelle-Incorporated Cisplatin With Sizes Ranging From 8 to 40 nm for the Therapy of Lewis Lung Carcinoma

Zhicheng Wang et al. Front Pharmacol. .

Abstract

Insufficient transport of therapeutic cargo into tumor bed is a bottleneck in cancer nanomedicine. Block copolymers are promising carriers with smaller particle size by ratio modification. Here, we constructed cisplatin nanoparticles with sizes ranging from 8 to 40 nm to study the permeability and therapy of Lewis lung carcinoma. We synthesized methoxypoly(ethylene glycol)2000-block poly(L-glutamic acid sodium salt)1979 loading cisplatin through complexation reaction. The cisplatin nanomedicine has high drug loading and encapsulation efficiency. In vitro data demonstrated that cisplatin nanoparticles had equivalent growth-inhibiting effects on Lewis lung carcinoma cells compared to free cisplatin. In vivo evidences showed cisplatin nanoparticles had superior antitumor effects on the Lewis lung carcinoma mouse model with no obvious side effects. All results indicated that optimizing the ratio of block copolymers to obtain smaller sized nanomedicine could act as a promising strategy for overcoming the inadequate accumulation in poorly vascularized tumors.

Keywords: block copolymers; cisplatin; drug delivery; lung cancer; nanomedicine; nanoparticles.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
Platinum-based chemotherapy drugs with different chemical structures.
FIGURE 2
FIGURE 2
The route of synthesis sodium salt of MPEG-P(Glu).
FIGURE 3
FIGURE 3
(A) Preparative procedure of CISP-NPS. (B) The intracorporal process of CISP-NPs after administration.
FIGURE 4
FIGURE 4
The FTIR spectra of (1) MPEG-OH, (2) MPEG-NH2, and (3) MPEG-PBLG.
FIGURE 5
FIGURE 5
The 1H NMR spectra for MPEG2000-PBLG (A) and sodium salt of MPEG2000-P(Glu)1979 (B).
FIGURE 6
FIGURE 6
(A) XRD patterns spectra of (A) MPEG2000-P(Glu)1979 material, (B) CISP crystalline powder, (C) CISP-NPs lyophilized powder (DL = 31.7%), (D) physical mixtures of CISP and MPEG2000-P(Glu)1979 (30:70); (B) TEM image of CISP-NPs and the scale bar 50 nm; (C) particle size distribution of CISP-NPs; (D) AFM image of CISP-NPs.
FIGURE 7
FIGURE 7
(A) Cytotoxicity of free CISP and CISP-NPs at different concentration of CISP on LLC cells for 24, 48, and 72 h. (B) Cytotoxicity of blank MPEG2000-P(Glu)1979 material on LLC cells for 24, 48, and 72 h (n = 6).
FIGURE 8
FIGURE 8
(A–C) The cycle kinetics of LLC cells incubated in negative control group (NS) and free CISP, CISP-NPs group at 12.55 μg/ml of CISP for 48 h, respectively. (D) Quantitative analysis of cell cycle distribution by flow cytometry of the NS group, free CISP and CISP-NPs group. (n = 3, *p < 0.05).
FIGURE 9
FIGURE 9
H&E staining of tumor tissue image collected from (A) NS group; (B) free CISP group; (C) CISP-NPs group (6 mg/kg); (D) CISP-NPs group (12 mg/kg) (×400).
FIGURE 10
FIGURE 10
H&E staining of heart, liver, spleen, and kidney tissue excised from LLC tumor-bearing mice following 5 times at 2-day treatment with NS, Free CISP, CISP-NPs (6 mg/kg) and CISP-NPs (12 mg/kg) (yellow arrows one and two represent the glomerular and glomerular wall, respectively, ×400).
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