In Silico, In Vitro, and In Vivo Investigations of Anticancer Properties of a Novel Platinum (II) Complex and Its PLGA Encapsulated Form

Abstract

In recent years, the development of multinuclear platinum complexes has introduced a new era in platinum-based chemotherapy, offering improved cytotoxicity and the ability to overcome resistance. However, these complexes still face challenges related to water solubility, biodistribution, and targeted delivery. This study provides a comprehensive investigation of a novel platinum (II) complex, [Pt₂(μ-bpy-2H) (Me)₂(dmso)₂] (C1), focusing on its DNA binding ability and anticancer activity. Computational and experimental approaches revealed that C1 binding to guanine bases and involvement of intercalative interactions. C1 exhibited cytotoxicity in both cisplatin sensitive and resistant cancer cell lines. To enhance the pharmacokinetic and pharmacodynamic properties of C1, it was encapsulated using poly (D, L-lactic-co-glycolic acid) (PLGA). Molecular dynamic simulations predicted the formation of stable C1/PLGA complexes during the early stages of simulation. Encapsulated C1 showed superior antitumor activity with significantly reduced side effects in tumor-bearing mouse models. In conclusion, this study highlights the novel platinum (II) complex C1 as a promising anticancer agent, especially when paired with PLGA encapsulation to improve its effectiveness and reduce side effects.

Keywords: PLGA; antitumor; apoptosis; nanoencapsulation; platinum complex.

Figure 1

Molecular structure of C1. Me is deprotonated methyl and DMSO is deprotonated dimethyl sulfoxide.

Figure 2

(a) The absorption spectra of C1 (50 μM) in the presence of increasing concentration of DNA (0–2.6 mM). The red spectrum is the absorption of C1 in the absence of DNA. The inset is [DNA]/(ε_a-ε_f) versus [DNA] plot. (b) Emission spectra of ethidium bromide (100 μM) mixed with DNA (10 μM) in the presence of increasing concentration of C1 (0–58 μM). The emission spectrum of ethidium bromide in the absence of C1 is shown in red. The inset indicates the F₀/F₁ versus [Q] or [C1] plot. (c) Relative viscosity changes of a DNA solution upon addition of increasing amounts of ethidium bromide and C1.

Figure 3

Molecular interactions of C1 with (a) a poly-G DNA and (b) a random sequence of DNA.

Figure 4

The IC50 values (μM) of cisplatin and C1, determined by treatment of MCF7, MRC5, A2780, and A2780R cell lines for 24 h. The statistical analysis was performed with a two-tailed student's t-test (p value < 0.05). ^∗indicates p value < 0.05 and ^∗∗∗indicates p value < 0.001.

Figure 5

The annexin V-PI staining of MCF7, MRC5, A2780 and A2780R cells treated with cisplatin and C1 for 24 h. Viable cells, early apoptotic, late apoptotic, and nonviable necrotic cells appear in the lower left, lower right, upper right and upper left quadrants, respectively.

Figure 6

Platinum content of (a) the cells treated with cisplatin and C1, (b) the extracted gDNA from the cells treated by cisplatin and C1. The data were normalized to the total protein and DNA concentrations, respectively. The statistical analysis was performed with a two-tailed student's t-test (p value < 0.05). ^∗indicates p value < 0.05.

Figure 7

Snapshots of the simulation of C1/PLGA complex formation (top), analysis of (a) RMSD, (b) number of contacts, (c) the intermolecular distance and (d) solvent accessible surface area of the system.

Figure 8

SEM images of (a) cisplatin-NP, (b) C1-NP. The scale bar is 500 nm (c) IC50 values (μM) of cisplatin-NP and C1-NP, determined by treatment of A2780, and A2780R cell lines for 24 h. The statistical analysis was performed using two-tailed student's t-test (p value < 0.05). ^∗indicates p value < 0.05.

Figure 9

(a) Survival plot and (b) tumor volumes of control, cisplatin-NP, and C1-NP treated mice. Treatments were done through the tail vein once a week. The statistical analysis was performed using two-way ANOVA and repeated measures ANOVA (p value < 0.05). ^∗indicates p value < 0.05 and ^∗∗∗indicates p value < 0.001.

Figure 10

Histological changes of liver tissues of mice treated with cisplatin-NP (e, f) and C1-NP (g–i) compared to controls (a–d). Please refer to the text for definitions of arrows, arrowheads, and color codes.

Figure 11

Histological changes of kidney tissues of mice treated with cisplatin-NP (d–f) and C1-NP (g, h) compared to controls (a–c). Please refer to the text for definitions of arrows, arrowheads, and color codes.

Figure 12

Histological changes of lung tissues of mice treated with cisplatin-NP (c, d) and C1-NP (e–g) compared to controls (a, b). Please refer to the text for definitions of arrows, arrowheads, and color codes.