Impact of pH-Responsive Cisplatin/Ribavirin-Loaded Monodispersed Magnetic Silica Nanocomposite on A549 Lung Cancer Cells

Abstract

Background/Objectives: Nanocarrier particle design for treating chronic pulmonary diseases presents several challenges, including anatomical and physiological barriers. Drug-repurposing technology using monodispersed spherical silica is one of the innovative ways to deliver drugs. In the present study, the anticancer potential of combinational cisplatin/ribavirin was explored for targeted lung cancer therapeutics. Methods: Monodispersed spherical silica (80 nm) capable of diffusing into the tracheal mucus region was chosen and doped with 10 wt% superparamagnetic iron oxide nanoparticles (SPIONs). Subsequently, it was wrapped with chitosan (Chi, 0.6 wt/vol%), functionalized with 5% wt/wt cisplatin (Cp)/ribavarin (Rib) and angiotensin-converting enzyme 2 (ACE-2) (1.0 μL/mL). Formulations are based on monodispersed spherical silica or halloysite and are termed as (S/MSSiO₂/Chi/Cp/Rib) or (S/Hal/Chi/Cp/Rib), respectively. Results: X-ray diffraction (XRD) and diffuse reflectance UV-visible spectroscopy (DRS-UV-vis) analysis of S/MSSiO₂/Chi/Cp/Rib confirmed the presence of SPION nanoclusters on the silica surface (45% coverage). The wrapping of chitosan on the silica was confirmed with a Fourier transformed infrared (FTIR) stretching band at 670 cm^-1 and ascribed to the amide group of the polymer. The surface charge by zetasizer and saturation magnetization by vibrating sample magnetometer (VSM) were found to be -15.3 mV and 8.4 emu/g. The dialysis membrane technique was used to study the Cp and Rib release between the tumor microenvironment and normal pH ranges from 5.5 to 7.4. S/MSSiO₂/Chi formulation demonstrated pH-responsive Cp and Rib at acidic pH (5.6) and normal pH (7.4). Cp and Rib showed release of ~27% and ~17% at pH 5.6, which decreases to ~14% and ~3.2% at pH 7.4, respectively. To assess the compatibility and cytotoxic effect of our nanocomposites, the cell viability assay (MTT) was conducted on cancer lung cells A549 and normal HEK293 cells. Conclusions: The study shows that the designed nanoformulations with multifunctional capabilities are able to diffuse into the lung cells bound with dual drugs and the ACE-2 receptor.

Keywords: SPIONs; antiviral; cancer; monodispersed spherical silica; multifunctional; pulmonary drug delivery.

Scheme 1

Fabrication of magnetic-monodispersed spherical silica loaded with cisplatin/ribavirin for potential treatment of lung cancer.

Figure 1

(A). X-ray diffraction (XRD) patterns of the following: (a) MSSiO₂; (b) SPIONs; (c) chitosan; (d) SPIONs/MSSiO₂; (e) SPIONs/MSSiO₂/Chi. (B) Nitrogen adsorption–desorption isotherms of the following: (a) MSSiO₂; (b) SPIONs/MSSiO₂; (c) chitosan-wrapped SPIONs/MSSiO₂. (C) FTIR spectra of the following: (a) MSSiO₂; (b) cisplatin; (c) chitosan wrapped SPIONs/MSSiO₂; (d) chitosan. (D) VSM analysis of the following: (a) SPIONs/MSSiO₂; (b) SPIONs/Hal. Hollow symbols represent “Desorption”, solid symbols represent “Adsorption”.

Figure 2

(a) Zeta potential of MSSiO₂/Cp and MSSiO₂/Chi/Cp/Rib. (b) Diffuse reflectance spectra of 10 wt% SPIONs/MSSiO₂. (c,d) HRTEM images of MSSiO₂/Chi/Cp/Rib at different magnification scales of 200 nm and 50 nm.

Figure 3

(a–d) In vitro release profiles of Cp and Rib from S/MSSiO₂/Chi/Rib/Cp and S/Hal/Chi/Rib/Cp nanoformulations at pH 5.6 and 7.4, respectively.

Figure 4

Cell Viability Assay. (A) A549 and (B) HEK293 cells were treated with S/MSSiO₂/Chi, S/Hal/Chi, Cp, Rib, S/MSSiO₂/Chi/Cp, S/Hal/Chi/Cp, S/MSSiO₂/Chi/Cp/Rib, and S/Hal/Chi/Cp/Rib for 48 h.

Figure 4

Cell Viability Assay. (A) A549 and (B) HEK293 cells were treated with S/MSSiO₂/Chi, S/Hal/Chi, Cp, Rib, S/MSSiO₂/Chi/Cp, S/Hal/Chi/Cp, S/MSSiO₂/Chi/Cp/Rib, and S/Hal/Chi/Cp/Rib for 48 h.

Figure 5

Immunofluorescent imaging of A549 and HEK293 cells treated with S/MSSiO₂/Chi/Cp/Rib and S/MSSiO₂/Chi/Cp/Rib/ACE-2/NR at 0.1 mg/mL for 24 h. Scale bar is 20 µm.