Formulation of Folate Receptor-Targeted Silibinin-Loaded Inhalable Chitosan Nanoparticles by the QbD Approach for Lung Cancer Targeted Delivery

Abstract

Aim: Targeted delivery of chemotherapeutics by functionalized nanoparticles exhibits a wonderful prospect for cancer treatment. The main objective of this research was to develop folate receptor-targeted silibinin (SB)-loaded inhalable polymeric nanoparticles (FA-CS-SB-NPs) for the treatment of lung cancer. Method: The qbD approach was implemented to prepare SB-loaded nanoparticles. Folic acid was conjugated by electrostatic conjugation in an optimized batch. The therapeutic potentials of formulations were determined using a lung cancer cell-bearing rat model. Result: Optimized formulation exhibited a spherical surface with a mean particle size of 275 ± 1.20 nm, a PDI of 0.234 ± 0.07, a ζ-potential of 32.50 ± 0.21, an entrapment efficiency of 75.52 ± 0.87%, and a CDR of 63.25 ± 1.21% at 48 h. Aerodynamic behaviors such as the mass median aerodynamic diameter (MMAD) and geometric size distribution (GSD) were found to be 2.75 ± 1.02 and 3.15 ± 0.88 μm, respectively. After 24 h of incubation with FA-CS-SB-NPs, the IC50 value was found to be 24.5 g/mL. FA-SB-CS-NPs maintained a significantly higher deposition of SB in lung tissues. Conclusions: Thus, the noninvasive nature and target specificity of FA-CS-SB-NPs pave the way for pulmonary delivery for treating lung cancer.

Figure 1

Fishbone diagram for SB-loaded chitosan nanoparticle formulation.

Figure 2

Response surface plot and contour plot for (A) particle size, (B) % entrapment efficiency, and (C) CDR at 48 h.

Figure 3

(A) NMR spectrum of FA-CS-SB-NPs and (B) aerosolization behavior of CS-SB-NP and FA-CS-SB-NPs from the Anderson cascade impactor.

Figure 4

(A) FTIR spectra of (a) silibinin, (b) chitosan, (c) CS-SB-NPs, and (d) FA-CS-SB-NPs. (B) DSC spectra of (a) silibinin, (b) CS-SB-NPs, and (c) FA-CS-SB-NPs. (C) Scanning electron microscopy images of the optimized batch (FA-CS-SB-NPs) for surface study. (D) XRD of a (a) pure drug and (b) optimized formulation (FA-CS-SB-NPs).

Figure 5

(A) In vitro cytotoxicity analysis of SB, CS-SB-NPs, and FA-CS-SB-NPs in A549 cancer cells using MTT assay. (B) Analyzing the morphology of A549 cancer cells post-treatment with (a) control, (b) SB, (c) CS-SB-NPs, and (d) FA-CS-SB-NPs.

Figure 6

Microscopic images illustrating pathological alterations in different organs. (A) Control group, (B) group treated with NNK after 3 months, (C) group treated with NNK after 5 months, (D) treatment with CS-SB-NP formulation after the 2nd month, and (E) treatment with FA-CS-SB-NP formulation after the 2nd month.

Figure 7

Biodistribution study of CS-SB-NP and FA-CS-SB-NP formulations in various organs (liver, lungs, kidneys, spleen, and plasma) at 2, 8, 24, 48 h.

Figure 8

(A) Alterations in the rat tumor volume following the administration of saline, SB, CS-SB-NPs, and FA-CS-SB-NPs. (B) Assessing mice tumor weights following a 30-day treatment period. (C) Plasma kinetics of nanoparticles (CS-SB-NPs and FA-CS-SB-NPs) in the rat. (D) Lung kinetics of nanoparticles (CS-SB-NPs and FA-CS-SB-NPs) in the rat after inhalation administration of nanoparticles.