In silico modeling, development, characterization, in-vitro cytotoxicity, pharmacokinetic, and toxicological studies of folate-receptor targeted micelles containing cisplatin and upconversion nanoparticles for lung cancer therapy

Abstract

Folate receptor α (FRα) is one of the best motifs to recognize lung cancer, therefore it can be utilized for targeted delivery of therapeutic agents in lung cancer therapy. Herein, we developed folate-receptor-targeted micelles (CPTT-FA) for the co-delivery of cisplatin (CDDP) and upconversion nanoparticles (UCNP) as theranostics for lung cancer therapy. Initially, the binding affinity of FRα (4MK6) was studied, resulting in good docking scores of −7.6 towards 4MK6 by stimulating PI3K inhibition in lung cancer cells. Micelles, fabricated using the solvent-casting technique, exhibited favorable characteristics, including an average size ranging from 80 to 190 nm with a narrow size distribution and spherical morphology. The zeta potential of −29.4 mV indicates stability and potential for targeted delivery. The drug encapsulation efficiency of the micelles was high, ranging from 70 % to 90 %. In vitro, release studies demonstrated an initial burst release of 40 % within 4 h, the release rate was controlled up to 72 h in PBS at pH 6.8. Afterthat, IC50 of the CPTT-FA micelles was found to be 11.6-fold lower than Ciszest-50. Heamolysis study has proven the greater biocompatibility of CPTT-FA. Pharmacokinetic investigations exhibited a significant enhancement with a three-fold increase in the area under the concentration-time curve (AUC0-t) and a 3.7-fold extension in half-life (t1/2). CDDP resistance in lung cancer presents a promising avenue for targeted therapy using UCNP, addressing challenges posed by FRα-positive cases and improving prognosis. Further clinical investigations are needed to validate the effectiveness and safety of this approach before its widespread implementation.