Fabrication, in-silico, in-vitro, and in-vivo characterization of transferrin-targeted micelles containing cisplatin and gadolinium for improved theranostic applications in lung cancer therapy

The targeted delivery of therapeutic and imaging agents is quite challenging in lung cancer therapy. Thus, lung cancer causes high mortality across the world. Herein, we developed TPGS-PF127 micelles containing cisplatin (CDDP) as a model anticancer drug and gadolinium (Gd) as a diagnostic agent by a slightly modified solvent casting method, further, the surface of the micelles was modified using TPGS-transferrin (TPGS-Tf) conjugate to improve targeted delivery of micelles to the lung cancer cells. Prior to this, the binding affinity of Tf over TfR (1E7U) and TfR (1E8W) was investigated with the help of in-silico studies. In-silico results showed good docking scores -7.8 and -7.2 kcal/mol of Tf -ligand towards 1E8W and 1E7U respectively promoting PI3K inhibition. Micelles have shown an average particle size range of 80-200 nm and have shown spherical morphology. The encapsulation efficiency of cisplatin (CDDP) in the CPT, CGPT, and CGPT-Tf micelles ranged from 75.63 % +/- 1.58 % to 85.07 % +/- 2.65 %. Furthermore, the encapsulation efficiency of gadolinium (Gd) in the CGPT and CGPT-Tf micelles was found to be 67.50 +/- 0.32 % and 62.52 +/- 0.52 %, respectively. CGPT-Tf micelles exhibited sustained release fashion for CDDP up to 48 h in physiological conditions. In the cytotoxicity study, CGPT-Tf micelles achieved higher cytotoxicity and caused a more antiproliferative effect in A549 cells compared to a commercial CDDP injection (Ciszest 50), after 24 h of treatment. Furthermore, the pharmacokinetic studies have proven the pharmacological effectiveness of developed CGPT-Tf micelles by achieving higher Cmax, Tmax, t1/2, and MRT of CDDP in systemic circulation compared to its counterparts and Ciszest 50. In lung theranostic observations, a higher internalization of Gd was noted in CGPT-TF compared to free Gd. The biochemical studies have proved the biocompatibility of developed micelles formulations by showing no sign of toxicity in the lungs. The developed micelles have great potential to be utilized in treating and diagnosing a wide variety of cancers.