Novel redox-sensitive thiolated TPGS based nanoparticles for EGFR targeted lung cancer therapy

• Published in: International journal of pharmaceutics 2021-06, Vol.602, p.120652-120652, Article 120652
• Main Authors: Viswanadh, Matte Kasi, Agrawal, Nishi, Azad, Shaik, Jha, Abhishek, Poddar, Suruchi, Mahto, Sanjeev Kumar, Muthu, Madaswamy S.
• Format: Article
• Language: English
• Subjects: Benzo(a)pyrene; Cetuximab; Glutathione; Lung cancer; Redox sensitive; Targeted nanomedicine; Thiolated TPGS
• ISSN: 0378-5173; 1873-3476
• DOI: 10.1016/j.ijpharm.2021.120652

[Display omitted] •Novel redox sensitive TPGS-SH was successfully synthesized by carbodiimide chemistry.•Docetaxel loaded non-targeted and EGFR targeted TPGS-SH NP were prepared by dialysis method.•The in-vitro drug release was found to be faster at lower pH and higher GSH levels.•The particles were found to be stable at higher pH and lower GSH levels from pH and redox sensitivity studies.•In-vitro cytotoxicity, uptake, migration and apoptosis studies have reckoned the superiority of targeted NP.•Both the redox sensitive NP caused less toxicity to vital organs than DTX standard.•Cell number was significantly reduced by targeted NP in benzo(a)pyrene mice lung cancer model. Novel glutathione (GSH) redox-sensitive thiolated vitaminE-PEG1000-succinate (TPGH-SH) was synthesized by conjugating TPGS with 4-amino thiophenol (4-ATP) and confirmed by FTIR and NMR studies. Following, docetaxel (DTX) loaded, cetuximab (CTB) conjugated redox sensitive TPGS-SH nanoparticles (TPGS-SH NP) were prepared by dialysis method and screened for size, charge, DTX entrapment, which revealed that size, surface charge and percent entrapment are in the range of 183–227 nm, +18 to +26 mV and 68–71%. SEM, TEM, AFM have reflected the spherical and uniform size of NP with a smooth surface. In-vitro release studies were performed in media containing different concentrations of GSH to study their effect on drug release and drug release of up to 94.5%, at pH 5.5, GSH 20 mM, is observed within 24 h. The pH/redox sensitivity studies revealed the better stability of NP at higher pH and lower GSH concentrations. In-vitro cytotoxicity, cellular uptake, migration and apoptotic assays, performed on A549 cells, have proved that targeted formulation produced higher cytotoxicity (significantly less IC50 value) and uptake and also prevented cell migration. Pharmacokinetic and histopathological screening were performed on CF rats, which demonstrated promising results. The in-vivo efficacy studies on benzo(a)pyrene induced mice lung cancer model showed that targeted TPGS-SH NP has significantly reduced the cell number than the model control.