EGFR Targeted Redox Sensitive Chitosan Nanoparticles of Cabazitaxel: Dual-Targeted Cancer Therapy, Lung Distribution, and Targeting Studies by Photoacoustic and Optical Imaging

Biomacromolecules. 2023 Nov 13;24(11):4989-5003. doi: 10.1021/acs.biomac.3c00658. Epub 2023 Oct 23.

Abstract

In this research, we have modified tocopheryl polyethylene glycol succinate (TPGS) to a redox-sensitive material, denoted as TPGS-SH, and employed the same to develop dual-receptor-targeted nanoparticles of chitosan loaded with cabazitaxel (CZT). The physicochemical properties and morphological characteristics of all nanoparticle formulations were assessed. Dual-receptor targeting redox-sensitive nanoparticles of CZT (F-CTX-CZT-CS-SH-NPs) were developed by a combination of pre- and postconjugation techniques by incorporating synthesized chitosan-folate (F) and TPGS-SH during nanoparticle synthesis and further postconjugated with cetuximab (CTX) for epidermal growth factor receptor (EGFR) targeting. The in vitro release of the drug was seemingly higher in the redox-sensitive buffer media (GSH, 20 mM) compared to that in physiological buffer. However, the extent of cellular uptake of dual-targeted nanoparticles was significantly higher in A549 cells than other control nanoparticles. The IC50 values of F-CTX-CZT-CS-SH-NPs against A549 cells was 0.26 ± 0.12 μg/mL, indicating a 6.3-fold and 60-fold enhancement in cytotoxicity relative to that of dual-receptor targeted, nonredox sensitive nanoparticles and CZT clinical injection, respectively. Furthermore, F-CTX-CZT-CS-SH-NPs demonstrated improved anticancer activity in the benzo(a)pyrene lung cancer model with a higher survival rate. Due to the synergistic combination of enhanced permeability and retention (EPR) effect of small-sized nanoparticles, the innovative and redox sensitive TPGS-SH moiety and the dual folate and EGFR mediated augmented endocytosis have all together significantly enhanced their biodistribution and targeting exclusively to the lung which is evident from their ultrasound/photoacoustic and in vivo imaging system (IVIS) studies.

MeSH terms

  • Cell Line, Tumor
  • Chitosan* / chemistry
  • Drug Delivery Systems / methods
  • ErbB Receptors
  • Folic Acid / chemistry
  • Humans
  • Lung
  • Lung Neoplasms* / drug therapy
  • Nanoparticles* / chemistry
  • Optical Imaging
  • Oxidation-Reduction
  • Polyethylene Glycols / chemistry
  • Taxoids* / pharmacology
  • Tissue Distribution
  • alpha-Tocopherol / chemistry

Substances

  • alpha-Tocopherol
  • cabazitaxel
  • Chitosan
  • EGFR protein, human
  • ErbB Receptors
  • Folic Acid
  • Polyethylene Glycols
  • Taxoids