Dual pH/redox-responsive size-switchable polymeric nano-carrier system for tumor microenvironment DTX release

Abstract

Innovation chemotherapeutic nano drug delivery systems (NDDSs) with various pharmacological achievement have become one of the hopeful therapeutic strategies in cancer therapy. This study focused on low pH, and high levels of glutathione (GSH) as two prominent characteristics of the tumor microenvironment (TME) to design a novel TME-targeted pH/redox dual-responsive P (AMA-co-DMAEMA)-b-PCL-SS-PCL-b-P (AMA-co-DMAEMA) nanoparticles (NPs) for deep tumor penetration and targeted anti-tumor therapy. The positively charged NPs exhibit strong electrostatic interactions with negatively charged cell membranes, significantly enhancing cellular uptake. Moreover, these NPs possess the unique size-shrinkable property, transitioning from 98.24 ± 27.78 to 45.56 ± 20.62 nm within the TME. This remarkable size change fosters an impressive uptake of approximately 100% by MDA-MB-231 cells within just 30 min, thereby greatly improving drug delivery efficiency. This size switchability enables passive targeting through the enhanced permeability and retention (EPR) effect, facilitating deep penetration into tumors. The NPs also demonstrate improved pH/redox-triggered drug release (∼70% at 24 h) within the TME and exhibit no toxicity in cell viability test. The cell cycle results of treated cells with docetaxel (DTX)-loaded NPs revealed G2/M (84.6 ± 1.16%) arrest. The DTX-loaded NPs showed more apoptosis (62.6 ± 3.7%) than the free DTX (51.8 ± 3.2%) in treated cells. The western blot and RT-PCR assays revealed that apoptotic genes and proteins expression of treated cells were significantly upregulated with the DTX-loaded NPs vs. the free DTX (P_value<.001). In conclusion, these findings suggest that this novel-engineered NPs holds promise as a TME-targeted NDDS.

Keywords:

• Tumor microenvironment (TME)
• pH/redox dual-responsive
• size shrink
• glutathione (GSH)
• apoptosis

Acknowledgments

The authors would like to acknowledge the support received from the Research Council of Urmia University.

Disclosure statement

The authors declare no competing interest.

Authors contributions

Fahimeh Badparvar: Data curation, Investigation, Writing – original draft, Methodology, Data curation, Data interpretation, Conceptualization. Ahmad Poursattar Marjani: Supervision, Data interpretation, and edition. Roya Salehi: Project administration, Supervision, Conceptualization, Data curation, and interpretation Fatemeh Ramezani: Data curation, Data interpretation. Hanieh Beyrampour Basmenj: Data curation, Data interpretation. Mehdi Talebi: Data curation, Data interpretation.

Data availability statement

All data generated or analyzed during this study are included in this published article.

Additional information

Funding

The author(s) reported there is no funding associated with the work featured in this article.