Biodegradable Silk Fibroin Nanocarriers to Modulate Hypoxia Tumor Microenvironment Favoring Enhanced Chemotherapy

Abstract

Biopolymer silk fibroin (SF) is a great candidate for drug carriers characterized by its tunable biodegradability, and excellent biocompatibility properties. Recently, we have constructed SF-based nano-enabled drug delivery carriers, in which doxorubicin (Dox) and atovaquone (Ato) were encapsulated with Arg-Gly-Asp-SF-Polylactic Acid (RSA) to form micellar-like nanoparticles (RSA-Dox-Ato NPs). The RGD peptide was decorated on micellar-like nanoparticles, promoting tumor accumulation of the drug. Meanwhile, Ato, as a mitochondrial complex III inhibitor inhibiting mitochondrial respiration, would reverse the hypoxia microenvironment and enhance chemotherapy in the tumor. In vitro, the biopolymer alone showed extremely low cytotoxicity to 4T1 cell lines, while the RSA-Dox-Ato demonstrated a higher inhibition rate than other groups. Most significantly, the ROS levels in cells were obviously improved after being treated with RSA-Dox-Ato, indicating that the hypoxic microenvironment was alleviated. Eventually, SF-based targeted drug carrier provides biocompatibility to reverse hypoxia microenvironment in vivo for enhancing chemotherapy, strikingly suppressing tumor development, and thereby suggesting a promising candidate for drug delivery system.

Prognostic Assessment of Oxidative Stress-Related Genes in Colorectal Cancer and New Insights into Tumor Immunity

“…Oxidative DNA damage has been widely accepted as an important feature of the occurrence of malignant tumors. At present, researchers have found a variety of novel treatment methods based on ROS to restore chemoresistance and overcome radiotherapy resistance, enhance the efficacy of chemoradiotherapy, [27][28][29][30][31] and bring certain guiding significance to clinical treatment. At the same time, oxidative stress products in the tumor microenvironment also affect the immune response of the body.…”

Nanomedicine Strategies in Conquering and Utilizing the Cancer Hypoxia Environment

“…In addition, ATO load NPs (RSA-Dox-Ato NPs) can reverse the hypoxia microenvironment as a mitochondrial complex III inhibitor to up-regulate the level of ROS in cells. 277 The relived hypoxia TME enhanced the chemotherapy in the tumor after being treated with RSA-Dox-Ato. Tumor hypoxia is a tremendous challenge of O 2dependent PDT.…”

“…This nanostrategy reverted the immunosuppressive state of the tumor by relieving tumor hypoxia and acidic TME to get immune stimulation performance and enhanced SDT for tumor growth suppression and lung metastasis inhibition (Figure d, e, f). In addition, ATO load NPs (RSA-Dox-Ato NPs) can reverse the hypoxia microenvironment as a mitochondrial complex III inhibitor to up-regulate the level of ROS in cells . The relived hypoxia TME enhanced the chemotherapy in the tumor after being treated with RSA-Dox-Ato.…”