Tumor-Associated Neutrophil Extracellular Traps Regulating Nanocarrier-Enhanced Inhibition of Malignant Tumor Growth and Distant Metastasis

Abstract

Tumor-associated neutrophil extracellular traps (NETs) play a critical role in promoting tumor growth and assisting tumor metastasis. Herein, a smart nanocarrier (designated as mP-NPs-DNase/PTX) based on regulating tumor-associated NETs has been developed, which consists of a paclitaxel (PTX) prodrug nanoparticle core and a poly-l-lysine (PLL) conjugated with the matrix metalloproteinase 9 (MMP-9)-cleavable Tat-peptide-coupled deoxyribonuclease I (DNase I) shell. After accumulating at the site of the tumor tissue, the nanocarrier can release DNase I in response to MMP-9 to degrade the structure of NETs. Then, the remaining moiety can uptake the tumor cells via the mediation of exposed cell penetrating peptide, and the PTX prodrug nanoparticles will lyse in response to the high intracellular concentration of reduced glutathione to release PTX to exert a cytotoxic effect of tumor cells. Through in vitro and in vivo evaluations, it has been proven that mP-NPs-DNase/PTX could serve as potential NET-regulated nanocarrier for enhanced inhibition of malignant tumor growth and distant metastasis.

An Inhalable Hybrid Biomimetic Nanoplatform for Sequential Drug Release and Remodeling Lung Immune Homeostasis in Acute Lung Injury Treatment

“…First, the DNase I−MMP-9 cleavable peptide was synthesized as previously reported. 55 Briefly, the DNase I and sulfo-SMCC (mole ratio = 1:10) were reacted in protein storage solution (pH 7.4, including 0.4 M N-2-hydroxyethylpiperazine-N′-2-ethanesulfonic acid (HEPES) and 0.1 M NaCl) with gentle stirring at 4 °C for 2 h and allowed to react with 5-azidopentanoic acid−GPLGLAGQC polypeptide (MMP-9 responsive peptide; mole ratio = 1:1.2) at room temperature for another 4 h. The DNase I−MMP-9 cleavable peptide was obtained after dialysis using a 3.5 kDa cutoff membrane (Beyotime, Beijing, China) against PBS overnight at 4 °C and freeze-dried for further use. For comparison, the MMP-9 nonreactive conjugate was synthesized by replacing all L-type amino acids of polypeptide with D-type.…”

Neutrophils: Musketeers against immunotherapy

“…It has also been reported that neutrophils interact with tumor cells by using the same molecular machinery that induces EMT such as TGF-β, IL-8, CCl2, TNF-α, and IL-17a ( 61 , 100 ). Consistently, TGF-β pathways stimulate both EMT and the neutrophil pro-tumor phenotype (N2), which is likewise associated with therapy resistance ( 101 ). Emerging evidence suggests that neutrophils stimulate tumor progression through inducing EMT ( 60 , 109 , 110 ).…”

“…Tumor metastasis is the major reason of huge number of cancer-associated deaths ( 97 ). In recent years, emerging studies have shown that NETs foster tumor metastasis in a wide range of cancer types ( 98 – 100 ), whereas NET depletion markedly decreases tumor metastasis ( 101 ). In line with these reports, in a more recent study published in Cancer Cell, Xiao et al.…”

Recent advances in selective and targeted drug/gene delivery systems using cell-penetrating peptides

“…By combining CPP with drugs or other functional materials, it is possible to ‘switch on’ cellular uptake and drug delivery under MMP9-rich conditions. Yin et al ( 2021 ) developed an enzyme-cleavable targeted delivery system for the inhibition of malignant tumor growth designated as mP-NPs-DNase/PTX (Fig. 3 ) .…”

“…3 Schematic representation of MMP9 responsive mP-NPs-DNase/PTX construction and NET regulation to enhance the inhibition of malignant tumor growth and distant metastasis. Reprinted with permission (Yin et al 2021 ) …”