Abstract
AbstractIncreased tissue stiffness is a hallmark of cancer and promotes tumor progression. It is hypothesized that decreased tumorous stress may aid or sensitize chemotherapies. To overcome extracellular matrix (ECM) stiffening and fulfill sensitized chemotherapy in one nanosystem, a reactive oxygen species‐activatable nanoenzyme (SP‐NE) based on a dendritic polyglycerol scaffold, integrating collagenase and paclitaxel (PTX) prodrug, is constructed. The dense and tough ECM is highly remitted by SP‐NE in the tumor microenvironment (TME) mimicking gelatin hydrogel models, which causes cell shrinkage, disorders cytoskeletal constructions, and subsequently enhances chemotherapeutic efficacy. ECM softening via SP‐NE downregulates mechanotransduction signaling pathways of integrin‐focal adhesion kinase (FAK)‐Ras homolog family member A (RhoA) implicated in cytoskeletal assembly, and integrin‐FAK‐phosphorylated extracellular signal regulated kinase (pERK 1/2) mediating mitosis. Notably, this programmed nanosystem in human breast MCF‐7 tumor‐bearing mice models displays a significant relief of ECM stress from 4300 to 1200 Pa and results in 87.1% suppression of tumor growth at a low PTX dosage of 3 mg kg−1. The attenuated expression of the key players RhoA and pERK 1/2 involved in cellular mechano‐sensing is further verified in vivo. This study thus provides a new and potential nanoplatform to selectively decrease TME stiffness for enhanced chemotherapy.
Highlights
Introduction progressionIt is hypothesized that decreased tumorous stress may aid or Nanomedicines for anti-cancer applicasensitize chemotherapies
To further support our proof of concept, we explore the underlying mechanism and find that nanoenzymemodified tumor microenvironment (TME) interferes the mechanical signaling transduction of integrin-focal adhesion kinase (FAK)-Ras homolog family member A (RhoA) in enhancing actin cytoskeleton dynamics and integrin-FAK-phosphorylated extracellular signal regulated kinase in promoting mitosis, resulting in improved chemosensitivity and treatment outcomes (Figure 1b)
The results revealed that the protein levels of FAK and RhoA, which fundamentally manipulates cellular behaviors,[40,41] were severely diminished in cells treated with S-NE, species-activatable nanoenzyme (SP-NE), and collagenase (Figure 3c)
Summary
Three main components were prepared to fabricate TMEactivatable nanogels (SP-NG), containing i) dendritic azido polyglycerol sulfate (dPGS-N3) with a negative charge for enzyme packaging via electrostatic interaction, ii) pH-sensitive acetal-linked paclitaxel-dendritic azido polyglycerol macro molecular prodrug (dPG(N3)-ace-PTX) which can release PTX in its pristine nature under endo/lysosomal pH within tumor cells,[33] and iii) the ROS-labile crosslinker dialkynyl-terminated oxalate due to the abundant ROS content in TME.[34] dPGS-N3 (10 kDa, 82% sulfation, 10% azidation) was synthesized according to a previous work of our group.[35] pHsensitive vinyl ether acrylate-PTX (VEA-PTX) was obtained via a “click” type coupling between hydroxyl groups of PTX and vinyl ether of VEA, the resultant VEA-PTX was subsequently grafted to the dPG(N3)-SH backbone (10 kDa, 8% azidation, 1% sulfhydrylation), yielding dPG(N3)-ace-PTX (Figure S1a, Supporting Information). From TEM graphs, the intact spherical shapes were partially dissociated, accompanying with some newly appeared small-sized dots at 0.5 h incubation upon H2O2 (Figure 2b). After another 22 h incubation, considerable small dots with size around several nanometers were observed (Figure 2c). SP-NE was subjected to PB at pH 7.4 containing 50 μm H2O2 at 37 °C; the release of FITC-collagenase was rapid with enzyme cumulative release of 69% within 24 h incubation, while less than 20% FITC-collagenase leakage was observed under a physiological condition without H2O2 (Figure 2e), indicating ROS-responsive cleavage of the crosslinkers and the subsequent efficient enzyme release. The programmed disassociation of the nanoarchitectures as well as the consequent payload release facilitated enzymatic activities in TME and antitumor activities in tumor cells
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