Dataset Information

A pH/ROS cascade-responsive and self-accelerating drug release nanosystem for the targeted treatment of multi-drug-resistant colon cancer.

ABSTRACT: The efficacy of chemotherapeutic agents for colon cancer treatment is limited by multidrug resistance (MDR) and insufficient intracellular release of the administered nanomedicine. To overcome these limitations, we constructed a pH/ROS cascade-responsive and self-accelerating drug release nanoparticle system (PLP-NPs) for the treatment of multidrug-resistant colon cancer. The PLP-NPs comprised a reactive oxygen species (ROS)-sensitive polymeric paclitaxel (PTX) prodrug (DEX-TK-PTX), a pH-sensitive poly(l-histidine) (PHis), and beta-lapachone (Lapa), a ROS-generating agent. We found that PLP-NPs could accumulate in tumor tissue through enhancement of the permeability and retention (EPR) effect, and were subsequently internalized by cancer cells via the endocytic pathway. Within the acidic endo-lysosomal environment, PHis protonation facilitated the escape of the PLP-NPs from the lysosome and release of Lapa. The released Lapa generated a large amount of ROS, consumed ATP, and downregulated P-glycoprotein (P-gp) production through the activity of NQO1, an enzyme that is specifically overexpressed in tumor cells. In addition, the generated ROS promoted the release of PTX from DEX-TK-PTX to kill cancer cells, while ATP depletion inhibited P-gp-mediated MDR. In vitro and in vivo experiments subsequently confirmed that PLP-NPs induced tumor-specific cytotoxicity and overcame the MDR of colon cancer. Our findings indicate that the use of the PLP-NPs system represents a promising strategy to counter MDR in the treatment of colon cancer.

SUBMITTER: Chang N

PROVIDER: S-EPMC7470062 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

Project description:Reactive oxygen species (ROS) play a key role in several biological functions like regulating cell survival and signaling; however, their effect can range from beneficial to nondesirable oxidative stress when they are overproduced causing inflammation or cancer diseases. Thus, the design of tailor-made ROS-responsive polymers offers the possibility of engineering hydrogels for target therapies. In this work, we developed thioether-based ROS-responsive difunctional monomers from ethylene glycol/thioether acrylate (EGnSA) with different lengths of the EGn chain (n = 1, 2, 3) by the thiol-Michael addition click reaction. The presence of acrylate groups allowed their photopolymerization by UV light, while the thioether groups conferred ROS-responsive properties. As a result, smart PEGnSA hydrogels were obtained, which could be processed by four-dimensional (4D) printing. The mechanical properties of the hydrogels were determined by rheology, pointing out a decrease of the elastic modulus (G') with the length of the EG segment. To enhance the stability of the hydrogels after swelling, the EGnSA monomers were copolymerized with a polar monomer, 2-hydroxyethyl acrylate (HEA), leading to P[(EGnSA)x-co-HEAy] with improved compatibility in aqueous media, making it a less brittle material. Swelling properties of the hydrogels increased in the presence of hydrogen peroxide, a kind of ROS, reaching values of ≈130% for P[(EG3SA)7-co-HEA93] which confirms the stimuli-responsive properties. Then, the P[(EG3SA)x-co-HEAy] hydrogels were employed as matrixes for the encapsulation of a chemotherapeutic drug, 5-fluorouracil (5FU), which showed sustained release over time modulated by the presence of H2O2. Finally, the effect of the 5-FU release from P[(EG3SA)x-co-HEAy] hydrogels was tested in vitro with melanoma cancer cells B16F10, pointing out B16F10 growth inhibition values in the range of 40-60% modulated by the EG3SA percentage and the presence or absence of ROS agents, thus confirming their excellent ROS-responsive properties for the treatment of localized pathologies.

Dataset Information

A pH/ROS cascade-responsive and self-accelerating drug release nanosystem for the targeted treatment of multi-drug-resistant colon cancer.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets