Design, Synthesis, and Biological Evaluation of Potent and Selective PROTAC Degraders of Oncogenic KRASG12D.

KRASG12D, the most frequent KRAS oncogenic mutation, is a promising target for cancer therapy. Herein, we report the design, synthesis, and biological evaluation of a series of KRASG12D PROTACs by connecting the analogues of MRTX1133 and the VHL ligand. Structural modifications of the linker moiety and KRAS inhibitor part suggested a critical role of membrane permeability in the degradation activity of the KRASG12D PROTACs. Mechanism studies with the representative compound 8o demonstrated that the potent, rapid, and selective degradation of KRASG12D induced by 8o was via a VHL- and proteasome-dependent manner. This compound selectively and potently suppressed the growth of multiple KRASG12D mutant cancer cells, displayed favorable pharmacokinetic and pharmacodynamic properties in mice, and showed significant antitumor efficacy in the AsPC-1 xenograft mouse model. Further optimization of 8o appears to be promising for the development of a new chemotherapy for KRASG12D-driven cancers as the complementary therapeutic strategy to KRAS inhibition.

Black Phosphorus-Based Conductive Hydrogels Assisted by Electrical Stimulus for Skin Tissue Engineering.

Conductive hydrogels have shown great potential in wound healing and skin tissue engineering, owing to their electroactive, mechanical, and chemical properties. However, it still remains as a challenge to incorporate other functions into conductive hydrogels, such as antibacterial ability, controllable drug release, and biodegradability. In this study, a black phosphorus-based conductive hydrogel (HA-DA@BP) is prepared by an amidation reaction coupled with a coordination of Fe3+ -catechol. The hydrogel could be changed from the sol phase to the gel phase under electrical stimulus (ES). The results show that BP could be released under slight acidity, which is cell compatible but could achieve synergistic electrical antibacterial action and promote wound healing. This study proves that BP is a strong candidate for electroactive materials and provides a new insight for the development of BP-based biomedical materials in skin tissue engineering.

Immobilization of Cu (II) via a graphene oxide-supported strategy for antibacterial reutilization with long-term efficacy.

The past several decades have witnessed tremendous research to discover ways for controlling heavy metal pollution, but most of the strategies do not involve reuse of the captured heavy metals. Herein, we propose a graphene oxide -based strategy for the effective removal of Cu2+ ions from water, coupled with their reuse as an antibacterial agent. Using GO nanosheets as an adsorbent and nanosupport, the Cu2+ ions were effectively extracted from water (>99.9%) and reduced in situ to copper nanoparticles (Cu NPs) containing both crystalline Cu and Cu2O. The as-captured Cu NPs showed efficient in vitro antibacterial ability against Escherichia coli, reducing the bacteria from 109 to 101 CFU mL-1 by using 1 mg mL-1 Cu NPs/GO NSs for 1 h. The minimum inhibitory concentration determined to be only 16 µg mL-1. For practical applications, Cu recovered from wastewater could reduce bacteria by 8 log CFU in 1 h. The recovered Cu was still able to reduce the bacteria by 7 log CFU after 2 months of storage in an argon atmosphere. This strategy of extracting heavy metals and subsequently reutilizing to kill bacteria will be of great significance for environmental remediation and public healthcare.

2D Black Phosphorus-Based Cytomembrane Mimics with Stimuli-Responsive Antibacterial Action Inspired by Endotoxin-Associated Toxic Behavior.

Biomimetic membrane materials have been widely explored and developed for drug loading and tissue engineering applications due to their excellent biocompatibility and abundant reaction sites. However, novel cytomembrane mimics have been lacking for a long time. In this study, black phosphorus (BP) was used as the foundation for a new generation of promising cytomembrane mimics due to its multiple similarities to cytomembranes. Inspired by the dual function of endotoxins on membranes, we prepared a BP-based cytomembrane mimic with controllable antibacterial ability via electrostatic interaction between BP and [1-pentyl-1-quaternary ammonium-3-vinyl-imidazole]Br ([PQVI]Br). The release of PQVI could be manipulated in different conditions by adjusting the electrostatic force, thereby achieving controllable antibacterial ability. This report confirms the possibility of using BP as a new material to mimic cytomembranes and provides a new concept of controllable antibacterial action based on endotoxins.