A Novel NQO1 Enzyme-Responsive Polyurethane Nanocarrier for Redox-Triggered Intracellular Drug Release.

The design of nano-drug delivery vehicles responsive to tumor microenvironment stimuli has become a crucial aspect in developing cancer therapy in recent years. Among them, the enzyme-responsive nano-drug delivery system is particularly effective, as it utilizes tumor-specific and highly expressed enzymes as precise targets, leading to increased drug release at the target sites, reduced nonspecific release, and improved efficacy while minimizing toxic side effects on normal tissues. NAD(P)H:quinone oxidoreductase 1 (NQO1) is an important reductase associated with cancer and is overexpressed in some cancer cells, particularly in lung and breast cancer. Thus, the design of nanocarriers with high selectivity and responsiveness to NQO1 is of great significance for tumor diagnosis and treatment. It has been reported that under physiological conditions, NQO1 can specifically reduce the trimethyl-locked benzoquinone structure through a two-electron reduction, resulting in rapid lactonization via an enzymatic reaction. Based on this, a novel reduction-sensitive polyurethane (PEG-PTU-PEG) block copolymer was designed and synthesized by copolymerizing diisocyanate, a reduction-sensitive monomer (TMBQ), and poly(ethylene glycol). The successful synthesis of monomers and polymers was verified by nuclear magnetic resonance (1H NMR) and gel permeation chromatography (GPC). Then, the PEG-PTU-PEG micelles were successfully prepared by self-assembly, and their reductive dissociation behavior in the presence of Na2S2O4 was verified by dynamic light scattering (DLS), 1H NMR, and GPC. Next, the model drug doxorubicin (DOX) was encapsulated into the hydrophobic core of this polyurethane micelles by microemulsion method. It was observed that the drug-loaded micelles could also achieve a redox response and rapidly release the encapsulated substances. In vitro cell experiments demonstrated that PEG-PTU-PEG micelles had good biocompatibility and a low hemolysis rate (<5%). Furthermore, in the presence of an NQO1 enzyme inhibitor (dicoumarol), lower drug release from micelles was observed in A549 and 4T1 cells by both fluorescence microscopy and flow cytometry assays, but not in NIH-3T3 control cells. Predictably, DOX-loaded micelles also showed lower cytotoxicity in 4T1 cells in the presence of NQO1 enzyme inhibitors. These results indicate that drug-loaded polyurethane micelles could accomplish specific drug release in the reducing environment in the presence of NQO1 enzymes. Therefore, this study provides a new option for the construction of polyurethane nanocarriers for precise targeting and reductive release, which could benefit the intracellular drug-specific release and precision therapy of tumors.

Novel Donor-Acceptor Conjugated Polymer-Based Nanomicelles for Photothermal Therapy in the NIR Window.

In this study, a novel donor-acceptor conjugated polymer PDPPDTP was designed and synthesized by D-A polymerization using 2,6-di(trimethyltin)-N-dithieno[3,2-b:20,30-d]pyrrole as the electron-donating (D) unit and 3,6-bis(5-bromothiophen-2-yl)-2,5-dihexadecylpyrrolo[3,4-c]pyrrole-1,4-dione as the electron-accepting (A) unit. The prepared polymer has strong absorption in the near-infrared (NIR) range of 700-900 nm. Moreover, it shows excellent photothermal performance under irradiation at 808 nm. Next, the biodegradable amphiphilic polymer polyethylene glycol-polycaprolactone was used to encapsulate the new conjugated polymer into nanomicelles by the microemulsion method. The obtained PDPPDTP-loaded micelles exhibited a regular spherical structure, and their hydrodynamic diameter was about 78 nm, characterized by transmission electron microscopy and dynamic light scattering. Notably, the micelles exhibited good stability, and the encapsulation efficiency of the conjugated polymer in the micelles was ∼80%. In vitro cell experiments demonstrated that the nanomicelles not only showed good biocompatibility and low toxicity but also could effectively inhibit the proliferation of breast cancer cells 4T1 under the NIR light irradiation of 808 nm. Furthermore, in vivo studies of photothermal therapy (PTT) efficacy showed that the PDPPDTP-loaded micelles exhibited a remarkable tumor growth inhibition in a syngeneic murine tumor model, indicating that the nanomicelles loaded with this novel conjugated polymer could be further explored as a new type of theranostic agent and applied in the PTT of tumors.

Recent progress of nanomedicine in secreted phospholipase A2 as a potential therapeutic target.

Overexpressed secretory phospholipase A2 (sPLA2) is found in many inflammatory diseases and various types of cancer. sPLA2 can catalyze the hydrolysis of phospholipid sn-2 ester bonds to lysophosphatidylcholine and free fatty acids, and its catalytic substrate and downstream products mediate a series of cascade reactions and inflammatory responses. Furthermore, different subtypes of sPLA2 can participate in different physiological processes by driving unique lipid pathways. Recently, many diseases have not been treated by appropriate chemotherapy methods due to low bioavailability and severe side effects of clinically available small-molecule drugs. Therefore, they have great development prospects of revealing the therapeutic mechanism of sPLA2 and use sPLA2 as a potential therapeutic target for designing and exploring new drugs and their delivery systems. Notably, the emergence of nanomedicines in recent years provides a practical and innovative means for overcoming the challenges associated with chemotherapy. With these considerations in mind, this paper systematically reviews recent studies on nanomedicines targeting sPLA2 overexpression in various diseases during the past few years.

Negative control of diacylglycerol kinase ζ-mediated inhibition of T cell receptor signaling by nuclear sequestration in mice.

Diacylglycerol kinases (DGKs) play important roles in restraining diacylglycerol (DAG)-mediated signaling. Within the DGK family, the ζ isoform appears to be the most important isoform in T cells for controlling their development and function. DGKζ has been demonstrated to regulate T cell maturation, activation, anergy, effector/memory differentiation, defense against microbial infection, and antitumor immunity. Given its critical functions, DGKζ function should be tightly regulated to ensure proper signal transduction; however, mechanisms that control DGKζ function are still poorly understood. We report here that DGKζ dynamically translocates from the cytosol into the nuclei in T cells after TCR stimulation. In mice, DGKζ mutant defective in nuclear localization displayed enhanced ability to inhibit TCR-induced DAG-mediated signaling in primary T cells, maturation of conventional αßT and iNKT cells, and activation of peripheral T cells compared with WT DGKζ. Our study reveals for the first time nuclear sequestration of DGKζ as a negative control mechanism to spatially restrain it from terminating DAG mediated signaling in T cells. Our data suggest that manipulation of DGKζ nucleus-cytosol shuttling as a novel strategy to modulate DGKζ activity and immune responses for treatment of autoimmune diseases and cancer.