Tumor-targeted PROTAC prodrug nanoplatform enables precise protein degradation and combination cancer therapy.

Proteolysis targeting chimeras (PROTACs) have emerged as revolutionary anticancer therapeutics that degrade disease-causing proteins. However, the anticancer performance of PROTACs is often impaired by their insufficient bioavailability, unsatisfactory tumor specificity and ability to induce acquired drug resistance. Herein, we propose a polymer-conjugated PROTAC prodrug platform for the tumor-targeted delivery of the most prevalent von Hippel-Lindau (VHL)- and cereblon (CRBN)-based PROTACs, as well as for the precise codelivery of a degrader and conventional small-molecule drugs. The self-assembling PROTAC prodrug nanoparticles (NPs) can specifically target and be activated inside tumor cells to release the free PROTAC for precise protein degradation. The PROTAC prodrug NPs caused more efficient regression of MDA-MB-231 breast tumors in a mouse model by degrading bromodomain-containing protein 4 (BRD4) or cyclin-dependent kinase 9 (CDK9) with decreased systemic toxicity. In addition, we demonstrated that the PROTAC prodrug NPs can serve as a versatile platform for the codelivery of a PROTAC and chemotherapeutics for enhanced anticancer efficiency and combination benefits. This study paves the way for utilizing tumor-targeted protein degradation for precise anticancer therapy and the effective combination treatment of complex diseases.

Rheology and microstructure of myofibrillar protein-olive oil composite gels: effect of different non-meat protein as emulsifier.

BACKGROUND: Heat-induced composite gels were prepared with 20 g kg-1 (2%) myofibrillar protein (MP) sol and 100 g kg-1 (10%) olive oil pre-emulsified by MP or non-meat protein in 0.6 mol L-1 NaCl, at pH 6.2. The effect of different non-meat protein (soy protein isolate, egg-white protein isolate and sodium caseinate) pre-emulsions on the rheological properties and microstructure of MP gel was evaluated. RESULTS: Adding emulsion enhanced the gel strength of MP gel except for the soy protein isolate (SPI) as emulsifier group, but all emulsion group markedly improved (P < 0.05) the water-holding capacity and the storage modulus (G') of MP gels. SDS-PAGE show that some non-meat protein bands partially participated in the formation of MP composite gels with different kinds of emulsion added. Micrographs revealed that these emulsions made the gels become denser and more compact with subtle diverse effects. CONCLUSION: Different meat or non-meat proteins as emulsifier have varied impacts on the rheology and microstructure of MP gels, indicating the potential and feasibility of these non-meat proteins as emulsifiers to modify the textural properties in comminuted meat products. © 2017 Society of Chemical Industry.

Pectate Lyase Gene VvPL1 Plays a Role in Fruit Cracking of Table Grapes.

Fruit cracking seriously affects the commercial value of table grapes. To explore whether cell wall disassembly influences grape berry cracking, first, the differences in the cell wall metabolism were compared between cracking-resistant "Shennongjinhuanghou" (SN) and cracking-susceptible "Xiangfei" (XF) varieties. Our results showed that cell wall disassembly events were extremely different between "SN" and "XF." The cracking-resistant "SN" had a higher pectinmethylesterase activity in the early stage and lower polygalacturonase, ß-galactosidase, pectate lyase, and cellulase activities from veraison, cooperatively yielding higher ionically bound pectin, covalently bound pectin, hemicellulose, and lower water-soluble pectin, leading to a stronger skin break force and elasticity and conferring "SN" with higher cracking resistance. Furthermore, the function of the VvPL1 gene in fruit cracking was verified by heterologously transforming tomatoes. The transgenic experiment showed that overexpressed fruits had a higher activity of pectate lyase from the breaking stage and a lower level of covalently bound pectin, ionically bound pectin, cellulose, and hemicellulose and a higher level of water-soluble pectin at the red ripe stage, which resulted in a significantly reduced skin break force and flesh firmness and increased fruit cracking incidences. In conclusion, our results demonstrated that the cracking susceptibility of the grape berry is closely related to cell wall disassembly events and VvPL1 plays an important role in fruit cracking.

Stimuli-activatable PROTACs for precise protein degradation and cancer therapy.

The proteolysis targeting chimeras (PROTACs) approach has attracted extensive attention in the past decade, which represents an emerging therapeutic modality with the potential to tackle disease-causing proteins that are historically challengeable for conventional small molecular inhibitors. PROTAC harnesses the endogenic E3 ubiquitin ligase to degrade protein of interest (POI) via ubiquitin-proteasome system in a cycle-catalytic manner. The event-driven pharmacology of PROTAC is poised to pursue those targets that are conventionally undruggable, which enormously extends the space of drug development. Furthermore, PROTAC has the potential to address drug resistance of small molecular inhibitors by degrading the whole POI. Nevertheless, PROTACs display high-efficiency and always-on properties to degrade POI, they may cause severe side effects due to an "on-target but off-tissue" protein degradation profile at the undesirable tissues and cells. Given that, the stimuli-activatable PROTAC prodrugs have been recently exploited to confine precise protein degradation of the favorable targets, which may conquer the adverse effects of PROTAC due to uncontrollable protein degradation. Herein, we summarized the cutting-edge advances of the stimuli-activatable PROTAC prodrugs. We also overviewed the progress of PROTAC prodrug-based nanomedicine to improve PROTAC delivery to the tumors and precise POI degradation in the targeted cells.