Ferrocene-Conjugated Paclitaxel Prodrug for Combined Chemo-Ferroptosis Therapy of Cancer.

Herein, we developed a paclitaxel prodrug (PSFc) through the conjugation of paclitaxel (PTX) and ferrocene via a redox-responsive disulfide bond. PSFc displays acid-enhanced catalytic activity of Fenton reaction and is capable of forming stable nanoparticles (PSFc NPs) through the assembly with distearoyl phosphoethanolamine-PEG2000. After being endocytosed, PSFc NPs could release PTX to promote cell apoptosis in response to overexpressed redox-active species of tumor cells. Meanwhile, the ferrocene-mediated Fenton reaction promotes intracellular accumulation of hydroxyl radicals and depletion of glutathione, thus leading to ferroptosis. Compared with the clinically used Taxol, PSFc NPs exhibited more potent in vivo antitumor outcomes through the combined effect of chemotherapy and ferroptosis. This study may offer insight into a facile design of a prodrug integrating different tumor treatment methods for combating malignant tumors.

A Paclitaxel Prodrug with Copper Depletion for Combined Therapy toward Triple-Negative Breast Cancer.

Tuning the content of copper is of great significance for the treatment of cancer and neurodegenerative diseases. Herein, we synthesized a redox-responsive paclitaxel (PTX) prodrug by conjugating PTX with a copper chelator through a disulfide bond. The as-fabricated prodrug (PSPA) showed specific chelation toward copper ions and could assemble with distearoyl phosphoethanolamine-PEG2000 to form stable nanoparticles (PSPA NPs) in aqueous media. Upon being internalized by tumor cells, PSPA NPs could respond to high levels of redox-active species inside cells and efficiently release PTX. The copper chelator could increase oxidative stress- and abnormal metabolism-induced cell death through intracellular copper depletion. The combination of chemotherapy and copper depletion therapy generated an enhanced therapeutic outcome toward triple-negative breast cancer with an ignorable systemic toxicity. Our work may provide insight into the combination of metabolic regulation and chemotherapy for combating malignant tumors.

Carboxylated paclitaxel prodrug nanofibers for enhanced chemotherapy.

The facile availability of nanoformulations with enhanced antitumor performance remains a big challenge. Herein, we synthesize paclitaxel prodrugs with amphiphilic structures and robust assembling ability. Carboxylated paclitaxel prodrugs (PSCB) containing disulfide bonds prefer to form exquisite nanofibers, while phenylcarbinol end capped paclitaxel prodrugs (PSP) assemble into spherical nanoparticles. The transformation of morphology from nanofibers to nanorods can be realized via tuning the content of paclitaxel. Hydrophilic domains of PSCB nanofibers accelerate the cleavage of disulfide bond for rapid drug release in tumor cells, thus exhibiting the enhanced cytotoxicity and antitumor activity. This study provides a crucial insight into the functional design of hydrophobic drugs to improve chemotherapy.

Functional Characterization of Two RNA Methyltransferase Genes METTL3 and METTL14 Uncovers the Roles of m6A in Mediating Adaptation of Plutella xylostella to Host Plants.

N6-methyladenosine (m6A) is one of the major epigenetic modifications in eukaryotes. Although increasing functions of m6A have been identified in insects, its role in Plutella xylostella L. for host plant adaptation remains unclear. In the current study, we show that the m6A content of P. xylostella was relatively low in different developmental stages and tissues, with no significant differences. Two RNA methyltransferase genes, PxMETTL3 (methyltransferase-like 3) and PxMETTL14 (methyltransferase-like 14), were identified and characterized. PxMETTL3 could be transcribed into two transcripts, and PxMETTL14 had only one transcript; both of these genes were highly expressed in egg and adult stages and reproductive tissues. The CRISPR/Cas9-mediated knockout of PxMETTL3 (ΔPxMETTL3-2) or PxMETTL14 (ΔPxMETTL14-14) confirmed their function in m6A installation into RNA. Furthermore, upon transfer from an artificial diet to the host plant, the mutant strains were affected in terms of larval and pupal weight or adult emergence rate, while the wildtype (WT) strain did not exhibit any difference. In addition, the fecundity and egg hatching rate of the WT strain decreased significantly, whereas only the ΔPxMETTL14-14 mutant strain displayed significantly decreased fecundity. There seemed to be a tradeoff between the stress adaptation and reproduction in P. xylostella mediated by m6A modification. During host transfer, the expression of PxMETTL14 was consistent with the change in m6A content, which implied that PxMETTL14 could respond to host plant defense effectively, and may regulate m6A content. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis of the differentially expressed transcripts with changes in m6A levels revealed that the potential functions of m6A-related genes may be involved in steroid biosynthesis for larval performance and metabolic pathways for adult reproduction. Overall, our work reveals an epigenetic regulation mechanism for the rapid adaptation of P. xylostella to variations in the host environment.

Hypoxia-Activated PEGylated Paclitaxel Prodrug Nanoparticles for Potentiated Chemotherapy.

Developing controlled drug-release systems is imperative and valuable for increasing the therapeutic index. Herein, we synthesized hypoxia-responsive PEGylated (PEG = poly(ethylene glycol)) paclitaxel prodrugs by utilizing azobenzene (Azo) as a cleavable linker. The as-fabricated prodrugs could self-assemble into stable nanoparticles (PAP NPs) with high drug content ranging from 26 to 44 wt %. The Azo group in PAP NPs could be cleaved at the tumorous hypoxia microenvironment and promoted the release of paclitaxel for exerting cytotoxicity toward cancer cells. In addition, comparative researches revealed that the PAP NPs with the shorter methoxy-PEG chain (molecular weight = 750) possessed enhanced tumor suppression efficacy and alleviated off-target toxicity. Our work demonstrates a promising tactic to develop smart and simple nanomaterials for disease treatment.

Indocyanine green potentiated paclitaxel nanoprodrugs for imaging and chemotherapy.

Self-assembled prodrug nanoparticles with tumor-responsive capacity have great potential in tumor visualization and treatment. However, the nanoparticle formulas usually contain multiple components, especially polymeric materials, which result in various potential issues. Herein, we report an indocyanine green (ICG)-driven assembly of paclitaxel prodrugs integrating near-infrared fluorescence imaging and tumor-specific chemotherapy. By feat of the hydrophilic merit of ICG, paclitaxel dimer could form more uniformly monodispersed nanoparticles. This two-in-one strategy reinforces the complementary advantages, resulting in superior assembly behavior, robust colloidal stability, enhanced tumor accumulation as well as desirable near-infrared imaging and in vivo feedback of chemotherapy. The in vivo experiments validated the prodrug activation at tumor sites as evidenced by enhanced fluorescence intensity, potent tumor growth suppression, and reduced systemic toxicity compared with commercial Taxol. The universality of ICG potentiated strategy toward photosensitizers and fluorescence dyes was confirmed. This presentation provides deep insight into the feasibility of constructing clinical-close alternatives for improving antitumor efficacy.