Ai Chen,Sun Xiao,Xiao Shan,Guo Lu,Shang Mengmeng,Shi Dandan,Meng Dong,Zhao Yading,Wang Xiaoxuan,Li Jie
Despite rapid advances in metabolic therapies over the past decade, their efficacy in melanoma has been modest, largely due to the interaction between cancer-associated fibroblasts (CAFs) and cancer cells to promote cancer growth. Altering the tumor microenvironment (TME) is challenging and elusive. CAFs is critical for glutamine deprivation survival in melanoma. In this research, we assembled a CAFs-targeted, controlled-release nanodroplets for the combined delivery of the amino acid transporter ASCT2 (SLC1A5) inhibitor V9302 and GLULsiRNA (siGLUL). The application of ultrasound-targeted microbubble disruption (UTMD) allows for rapid release of V9302 and siGLUL, jointly breaking the glutamine metabolism interaction between CAFs and cancer cells on one hand, on the other hand, blocking activated CAFs and reducing the expression of extracellular matrix (ECM) to facilitate drug penetration. In addition, ultrasound stimulation made siGLUL more accessible to tumor cells and CAFs, downregulating GLUL expression in both cell types. FH-V9302-siGLUL-NDs also serve as contrast-enhanced ultrasound imaging agents for tumor imaging. Our study developed and reported FH-NDs as nanocarriers for V9302 and siGLUL, demonstrating that FH-V9302-siGLUL-NDs have potential bright future applications for integrated diagnostic therapy.
Graphical Abstract
Yang Chen,Wenzhe Xu,Hao Jin,Mengsi Zhang,Shuwei Liu,Yi Liu,Hao Zhang
Heterogeneous reprogrammed nutrient metabolic networks formed by oncogenes exhibit the potential for exploring novel druggable targets and developing innovative anticancer therapeutics. Herein, based on the heterogeneous metabolic characteristics of glutamine (Gln) addiction in pancreatic cancer cells, an iron-delivery system (IDS) with enhanced endocytosis is designed for efficient ferroptosis therapy. The IDS is characterized by Gln modification and can be recognized as a source of Gln nutrients for efficient endocytic uptake by pancreatic tumor cells. Because the IDS is flexible to combine with amino acid-like components, the IDS with enhanced endocytosis is further produced by loading the Gln transporter inhibitor of V9302. V9302 is capable of suppressing molecular Gln uptake via transporter ASCT2, which generates Gln deprivation to direct metabolic reprogramming of cancer cells and enhances cellular uptake of Gln-modified IDS via RAS-stimulated macropinocytosis. The enhanced endocytosis and high iron content of IDS facilitate ferroptosis in mice pancreatic tumor models; thus, an amino acid-like ferroptosis inducer of l-buthionine sulfoximine (BSO) is further combined. The enhanced endocytosis resulting from the synergism of Gln and V9302 enables the efficient delivery of iron and BSO for ferroptosis tumor therapy. This work provides an alternative approach for enhancing intracellular drug delivery of the tumors with heterogeneous nutrient metabolism by virtue of combining nutrient-modified nanodrugs with the corresponding nutrient transporter inhibitors.
Xuan Wei,Jiamin Cheng,Meijuan Geng,Siyu Chen,Liyang Gong,Siyu Meng,Keying Chen,Ziyan Wang,Zhang Yuan,Kaiyong Cai,Liangliang Dai
The inhibition of dependent glutamine metabolism is an effective treatment for triple-negative breast cancer (TNBC) starvation, but it is limited by compensatory glycolysis and inadequate delivery efficiency. Herein, we construct a pH-responsive size/charge-reprogrammed micelle with hierarchical delivery characteristics for TNBC suppression with glutamine depletion and vessel blockade. It consists of a positively charged prodrug micelle chemically grafted with the glutamine transport inhibitor V9302 as the inner core layer, the neovascular disruptor CA4P adsorbed in the middle layer, and a pH-responsive peelable polymer as the outer shell. The nanosystem PPD/PPQV@C could effectively reduce size and reverse charge in response to the tumor acidic microenvironment by removing the outer polymer PPD, as accompanying the release of CA4P. Furthermore, the remaining PPQV could responsively release V9302 in the cytoplasm of tumor cells, improving the bioavailability of cargoes and overcoming permeability barrier through precise hierarchical release strategy. Importantly, V9302 and CA4P localized in the tumor intracellular and extracellular matrix could effectively block TNBC-dependent glutamine metabolism and inhibit compensatory nutrient by blocking angiogenesis, achieving the desired tumor suppression with prolonged survival time. This work exhibits a smart nanoplatform for efficient TNBC treatment via dual blockade of the dependent glutamine metabolism and angiogenesis.
危险品化学品经营许可证（带存储）