The addition of temozolomide (TMZ) to radiotherapy (RT) improves survival of patients with glioblastoma (GBM). However, TMZ + RT causes excess toxicity in patients. In this study, we prepared angiopep-2 (A2) modified lipid-poly (hypoxic radiosensitized polyprodrug) nanoparticles for TMZ delivery (A2-P(MIs)25/TMZ) to achieve synergistic effects against glioma. This A2-P(MIs)25/TMZ display highly promising advantages: (1) a hydrophobic P-(MIs)25 core where poorly water-soluble TMZ can be encapsulated; (2) nitro groups of the hydrophobic P-(MIs)25 core that are converted into hydrophilic amino groups (P(NH
2
s)25) under low oxygen conditions to mimic the oxygen-increased sensitization to RT; (3) a lipid monolayer at the interface of the core and the shell to modify the A2 (a specific ligand for low-density lipoprotein receptor-related protein-1 (LRP-1), which are expressed in the blood-brain barrier (BBB) and human glioma cells), thereby enhancing the drug encapsulation efficiency in glioma. These nanoparticles appear as a promising and robust nanoplatforms for TMZ and hypoxic cell radiosensitization delivery.
Introduction: Temozolomide (TMZ) is the first-line chemotherapeutic option to treat glioma; however, its efficacy and clinical application are limited by its drug resistance properties. Polo-like kinase 1 (PLK1)-targeted therapy causes G2/M arrest and increases the sensitivity of glioma to TMZ. Therefore, to limit TMZ resistance in glioma, an angiopep-2 (A2)-modified polymeric micelle (A2PEC) embedded with TMZ and a small interfering RNA (siRNA) targeting PLK1 (siPLK1) was developed (TMZ-A2PEC/siPLK). Materials and Methods: TMZ was encapsulated by A2-PEG-PEI-PCL (A2PEC) through the hydrophobic interaction, and siPLK1 was complexed with the TMZ-A2PEC through electrostatic interaction. Then, an angiopep-2 (A2) modified polymeric micelle (A2PEC) embedding TMZ and siRNA targeting polo-like kinase 1 (siPLK1) was developed (TMZ-A2PEC/siPLK). Results: In vitro experiments indicated that TMZ-A2PEC/siPLK effectively enhanced the cellular uptake of TMZ and siPLK1 and resulted in significant cell apoptosis and cytotoxicity of glioma cells. In vivo experiments showed that glioma growth was inhibited, and the survival time of the animals was prolonged remarkably after TMZ-A2PEC/siPLK1 was injected via their tail vein. Discussion: The results demonstrate that the combination of TMZ and siPLK1 in A2PEC could enhance the efficacy of TMZ in treating glioma.
Glioma
is the most prevalent type of malignant brain tumor and
is usually very aggressive. Because of the high invasiveness and aggressive
proliferative growth of glioma, it is difficult to resect completely
or cure with surgery. Residual glioma cells are a primary cause of
postoperative recurrence. Herein, we describe a hypoxia-responsive
lipid polymer nanoparticle (LN) for fluorescence-guided surgery, chemotherapy,
photodynamic therapy (PDT), and photothermal therapy (PTT) combination
multitherapy strategies targeting glioma. The hypoxia-responsive LN
[LN (DOX + ICG)] contains a hypoxia-responsive component poly(nitroimidazole)25 [P-(Nis)25], the glioma-targeting peptide angiopep-2
(A2), indocyanine green (ICG), and doxorubicin (DOX). LN (DOX + ICG)
comprises four distinct functional components: (1) A2: A2 modified
nanoparticles effectively target gliomas, enhancing drug concentration
in gliomas; (2) P-(Nis)25: (i) the hydrophobic component
of LN (DOX + ICG) with hypoxia responsive ability to encapsulate DOX
and ICG; (ii) allows rapid release of DOX from LN (DOX + ICG) after
808 nm laser irradiation; (3) ICG: (i) ICG allows imaging-guided surgery,
combining PDT and PTT therapies; (ii) upon irradiation with an 808
nm laser, ICG creates a hypoxic environment; (4) DOX inhibits glioma
growth. This work demonstrates that LN (DOX + ICG) might provide a
novel clinical approach to preventing post-surgical recurrence of
glioma.
Aerobic glycolysis is the primary energy supply mode
for glioblastoma
(GBM) cells to maintain growth and proliferation. However, due to
the metabolic reprogramming of tumor cells, GBM can still produce
energy through fatty acid oxidation (FAO) and amino acid metabolism
after blocking this metabolic pathway. In addition, GBM can provide
a steady stream of nutrients through high-density neovascularization,
which puts the block energy metabolism therapy for glioma in the situation
of “internal and external problems”. Herein, based on
the abundant reactive oxygen species (ROS) and glutathione (GSH) in
the tumor microenvironment and cytoplasm, we successfully designed
and developed a cascade-responsive 2-DG nanocapsule delivery system.
This nanocapsule contains a conjugate of anti-VEGFR2 monoclonal antibody
(aV) and CPT1C siRNA (siCPT1C) linked by a disulfide cross-linker
(aV-siCPT1C). The surface of this nanocapsule (2-DG/aV-siCPT1C NC)
is loaded with the glycolysis inhibitor 2-DG, and it utilizes GLUT1,
which is highly expressed on the blood–brain barrier (BBB)
and GBM cells, to effectively penetrate the BBB and target GBM. The
nanocapsule realizes multidrug codelivery, jointly blocks glycolysis
and FAO of GBM, and reduces angiogenesis. Meanwhile, it also solves
the problems of low delivery efficiency of mAb in the central nervous
system (CNS) and easy degradation of siRNA. In general, this drug
joint delivery strategy could open up a new avenue for the treatment
of GBM.
Aim: The main of this study was to investigate the role of IGF2BP2 in oral squamous cell carcinoma (OSCC) with the overarching of providing new biomarkers or potential therapeutic targets for OSCC. Methods: We combined datasets downloaded from Gene Expression Omnibus (GEO), The Cancer Genome Atlas (TCGA), and samples collected from the clinic to evaluate the expression of IGF2BP2 in OSCC. IGF2BP2 survival analysis was respectively performed based on TCGA, GEO, and clinical samples. Correlations between IGF2BP2 expression and clinicopathological parameters were then analyzed, and signaling pathways associated with IGF2BP2 expression were identified using gene set enrichment analysis (GSEA 4.1.0). Moreover, an IGF2BP2 co-expressed gene network was constructed, followed by gene ontology (GO) functional enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis on IGF2BP2 co-expressed genes. Finally, TIMER and CIBERSORT were used to analyze the correlations among IGF2BP2, IGF2BP2-coexpressed genes, and tumor-infiltrating immune cells (TICs). Results: IGF2BP2 was highly expressed in OSCC and significantly correlated with overall survival of OSCC patients (p<0.01). High IGF2BP2 expression correlated with poor overall survival. The GSEA results showed that cell apoptosis-, tumor-, and immune-related pathways were significantly enriched in samples with high IGF2BP2 expression. Furthermore, GO and KEGG enrichment analysis results of IGF2BP2 co-expressed genes indicated that these genes are mainly associated with immunity/inflammation and tumorigenesis. In addition, IGF2BP2 and its co-expressed genes are associated with tumor-infiltrating immune cells (p<0.01). Conclusion: IGF2BP2 may be a potential prognostic biomarker in OSCC and correlates with immune infiltrates.
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