Cascade-Responsive 2-DG Nanocapsules Encapsulate aV-siCPT1C Conjugates to Inhibit Glioblastoma through Multiple Inhibition of Energy Metabolism

Abstract

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.

Intelligent Delivery Systems in Tumor Metabolism Regulation: Exploring the Path Ahead

“…Glioblastoma (GBM) is a malignant tumor type characterized by high GLUT1 protein expression, and due to the presence of the blood-brain barrier (BBB), drugs often have difficulty entering the tumor site. Zhang et al [44] modified 2-DG onto 3-acrylamidophenylboronic acid to form a nano-prodrug, which served as the shell of a nanocapsule (Figure 1A-C). These nanocapsules could cross the BBB in vitro and in vivo and were further selectively absorbed by GBM tumor cells (U87 cell line), where they released the drug reactively within the cells while inhibiting glucose metabolism and fatty acid oxidation (Figure 1D,E).…”

“…Delivery systems could act as triggers for the release of modulators, enhancing the specificity of drug delivery once they [44] Copyright 2023, American Chemical Society. entered tumor cells.…”

“…Zhang et al. [ 44 ] modified 2‐DG onto 3‐acrylamidophenylboronic acid to form a nano‐prodrug, which served as the shell of a nano‐capsule ( Figure A–C). These nanocapsules could cross the BBB in vitro and in vivo and were further selectively absorbed by GBM tumor cells (U87 cell line), where they released the drug reactively within the cells while inhibiting glucose metabolism and fatty acid oxidation (Figure 1D,E).…”

“…E) Bioluminescence of luciferase in tumor-bearing mice 5 min after injection of luciferin potassium solution and Cy5 fluorescence images of in vivo and in vitro mouse brains 12 h after nanocapsule injection. Reproduced with permission [44]. Copyright 2023, American Chemical Society.…”

Bioresponsive Chimaeric Polymersomes Mediate Sustained and Liver-Specific siRNA Transfection In Vivo

“…siRNA drugs must be delivered into the cytoplasm to achieve pronounced effects, for which vehicles to overcome the intracellular/extracellular barriers are needed. − The current clinically validated siRNA delivery strategies are mainly lipid nanoparticles (LNPs) and advanced enhanced stabilization chemistry (ESC) conjugates. LNPs protect siRNA through cationic lipids to achieve passive targeting to the liver, while advanced ESC conjugates with trivalent N -acetylgalactosamine (TriGalNAc) can actively target the hepatocytes in the liver. , It should be noted, nevertheless, that LNPs are often accompanied by stability and inflammation issues while advanced ESC conjugates demand a dedicated synthesis procedure and protection from degradation. , …”