Liposomes actively recognizing the glucose transporter GLUT₁ and integrin α_vβ₃ for dual‐targeting of glioma

Abstract

The treatment of glioma is a great challenge because of the existence of the bloodbrain barrier (BBB). In order to develop an efficient glioma-targeting drug delivery system to greatly improve the brain permeability of anti-cancer drugs and target glioma, a novel glioma-targeted glucose-RGD (Glu-RGD) derivative was designed and synthesized as ligand for preparing liposomes to effectively deliver paclitaxel (PTX) to cross the BBB and target glioma. The liposomes were prepared and characterized for particle size, zeta potential, encapsulation efficiency, release profile, stability, hemolysis, and cell cytotoxicity. Also, the Glu-RGD modified liposomes showed superior targeting ability in in vitro and in vivo evaluation as compared to naked PTX, non-coated, singly modified liposomes and liposomes co-modified by physical blending. The relative uptake efficiency and concentration efficiency were enhanced by 4.41-and 4.72-fold compared to that of naked PTX, respectively. What is more, the Glu-RGD modified liposomes also displayed the maximum accumulation of DiD-loaded liposomes at tumor sites compared to the other groups in in vivo imaging. All the results in vitro and in vivo suggested that Glu-RGD-Lip would be a potential delivery system for PTX to treat integrin α v β 3 -overexpressing tumor-bearing mice. K E Y W O R D Sdrug delivery, dual-targeting, glucose, liposomes, RGD peptide

Immunoengineering in glioblastoma imaging and therapy

“…Active targeting could be applied with conjugation of different targeting moieties (e.g., aptamers (X. Sun et al, ; Tang et al, ; X. Zhu et al, ), antibodies (Groysbeck et al, ; Sousa, Moura, Moreira, Martins, & Sarmento, ), peptides (Di et al, ; Fu et al, ), and several small molecules) on the surface of nanoparticles. The functionalized nanoparticles could bind to receptors expressed on GBM cells, including transferrin (Jhaveri, Luther, & Torchilin, ; Lakkadwala & Singh, ; X. Zhu et al, ), lactoferrin (J. Zhang et al, ), folic acid (M. Li et al, ), low‐density lipoprotein (Jiang, Zhang, Meng, & Zhong, ; Kim & Shin, ), and insulin receptor (Alibolandi, Charbgoo, Taghdisi, Abnous, & Ramezani, ).…”

“…For dual targeting of the glucose transporter GLUT1 and integrin αvβ3 receptors in glioma, liposomes carrying paclitaxel were modified with glucose and arginylglycylaspartic acid (RGD) peptide. In integrin αvβ3-overexpressing tumor-bearing mice, the dual target liposome improved brain permeability and targeting and exhibited high accumulation at tumor sites (Fu et al, 2019).…”

Modulating the blood–brain tumor barrier for improving drug delivery efficiency and efficacy

“…As one of the most effective transport systems, GLUT1 can effectively transport glucose through BBB to the brain. 76,77 Cancer cells frequently exhibit changes in glucose metabolism and an increased glucose demand. This leads to an overexpression of GLUTs in malignant tissues, especially GLUT1, which is related to the survival time of patients.…”

Targeting Non-coding RNA for Glioblastoma Therapy: The Challenge of Overcomes the Blood-Brain Barrier

“…Published data from Böckenhoff and collaborators demonstrated that ApoE, in comparison to other BBB permeable therapeutic polypeptides including Angiopep (Ang-2), Apolipoprotein B (ApoB), and Transactivator of Transcription (TAT) exhibited the highest brain accumulation of the lysosomal enzyme Arylsulfatase A (ASA) ( 202 ). Studies by Fu et al demonstrated that incorporating a glucose-RGD derivative into paclitaxel containing liposomes for dual targeting [via GLUT1 (glucose) and integrin αvβ3 (RGD)] increased liposome accumulation in Kunming mice bearing C6 glioma tumors compared to paclitaxel alone ( 203 ).…”