Recent advances in spatio-temporally controllable systems for management of glioma

Abstract

Malignant glioma remains one of the most aggressive intracranial tumors with devastating clinical outcomes despite the great advances in conventional treatment approaches, including surgery and chemotherapy. Spatio-temporally controllable approaches to glioma are now being actively investigated due to the preponderance, including spatio-temporal adjustability, minimally invasive, repetitive properties, etc. External stimuli can be readily controlled by adjusting the site and density of stimuli to exert the cytotoxic on glioma tissue and avoid undesired injury to normal tissues. It is worth noting that the removability of external stimuli allows for on-demand treatment, which effectively reduces the occurrence of side effects. In this review, we highlight recent advancements in drug delivery systems for spatio-temporally controllable treatments of glioma, focusing on the mechanisms and design principles of sensitizers utilized in these controllable therapies. Moreover, the potential challenges regarding spatio-temporally controllable therapy for glioma are also described, aiming to provide insights into future advancements in this field and their potential clinical applications.

Keywords: Glioma therapy; Magnetic therapy; Phototherapy; Radiotherapy; Sonodynamic therapy; Spatio-temporally controllable.

Graphical abstract

Fig. 1

A schematic overview of the spatio-temporally controllable glioma therapy.

Fig. 2

(A) Schematic illustration of RBT@MRN-SS-Tf/Apt nanoparticles for combinatory glioma therapy; (B) Tumor apoptosis of mice bearing glioma after intravenous injection of saline, RBT, RBT@MRN-SS-Tf or RBT@MRN-SS-Tf/Apt; (C) Survival curves of glioma-bearing mice in different groups (n = 5). Scale bars: 50 µm. Reproduced with permission from [53], Copyright 2018 Elsevier Ltd.

Fig. 3

(A) Schematic illustration of InN@In₂S₃ producing O₂ and ROS under 1270 nm laser irradiation. (B) Infrared thermal images of mice treated with PBS or InN@In2S3 (40 mg kg^-1) under different laser irradiation. (C) Bioluminescent images of glioma-bearing mice in different groups (n = 6). (D) Variations in glutathione (GSH), oxidized glutathione (GSSG), and malondialdehyde (MDA) levels of tumors treated with PBS or InN@In2S3 with different laser irradiation (0.5 W/cm², 5 min) ipsilaterally and contralaterally. *P < 0.5, ^⁎⁎P < 0.1, ^⁎⁎⁎P < 0. 01, ****P < 0.0001. Reproduced with permission from [55], Copyright 2023 Elsevier B.V. (E) Schematic illustration of cross-scale drug delivery based on MCR for combination therapy. (F) Front view, top view, and side view of MCR achieving macroscale delivery of DMs and optical fibers in a brain model. The circles indicate the locations where the MCR arrived. The yellow boxes highlight the expanded area. Reproduced with permission from [18], Copyright 2024 Wiley‐VCH GmbH.

Fig. 4

(A) Schematic showing the computer-controlled wireless power supply device for PTT of GBM; (B) Survival curves of mice in treatment groups and control groups (n = 10). Control 1: NPs(–), implantation(+); Control 2: NPs(+), microfibre(+), irradiation(–); Control 3: NPs(+), device(+), irradiation(–); Treatment 1: NPs(+), microfibre(+), irradiation (810 nm)(+); Treatment 2: NPs(+), 810 nm device(+), irradiation(+); Treatment 3: NPs(+), 940 nm device(+), irradiation(+) (P <0.05, employing the log-rank test). Reproduced with permission from [86], Copyright 2022 Springer Nature Limited; (C) Schematic illustration of EE@Fs-NPs crossing BBB and delivering anti-LAG3 to GBM for mild PTT-ICB therapy; (D) Infiltration of TNF-α in GBM tumor tissues, assessed by immunofluorescence staining in different groups; (E) Infiltration of CD8⁺ T cells and CD4⁺ T cells in GBM tumor tissues, assessed by immunofluorescence staining in different groups. Reproduced with permission from [93], Copyright 2023 Wiley-VCH GmbH.

Fig. 5

(A) Illustration for the advantage of dual-site FRET routes of ApoE-ZCU NPs compared to traditional FRET in brain-target phototherapy. (B) Bioluminescence images of glioma-bearing mice in different groups and (C) the corresponding quantified intensity of the tumor as a function of time. (D) Survival curves of the mice. Data are shown as the mean ± SEM, NS indicates no significance, *P < 0.05, ^⁎⁎P < 0.01. Reproduced with permission from [98], Copyright 2023 American Chemical Society.

Fig. 6

(A) Schematic illustration of MRI-guided FUS combined with 5-ALA for SDT; (B) T2-weighted images of F98 tumor (arrowhead, white dotted line) from Days 10 to 23. The yellow circle and dot mark the rise in temperature at the target site; (C) Tumor progression in different groups-control, 5-ALA, FUS group, and SDT-from Days 10 to 23 (Reproduced with permission from [107], Copyright 2018 World Federation for Ultrasound in Medicine & Biology); (D) Schematic illustration of the design of HA-Poly(I:C)/COS-PpIX nanosonosensitizer and sono-immunotherapy of glioma; (E) Bioluminescence images of mice bearing orthotopic GBM after various treatments on Days 0, 4 and 8; (F) Expression of CRT and (G) the infiltration of CD8⁺T cell in brain tumor tissue sections, assessed by immunofluorescence staining after different treatments. The red dotted line marks the boundary between GBM and normal brain tissue. Scale bar: 50 µm (Reproduced with permission from [111], Copyright 2022 Wiley‐VCH GmbH).

Fig. 7

(A) Schematic illustration of ACHL nanosensitizer platform used to cross the BBB and achieve precision SDT; (B) Survival curves of GL261-bearing mice in different groups (n = 6), data are presented as mean ± SD. *P < 0.05, ^⁎⁎P < 0.01, ^⁎⁎⁎P < 0.001; (C) Bioluminescent signals correlating to tumor growth over time. (Reproduced with permission from [115], Copyright 2019 Taylor & Francis); (D) Schematic illustration showing how ISZ@JUM crossed the BBB to target gene silencing and enhanced SDT of GBM; (E) Representative bioluminescence images of U87 tumor-bearing mice across all groups; (F) H&E staining images of brain sections of U87 tumor-bearing mice in all groups. Scale bar: 100 µm. Reproduced with permission from [118], Copyright 2023 American Chemical Society.

Fig. 8

(A) Schematic illustration of the synthesis and sono-chemotherapy of IR780/PTL nanoparticles; (B) Tumor volumes in different groups. ^⁎⁎P < 0.01; (C) Representative photographs of tumors after various treatments. (Reproduced with permission from [119], Copyright 2019 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim); (D) Schematic illustration of the design and the sonodynamic-enhanced cuproptosis-ferroptosis of Ce6@Cu NPs in GBM therapy; (E) Bioluminescence images of orthotopic U87MG-Luc tumor-bearing mice with various treatments and (F) corresponding bioluminescence signals at Days 12 and 18. ^⁎⁎⁎P < 0.001 (Reproduced with permission from [121], Copyright 2024 Wiley-VCH GmbH).

Fig. 9

(A) Illustration of the design of ¹⁷⁷Lu-MIL-101(Fe)/PEG-FA; (B) ¹⁷⁷Lu-MIL-101(Fe)/PEG-FA was designed for high-sensitive imaging and targeted radiotherapy of glioma; (C) Immunofluorescence staining of excised tumor tissues for TUNEL, caspase-3, and Ki67 on Day 6 after different treatments; Scale bar: 100 µm. (Reproduced with permission from [136], Copyright 2023 American Chemical Society); (D) Illustration of the synthesis and theranostics of Gd₂O₃ nanodot; (E) Tumor volumes of glioma in different groups of mice; (F) Histological evaluation of glioma tumor burden (outlined with black dotted lines) at the termination of the study in mice subjected to various treatments; (G) H&E staining images of tumor sections from each group after various treatments. Scale bar: 50 µm. (Reproduced with permission from [142], Copyright 2022 Elsevier Ltd).

Fig. 10

(A) Illustration of the synthesis of G/APH-M and its combination with anti-PD-L1 to enhance radio-immunotherapy of GBM; (B) IVIS images showing bioluminescence from GBM in mice on Days 0, 5, 10, 15 and 20 after different treatments. Blank areas indicate the dead mouse; (C) Survival curves of GBM-bearing mice in different groups. (Reproduced with permission from [19], Copyright 2023 Wiley‐VCH GmbH); (D) Illustration of the synthesis of ²¹¹At-PDA-FAPI and its application in synergistic targeted alpha therapy and PTT for the treatment of malignant tumors; (E) Survival curves of U87MG-bearing mice in different groups; (F) Images of TUNEL-stained tumor sections 15 d post-injection and H&E-stained spleen and liver sections after various treatments (I: saline, II: PDA-FAPI nanoparticles, III: PDA-FAPI with laser irradiation, IV: ²¹¹At-PDA-FAPI without laser irradiation, and V: ²¹¹At-PDA-FAPI with laser irradiation). Scale bar: 500 µm. (Reproduced with permission from [162], Copyright 2024 American Chemical Society).

Fig. 11

(A) Schematic illustration of targeted extracellular vesicles for RT of glioma; (B) The abundance of CD8⁺T cells (n = 6); (C) Representative zebra plots showing the expression of IFN-γ, TNF-α, and Granzyme B on tumor-infiltrating lymphocyte CD8⁺T cells in GBM; (D) Efficient function of tumor-infiltrating lymphocyte CD8⁺T cells quantified by the percentage of IFN-γ⁺, TNF-α⁺ and Granzyme B⁺ populations and their mean fluorescence intensity (n = 6); (E) Fluc bioluminescent signal correlating to tumor growth over time; (F) Quantification of tumor-associated Fluc radiance intensity after different treatments. Data presented as mean ± SEM; *P < 0.05, ^⁎⁎P < 0.01, ^⁎⁎⁎P < 0.001, ^⁎⁎⁎⁎P < 0.0001. (Reproduced with permission from [168], Copyright 2022 American Chemical Society).

Fig. 12

(A) Illustration of the design and MHT of magnetic dot; (B) Images of Rat glioma C6 cells dual-stained with acridine orange (green) and propidium iodide (red). Scale bar: 50 µm; (C) Cell cycle distribution (black area indicates cells in G0/G1 phase; blue area indicates S phase; red area indicates G2/M phase). (a) Cells only; (b) Cells immediately after the first cycle of magnetic hyperthermia-mediated cancer therapy (MHCT); (c) Cells 24 h post-first cycle of MHCT; (d) Cells immediately after two cycles of MHCT; (e) Cells 24 h post-two cycles of MHCT; (f) Cells exposed to 250 µg/ml magnetic dot alone for 24 h; (g) Cells immediately after the first round of MHCT with magnetic dot; (h) Cells 24 h post-first round of MHCT with magnetic dot; (i) Cells immediately after two rounds of MHCT with magnetic dot; (j) Cells 24 h post-two rounds of MHCT with magnetic dot. (Reproduced with permission from [180], Copyright 2021 Elsevier B.V.).