Nanoparticle Drug Delivery System for Glioma and Its Efficacy Improvement Strategies: A Comprehensive Review

Abstract

Gliomas are the most common tumor of the central nervous system. However, the presence of the brain barrier blocks the effective delivery of drugs and leads to the treatment failure of various drugs. The development of a nanoparticle drug delivery system (NDDS) can solve this problem. In this review, we summarized the brain barrier (including blood-brain barrier (BBB), blood-brain tumor barriers (BBTB), brain-cerebrospinal fluid barrier (BCB), and nose-to-brain barrier), NDDS of glioma (such as passive targeting systems, active targeting systems, and environmental responsive targeting systems), and NDDS efficacy improvement strategies and deficiencies. The research prospect of drug-targeted delivery systems for glioma is also discussed.

Keywords: brain barrier; deficiencies of NDDS; efficacy improvement strategies; nanoparticle drug delivery system; glioma.

Figure 1

Schematic diagram of this review.

Figure 2

Structure and drug transport route of BBB. (I) penetrating through the tight junctions; (II) passive diffusion across the endothelial cells; (III) carrier-mediated transport; (IV) adsorption-mediated transcytosis or endocytosis; and (V) receptor-mediated transcytosis.

Figure 3

Schematic diagram of the classification and transport mechanism of a targeted drug delivery system.

Figure 4

HFn-encapsulated Dox effectively improves anti-glioma tumor activity. (A) In vivo BLI images of GBM tumor cells in orthotopic mice that were intravenously injected with different formulations, ie, HFn-Dox, Doxil, free Dox, and HFn protein. (B) Quantitative analysis (n=5) of the BLI signals of (A). The red arrows indicate the time points of administration. (C) Animal survival curves in different groups. Asterisks indicate that the difference between HFn-Dox and free Dox or Doxil was statistically significant (Kaplan–Meier, p=0.0019 and 0.0023, respectively). (D) The effect of different treatments on mouse body weight (mean±SD, n=5). Reprinted with permission from Fan K, X Jia, M Zhou, et al Ferritin Nanocarrier Traverses the Blood Brain Barrier and Kills Glioma. ACS Nano. 2018; 12(5): 4105–4115. Copyright (2018) American Chemical Society.

Figure 5

(A) Schematic illustration of biomimetic proteolipid BLIPO-ICG for crossing the BBB and active targeting delivery of orthotopic glioma. (a) Preparation process of BLIPO-ICG. (b) Schematic of BLIPO-ICG for crossing BBB and active targeting imaging. (B) In vivo PTT of BLIPO-ICG in orthotopic glioma-bearing mice. (a) Representative in vivo infrared thermal images of the brain region before and after 808 nm laser irradiation (1 W/cm², 5 min). CLIPO-ICG = CBLIPO-ICG = ICG 1 mg/kg. (b) Representative bioluminescent images of C6-Luc glioma-bearing mice in different groups. (c) Semiquantitative bioluminescent signal intensity in the brain. **p < 0.01 versus control. #p < 0.05 versus LIPO-ICG+laser. (d) H&E staining of brain sections of orthotopic glioma-bearing mice in all groups. Scale bar = 200 μm. Reprinted with permission from Jia Y, X Wang, D Hu, et al Phototheranostics: Active Targeting of Orthotopic Glioma Using Biomimetic Proteolipid Nanoparticles. ACS Nano. 2019; 13(1): 386–398. Copyright (2019) American Chemical Society.