The potential of polymeric micelles in the context of glioblastoma therapy

Abstract

Glioblastoma multiforme (GBM), a type of malignant glioma, is the most common form of brain cancer found in adults. The current standard of care for GBM involves adjuvant temozolomide-based chemotherapy in conjunction with radiotherapy, yet patients still suffer from poor outcomes with a median survival of 14.6 months. Many novel therapeutic agents that are toxic to GBM cells in vitro cannot sufficiently accumulate at the site of an intracranial tumor after systemic administration. Thus, new delivery strategies must be developed to allow for adequate intratumoral accumulation of such therapeutic agents. Polymeric micelles offer the potential to improve delivery to brain tumors as they have demonstrated the capacity to be effective carriers of chemotherapy drugs, genes, and proteins in various preclinical GBM studies. In addition to this, targeting moieties and trigger-dependent release mechanisms incorporated into the design of these particles can promote more specific delivery of a therapeutic agent to a tumor site. However, despite these advantages, there are currently no micelle formulations targeting brain cancer in clinical trials. Here, we highlight key aspects of the design of polymeric micelles as therapeutic delivery systems with a review of their clinical applications in several non-brain tumor cancer types. We also discuss their potential to serve as nanocarriers targeting GBM, the major barriers preventing their clinical implementation in this disease context, as well as current approaches to overcome these limitations.

Keywords: controlled release; drug delivery; glioblastoma; micelles; nanoparticle; targeted delivery.

FIGURE 1

Comparison of NK012 micelle formulation with bevacizumab and CPT-11 therapy. Athymic mice were injected intracranially with Luciferase-labeled U87MG and treated starting 8 days after tumor cell implantation. NK012 was delivered at 30 mg/kg intravenously three times every 4 days. CPT-11 was delivered at 67 or 40 mg/kg three times every 4 days in conjunction with bevacizumab, which was delivered at 5 mg/kg intraperitoneally six times every 4 days. Reproduced with permission from Kuroda et al. (2010).

FIGURE 2

Activatable low molecular weight protamine (ALMWP)-modified micelles allow for increased accumulation of paclitaxel in an intracranial C6 glioma model in nude mice. (A–C) In vivo fluorescence imaging taken of nude mice bearing intracranial C6 glioma tumors. Mice were injected intravenoulsy with DiR-labeled micelles (A), LMWP-micelles (B), and ALMWP-micelles (C). (D) Images of organs taken from mice sacrificed 24 h after intravenous injection of the various micelle particles. (E) Accumulation of intravenously injected compounds at the tumor site from 0.5 to 24 h after administration. *p < 0.05, **p < 0.01, ***p < 0.001 was indicative of significant difference between the experimental and ALMWP-NP-PTX group. Error bars reflect the standard deviation. Reproduced with permission from Gu et al. (2013).

FIGURE 3

Overview of GBM-targeting mechanisms for micelle nanoparticles. (A) Section of brain containing a GBM tumor and normal brain parenchyma. (B) Close-up of tumor vasculature and surrounding glioma cells. Here, the vasculature displays disruption of the tight junctions between endothelial cells. Micelles can target tumors areas by two main pathways: (1) via the EPR effect where micelles diffuse passively through the disrupted BBB to reach glioma cells or (2) via interaction with endothelial cells and transcytosis to the tumor parenchyma. Examples of receptors more specific to the tumor vasculature and glioma cells include α_vβ₃ integrin and aminopeptidase N. (C) Close-up of normal vasculature with surrounding normal brain parenchyma. Here, micelles can interact with the intact BBB, allowing for transcytosis of particles. An example of a receptor mediating this pathway includes the Tf receptor. While receptor-mediated endocytosis is displayed in these images, other endothelial cell uptake mechanisms such as adsorptive-mediated endocytosis may take place at these sites as well.