Drug delivery approaches for the treatment of glioblastoma multiforme

Figures & data

Table I. Main characteristics of GBM.

	Characteristics of GBM	References
Survival rate	The mean survival rate is 10–12 months with therapy. 90% of the patients die within 18 months from diagnosis. Without therapy, survival is less than 6 months	Sathornsumetee and Rich (2006)
Age of recognition	The mean age of primary GBM patients is about 62, whereas the mean age of secondary GBM is about 45	Adamson et al. (2009), Kushnir and Tzuk-Shina (2011)
Sex ratio	GBM develops more frequently in males than in females with a M:F ratio of 3:1	Adamson et al. (2009)
Incidence	GBM accounts for 51.2% of all primary CNS gliomas. It affects approximately 3 per 100 000 individuals annually	Adamson et al. (2009), Molenaar (2011)
Pathological features	Most GBM are characterized by the presence of necrotic areas, vascular proliferation, unorganized blood vessels, and variable mitotic activity	Ramirez et al. (2013), Sathornsumetee and Rich (2006)
Symptoms and signs	Symptoms such as drowsiness (87%), dysphagia (71%), gradual neurological deficits (51%), seizures (45%), gradual cognitive deficits (33%), and headaches (33%) are very frequently observed in patients with GBM	Adamson et al. (2009), Sizoo et al. (2010)
Brain areas affected	GBM mostly affects the temporal lobe (31%), the parietal lobe (24%) and the frontal lobe (23%) of the cerebral cortex. It is less common (1–5%) in the cerebellum, the brainstem, and the spinal cord.	Singh et al. (2009), Shahideh et al. (2012), Stark et al. (2010)
Diagnosis tools	Imaging techniques commonly employed for the diagnosis of GBM are MRS, MRI, MRI diffusion, PET and CT	Adamson et al. (2009), Park et al. (2011), Sathornsumetee et al. (2007)
Environmental factors	Factors known to increase the risk to GBM include ionizing radiation, chemical carcinogens, high cholesterol level, hypertension, and smoking	Adamson et al. (2009), Kushnir and Tzuk-Shina (2011)
Associated genetic syndromes	GBM is associated with syndromes such as neurofibromatosis 1 and 2, tuberous sclerosis, retinoblastoma, Li–Fraumeni syndrome, and Turcot’s syndrome	Reilly (2009), Schwartzbaum et al. (2006)

Figure 1. Schematic representation of the BBB. The morphology of the BBB consists of a layer of endothelial cells that form tight junctions, to restrict the passage of most therapeutic molecules to the brain. The functional integrity of the BBB also depends on the basal lamina, pericytes, and astrocyte foot processes. (Taken with permission from Anderson et al. 2011).

Table II. Examples of nanotechnology-based delivery systems for the treatment of GBM.

Delivery systems	Characteristics	Advantage for the treatment of GBM	References
Nanoparticles ∼20–200 nm in diameter	They are made up of biodegradable polymers that can be conjugated to drugs and antibodies.	They have the ability to deliver therapeutic agents into cancer cells. They also provide enhanced drug efficacy and neuroprotection.	Hernández-Pedro et al. (2013), Upadhyay (2014), Xu et al. (2013)
Liposomes ∼100–400 nm in diameter	They are small artificial vesicles made up of lipid bilayers. Their surface can be easily modified to increase the circulation half-life.	They can be conjugated with some proteins or drugs to recognize cancer cells. They also have the potential to deliver higher therapeutic doses with minimally toxicity.	Huwyler et al. (2008), Laquintana et al. (2009)
CNTs ∼1–4 nm in diameter	They are single or multi-layered sheets of self-assembling carbon atoms having the form of cylindrical large molecules.	Due to their relatively high inner volume and external surface, they could load a large amount of drug and induce apoptosis of cancer cells.	Hernández-Pedro et al. (2013), Rastogi et al. (2014), Zhang et al. (2011)
Microcapsules ∼10–1000 nm in diameter	They are small structures of spherical shape with a semi-permeable membrane made of polymers having the ability to resist chemical and enzymatic degradation.	They have the ability to encapsulate large amount of drugs and their surface could be modified to control the kinetics of drug release.	Bhujbal et al. (2014), Fakhoury et al. (2014), Scott et al. (2011)
Polymeric micelles ∼10–100 nm in diameter	They are self-assembled particles made of surfactant molecules with a hydrophobic head and a hydrophilic tail.	Ligands could be easily incorporated into their structure offering the ability to target specific compartments in the brain.	Morshed et al. (2013), Xu et al. (2013)
Dendrimers ∼3–20 nm in diameter	They are monodisperse macromolecules with a tree-like architecture. They are made of several branched molecule which adopt a symmetrical three-dimensional morphology.	They can be conjugated to ligands that could serve as detecting agents. They also display low toxicity and increased diffusion in brain tissue.	Albertazzi et al. (2013), Hernández-Pedro et al. (2013)

Figure 2. Pathways for the penetration of CNTs into the cancer cell. (a) Non-receptor-mediated endocytosis: (1) The drug-loaded functionalized CNT is trapped into an endosome, (2) the CNT gets released from the endosome and the drug is delivered to the inside of the cell, and (3) the CNT is released from the cell by exocytosis; (b) Receptor-mediated endocytosis: (4) a membrane surrounds the CNT–receptor conjugate by forming endosomes, (5) the drug is released from the CNT, (6, 7, 8) the receptor is recycled back to the surface of the cell membrane; (c) Endocytosis-independent pathway: (9) drug-loaded functionalized CNTs directly penetrate into the cell, (10) the drug is released from the CNT, (11) the CNT is released from the cell (Taken with permission from Rastogi et al. 2014).

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