2.4. Peptide Based Therapeutics

There are three main types of peptide-based therapeutics—tumor homing peptides, peptides targeting aberrant cellular signaling pathways and cell-penetrating peptides [64]. GBM cells have increased expression of membrane proteins that are responsible for cellular function and maintenance, protein synthesis, intercellular signaling, cell movement, and antigen presentation [8,65]. Tumor homing peptides can bind to specific molecular targets on the surface of GBM cells and will be taken up by the cells by endocytosis [66]. The binding process of these peptides is faster than antibodies. These can also be used for in vivo tumor imaging. Binding of some of these peptides can also enhance or antagonize signal transduction pathways in cancer cells or tumor tissues. Peptides and their derivatives targeting aberrant cellular signaling pathways can improve the efficacy of tumor therapy by increased selectivity in their interaction with the oncogenic pathways [64]. Cell-penetrating peptides (CPPs) are small, basic, positively charged peptide derivatives that can pass through the cell membrane [64,67].

Highly selective tumor-targeting peptides obtained using a biopanning phage display library directed against GBM cells were able to cross the BBB and deliver the oncolytic virus VSVΔM51 to GBM in a mouse model in vivo [68]. These peptides, when delivered in combination with gadolinium, also enabled the visualization of the tumors via MRI. The use of peptides directed against multiple targets provides a mechanism for addressing the heterogeneity of the tumor while nevertheless allowing for tumor specific oncolytic virus delivery.

Self-assembled spherical nanoparticles containing a peptide probe (Cy5.5-SAPD-99mTc) that combines tumor homing ability with mitochondria targeting was found to have promising theranostic possibilities owing to the enhanced apoptosis in GBM cells coupled with imaging functionality [69]. Incorporating both tumor-homing and mitochondria-targeting components helps to increase the specificity of drug delivery.

Peptide derivatives of rabies virus glycoproteins, RVG29 and RVG15-liposome, were used to deliver anticancer chemotherapeutic docetaxel nanoparticles and paclitaxel-cholesterol to glioma-bearing ICR mice with a positive effect on animal survival [70,71]. The RVG peptides target the nicotinic acetylcholine receptor, the increased expression of which is noted in the hypoxic and ischemic conditions within the tumor microenvironment. Administration of RVG peptides thus aids in tumor-specific chemotherapeutic delivery.

WSW (also called PhrCACET1) is a tumor-targeting peptide (derived from Clostridium acetobutylicum) that was fused to paclitaxel nanosuspensions and used to target GBM cell membranes in a glioma mouse model. The use of WSW induced apoptosis and prolonged survival of the animals [72]. By combining BBB penetration with tumor targeting, this biomimetic drug delivery system has enhanced tumor-targeting specificity.

The use of polydopamine (PDA)-coated zein-curcumin nanoparticles functionalized with the peptide G23 inhibited cell proliferation and migration in glioma cells in vitro [73]. Here, the peptide G23 binds to ganglioside GM-1 and enables crossing of the BBB. The anti-inflammatory, antimicrobial, and anticancer activities of curcumin have been widely demonstrated [74,75,76].

A dual peptide nanocomplex created by combining SynB3 (a cell penetration peptide) with PVGLIG (an MMP-2 sensitive peptide) and paclitaxel inhibited cell migration and invasion in multiple GBM cell lines, suppressed GBM tumor growth in vivo, and increased overall survival in a mouse model of GBM [77]. The aberrant expression of matrix metalloproteinases (MMPs) has been widely reported in tumors, and the addition of an MMP-sensitive peptide increased the tumor specificity of the drug cargo in this system.

To enhance the membrane permeability of peptides, membrane receptors such as low-density lipoprotein receptor, IL-4 receptor, and transferrin receptor which are abundantly expressed on GBM cells have been used to direct the delivery of tumor-homing peptides to brain malignancies, utilizing receptor-mediated transcytosis [78,79,80]. Peptide-mediated drug delivery is limited by the poor in vivo stability due to the proteolytic degradation of peptides in the circulation when administered systemically. In addition, the short half-life of peptides results in limited bioavailability. This can be overcome by chemical modification or conjugation with macromolecules or nanocarriers with greater target specificity [64]. Identifying additional GBM-targeting peptides is needed to further exploit the benefits of this mode of drug delivery.