GBM tumors biologically present a number of challenges for development of anticancer drugs and their delivery to the tumor site.
Perhaps the biggest obstacle is the localization of tumors in the brain, which implies that the anti-cancer agent must be able to penetrate the blood brain barrier (BBB). The BBB is a highly selective permeability barrier that separates circulating blood from cerebrospinal fluid in the Central Nervous System (CNS). It is mainly formed by endothelial cells lining the brain microvessels. Pericytes envelope a part of the endothelium and have a common basal lamina. The “endfeet” of astrocytes surround the pericytes and endothelial cells and are connected to neurons through their numerous projections. The tight junctions …show more content…
Some major mechanisms for resistance to chemotherapy for GBM include active drug efflux through ABC family transporter proteins such as P-glycoprotein (encoded by MDR1 gene) and the presence of hypoxic areas in the core of the tumor due to lack of adequate vasculature resulting in non-dividing cells, and the presence of glioblastoma stem cells (GSCs). Standard of care chemotherapy agent Temozolomide is an alkylating agent which functions by methylation of DNA on N-7 or O-6 positions of guanine residues. Methylation damages DNA and triggers apoptosis of cells. However, about 50% GBM tumors express a protein encoded by the O-6-methylguanine-DNA methyltransferase (MGMT) gene which makes these tumors unresponsive to temozolomide therapy. Upon repeated exposure to a drug, tumor cells develop additional mutations, which make them resistant to the drug thus rendering the treatment …show more content…
Transcytosis is mediated by the binding of a receptor protein on the plasma membrane of an endothelial cell, with its specific ligand on the apical side. Caveolin-I protein present on the apical surface of the plasma membrane then forms microdomains called ‘caveolae’, which mediate transport of the ligand-receptor complex into the cell. Thus, coupling the nanocarrier-drug conjugate to a ligand that specifically binds a receptor protein on endothelial cells of the BBB, will ensure targeting of the conjugate to the brain and improve its penetration of the BBB by transcytosis. The Tet-1 peptide (amino acid sequence H-L-N-I-L-S-T-L-W-K-Y-R), was discovered by phage display and has affinity and cellular processing similar to the heavy chain of the Tetanus Toxin (TTC). Tet-1 peptide binds to trisialoganglioside clostridial toxin (GT1b) receptors, has affinity to neurons and retrograde transportation (from distal axonal projections of neurons to the cell body) properties so as order to facilitate targeting of the therapeutic agent to the brain.
Treatment of drug resistance:
In order to overcome the challenge of multi-drug resistant cancer cells, we need a design that can carry two drugs that work in a synergistic way while maintaining a steady bioavailability. For example, Doxorubicin is a
Perhaps the biggest obstacle is the localization of tumors in the brain, which implies that the anti-cancer agent must be able to penetrate the blood brain barrier (BBB). The BBB is a highly selective permeability barrier that separates circulating blood from cerebrospinal fluid in the Central Nervous System (CNS). It is mainly formed by endothelial cells lining the brain microvessels. Pericytes envelope a part of the endothelium and have a common basal lamina. The “endfeet” of astrocytes surround the pericytes and endothelial cells and are connected to neurons through their numerous projections. The tight junctions …show more content…
Some major mechanisms for resistance to chemotherapy for GBM include active drug efflux through ABC family transporter proteins such as P-glycoprotein (encoded by MDR1 gene) and the presence of hypoxic areas in the core of the tumor due to lack of adequate vasculature resulting in non-dividing cells, and the presence of glioblastoma stem cells (GSCs). Standard of care chemotherapy agent Temozolomide is an alkylating agent which functions by methylation of DNA on N-7 or O-6 positions of guanine residues. Methylation damages DNA and triggers apoptosis of cells. However, about 50% GBM tumors express a protein encoded by the O-6-methylguanine-DNA methyltransferase (MGMT) gene which makes these tumors unresponsive to temozolomide therapy. Upon repeated exposure to a drug, tumor cells develop additional mutations, which make them resistant to the drug thus rendering the treatment …show more content…
Transcytosis is mediated by the binding of a receptor protein on the plasma membrane of an endothelial cell, with its specific ligand on the apical side. Caveolin-I protein present on the apical surface of the plasma membrane then forms microdomains called ‘caveolae’, which mediate transport of the ligand-receptor complex into the cell. Thus, coupling the nanocarrier-drug conjugate to a ligand that specifically binds a receptor protein on endothelial cells of the BBB, will ensure targeting of the conjugate to the brain and improve its penetration of the BBB by transcytosis. The Tet-1 peptide (amino acid sequence H-L-N-I-L-S-T-L-W-K-Y-R), was discovered by phage display and has affinity and cellular processing similar to the heavy chain of the Tetanus Toxin (TTC). Tet-1 peptide binds to trisialoganglioside clostridial toxin (GT1b) receptors, has affinity to neurons and retrograde transportation (from distal axonal projections of neurons to the cell body) properties so as order to facilitate targeting of the therapeutic agent to the brain.
Treatment of drug resistance:
In order to overcome the challenge of multi-drug resistant cancer cells, we need a design that can carry two drugs that work in a synergistic way while maintaining a steady bioavailability. For example, Doxorubicin is a