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PHAGE DISPLAY is a process by which a peptide or a protein is expressed as an exterior fusion to a surface protein of a phage particle. The peptide or protein sequence can be deduced from its encoding DNA sequence that resides in the phage particle or in a transductant. Amplification of the DNA of interest can take place by phage/transductant propagation or by polymerase chain reaction PCR. By producing large amount of phage particles, each expressing a unique peptide or protein peptide and protein libraries can be obtained. The peptides or proteins interacting with defined molecular targets (most often proteins) can be isolated from such libraries by enrichments through repeated cycles of panning. So, the phage display can be regarded as a search engine of protein-target interaction.
Phages are bacterial viruses that have no native affinity to mammalian cells. But we can amazingly genetically reengineered to display peptides fusions to coat proteins that can recognize and bind to our mammalian cells. Oligonucleotide sequences encoding for foreign peptides are cloned into phage coat protein genes resulting in combinatorial libraries of billions of different phage clones displaying encoded peptides on their surfaces. This phage display libraries can be easily screened against various biological targets including the intact mammalian cells to give binding molecules with desired target-specific characteristics. Even the cell-specific peptides indentified through phage display can be used as delivery moieties for construction of gene therapy vectors, liposomes, or targeted drugs to diseased cells in many sorts of disorder including the cancer.
PHAGES AGAINST BRAIN TUMORS: Malignant brain tumors are very difficult to treat because they are heterogenous, migrate far into adjacent essential brain normal tissues, are resistant to chemotherapy and radiotherapy and also protected by the blood brain barrier.
The phage display might be so much effective against this fatal condition by following means.
- Phages can optimize the targeted delivery platforms to malignant brain cells using the cell specific peptides.
- The emerging of phage probes for profiling of brain tumors in individual patients and then making the personalized treatment based on the profiles of these tumors.
- To identify the targeting peptides for brain cancer stem cells and affinity isolations of the corresponding cell-specific biomarkers for the specific anti-cancer immunotherapy.
- To identify the peptides that cross the blood brain barrier for the effective drug delivery to the malignant brain cells.
The huge advantage of phages over the technologies targeting the tumors using the natural ligands or antibodies is that phage display can identify specific binders to both known and unknown biomarkers as well as non immunogenic targets while the other technologies can only target to known biomarkers.
PHAGE-DERIVED DELIVERY SYSTEMS TO BRAIN TUMORS: Using phage display methods, brain tumor specific peptides and many researches have been identified the brain tumors specific peptides.
The most important result from these research were that the peptides were glioma specific and could selectively deliver different cargos including DNA molecules, liposomes, and cytotoxic agents to glioma cells.
The research showed that the bacteriophages themselves can be used to construct the cell-specific gene delivery vectors. The phages carrying eukaryotic expression cassettes in their genome have the ability to mediate transgene expression in several types of mammalian cells. The other lucky fact is that the phages have been infused in humans with no apparent toxicity or side effects or immune reactions.
PHAGE PROBES FOR BRAIN TUMOR PROFILING: Cell surface molecules that are specific to cancers cells are very good targets for anti cancer treatments. Very selective delivery to these targets will get very effective anti cancer agents minimizing side effects. For this reason, the survey of cell-surface markers becomes the central to therapeutic success.
Phage display can be used for identification of proteins and peptides that recognize specifically and bind to cell-surface targets. Synthetic peptides with cell binding sequences or whole phage particles carrying such peptides have the potential for serving as probes for profiling cell surfaces of cancer specimens making the therapy outcome more predictable. Unlike antibodies, phage probes can be also developed for unknown and non antigenic cell surface markers. Probes which are designed to recognize the cancer specific surface markers can be applied to profile specimens from biopsies or tissues removed at surgery from the patients.
When tumor and normal brain sections were probed with the labeled expressing glioma-specific peptides, staining was observed on tumor sections but normal brain tissue portions showed no staining. This result validated the specificity of the phage probes.
PERSONALIZED CANCER TREATMENT WITH PHAGE: The design of the strategy is to match peptides drugs to the molecular profiles of individual tumors. This includes the use of phage probes for cell-surface molecular profiling of individual tumors followed by cytotoxic treatments formulated on the basis of the tumor profile. Cell-targeting peptides carrying phages are indentified using the surgical specimens and biopsies from multiple cancer patients and placed into the bank of phage probes. The bank of (cytotoxic plus targeting) peptides is also created in parallel. Then the molecular profiles of the individual tumors are established by using theses phage probes. The patient specific (individual tumor specific) combination of the drugs from the bank of peptide drugs is prepared based on the molecular profiles and then the patient is treated with this highly specific personalized treatment. This method has a great potential for the effective cancer killing agents for each individual without harming to any normal tissues.
NEW APPROACH AND TARGETS OF PHAGE DISPLAY AND BRAIN TUMORS
WHY brain cancer recurs?? Very recent studies showed that only a small portion of the tumor cells have true tumorigenic and unlimited proliferative potential. The brain cancer stem cell is the one which displays
- Resistant to radiation and chemotherapy
- Ability to migrate which is the factor directly associated with the brain tumor cell invasion and migration into adjacent normal tissues
So, They postulated that even though the chemotherapy can kill the tumor cells, the remaining part of the tumor stem cells which is more resistant to the therapy is very important part of the recurs of the brain cancers.
The current goal is to identify the brain cancer cells specific markers and proteins and then selectively target these stem cells without the harm to normal brain cells. Phage display can be used as to identify targeting molecules and markers that distinguish the brain cancer stem cells from their normal parts.
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