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 Table of Contents  
REVIEW ARTICLE
Year : 2019  |  Volume : 15  |  Issue : 8  |  Page : 1-10

Filamentous bacteriophage: A prospective platform for targeting drugs in phage-mediated cancer therapy


Department of Chemistry, GLA University, Mathura, Uttar Pradesh, India

Date of Web Publication22-Mar-2019

Correspondence Address:
Dr. Pankaj Garg
Department of Chemistry, GLA University, 17-km Stone, NH-2, Mathura-Delhi Road, Mathura - 281 406, Uttar Pradesh
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jcrt.JCRT_218_18

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 > Abstract 


A new modality of targeting therapeutic drugs based on the use of bacteriophage (virus), as an emerging tool for specific targeting and for vaccine development, has been an area of interest for genetic and cancer research. The approach is based on genetic manipulation and modification in the chemical structure of a filamentous bacteriophage that facilitates its application not only for in vivo imaging but also for therapeutic purpose, as a gene delivery vehicle, as drug carriers, and also as an immunomodulatory agent. Filamentous bacteriophage on account of its high surface holding ability with adaptable genetic engineering properties can effectively be used in loading of chemical and genetic drugs specifically on to the targeted lesion location. Moreover, the specific peptides/proteins exhibited on the phage surface can be applied directly as self-navigating drug delivery nanovehicles. The present review article has been framed with an objective to summarize the importance of bacteriophage in phage cancer therapy and to understand the possible future prospective of this approach in developing new tools for biotechnological and genetic research, especially in phage -mediated cancer therapy. Importantly, the peptides or proteins emerging from the surface of a nano carrier will make the expense of such peptides economically more effective as compared to other immunological tools, and this seems to be a potential approach for developing a new nanodrug carrier platform.

Keywords: Antibody/peptide–drug conjugate, drug delivery vehicle, phage display technology, phage nanoparticle


How to cite this article:
Garg P. Filamentous bacteriophage: A prospective platform for targeting drugs in phage-mediated cancer therapy. J Can Res Ther 2019;15, Suppl S1:1-10

How to cite this URL:
Garg P. Filamentous bacteriophage: A prospective platform for targeting drugs in phage-mediated cancer therapy. J Can Res Ther [serial online] 2019 [cited 2019 Nov 15];15:1-10. Available from: http://www.cancerjournal.net/text.asp?2019/15/8/1/249501




 > Introduction Top


There is a need for intensive research on bacteriophage and its role in cancer treatment, both in diagnosis and therapy as reported by researchers worldwide.[1],[2],[3],[4] A filamentous bacteriophage is considered to be a dependable performer in antibody engineering and is gaining importance in nanobiotechnology and cancer research. The possible specificity of bacteriophage for certain cell and tissue components makes it a crucial candidate to fight against cancer.[5],[6],[7] The specificity of the target is related to the proteins or peptides exhibits on the phage coat, which can further be conjugated with other therapeutic nanoparticles, endowing them with much specific targeting and drug-loading capacity. The genetic and chemical modification of these phages opens a modular target drug-carrying platform of nanometric dimensions, where the targeting moieties (biomolecules) and the conjugated drugs can be delivered at will.[8] The complete consignment may be assumed as a wrapped gene linked with bacteriophage genome for gene delivery applications or as imaging agents or cytotoxic drugs chemically conjugated on to the phage coat for therapeutic purposes.

Moreover, the peptides or proteins can also be directly self-assemble themselves into the phage imitative nanoparticles that can further be used as a self-guided nanomissile for drug delivery operations [Figure 1]a and [Figure 1]b. The present review signifies the potential of bacteriophages as an effective agent for targeted delivery by utilizing them as antibacterial and more importantly antitumor cancer cell nanomedicines.[9],[10]
Figure 1: (a) Chemically/genetically modified bacteriophage incorporated with nanocarriers such as liposomes and other nanoparticles, utilizing them as self-driven nanovehicles for gene/drug delivery applications. (b) Bacteriophage fused coat protein/peptide incorporated with liposomes and other polymeric nanoparticles self-assembling them to form a phage mimetic nanocapsules for successful delivery of gene/drug

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 > The Structure and Biological Mechanism of Filamentous Phage Top


Filamentous bacteriophages are viruses capable of infecting a variety of Gram-negative bacteria. The most characterized class of bacteriophages is the Ff class which includes M13, f1, and fd strains. A filamentous phage particle posses a single-stranded, closed DNA genome which includes 11 genes and is encased in a long capsid protein cylinder with a diameter of 7 nm and a length of 800–2000 nm. The bacteriophage coat contains five different proteins [Figure 2]. Approximately 2700 reprints of the major coat protein – pVIII [marked as g8 in [Figure 2] – cover the complete surface of the phage particle, and the remaining four minor coat proteins pVII, pIX, pIII and pVI [marked as g7, g9, g3, and g6 in [Figure 2] cover five copies per particle.[11],[12] All the proteins bestowed to the structural stability of a phage particle, but pIII protein is additionally responsible for host cell recognition and infection. pIII is the largest and most complicated among all the phage proteins and is composed of three distinct domains. The N1 terminal domain is responsible for initiating the translocation of viral DNA into  Escherichia More Details coli, the second N2 domain relates with host cell identification, while the third C-terminal domain is responsible for the integration of pIII on to the phage coat.[13],[14]
Figure 2: The biological structure of bacteriophage virus with single strand genome, encapsulated by a protein coat. The positions of phage coat proteins p-VIII and minor coat proteins pVII, pIX, pIII, pVI are marked with their intergenic regions as g8, g7, g9, g3, g6, respectively

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Infection in host initiate by the linkage of the phage through the N-terminal of the pIII ends to the male E. coli cell. The coat proteins are then disbanded on the cytoplasmic membrane, and the viral single- stranded circular DNA is translocated into the cytoplasm, where it is replicated by bacterial enzymes and converted into a double-stranded replicate form molecule. This molecule, in fact, acts as a template for synthesis of all the phage-related proteins.[15],[16]


 > Bacteriophage Interaction With Cancer Cell! How Ideal it May Be? Top


Current modalities for the treatment of cancer include surgery, chemotherapy, radiotherapy, hormonal therapy, and other advanced treatment methods including immunotherapy (tumor treatment using monoclonal antibodies [MoAbs], peptides antisense nucleotides, etc.), dendritic cell-based interventions, and immunogenic cell death inducers are some of the emerging nanobiotechnology techniques for cancer treatment. In the present scenario for a personalized medicinal approach, bacteriophage being a nanoparticle can ideally be suited as a unique component for various molecular therapies suggested and can be explored as a promising nanobiotechnological tool for the treatment of cancer.[17],[18],[19]

The therapeutic potential of bacteriophage lies itself in its structure. The minute and homogeneous size of bacteriophage (nanosize) makes it the most promising nanoparticle for drug delivery as well as for other purposes including phage display and cancer targeting. Moreover, bacteriophages are the most heavily populated species in the biosphere that leads to its licensing for human use due to its nonpathogenic nature and inert properties. Large amounts of their detection naturally in the saliva, serum, and stool sample confirm their findings and justify their observations as biocompatible.[20],[21]

Studies by different scientific groups relating to the interaction of bacteriophage with cancer cells have been reported in support. Benhar[22] successfully studied the potential of bacteriophage as a targeted drug delivery vehicle by utilizing them as antitumor nanomedicine. The phages were genetically modified successfully to develop selective target specificity on the phage minor protein coat. A large payload of a drug was then chemically conjugated to these targeted phages by means of a cleavable bond.[23],[24] The result obtained shows growth inhibition with positive toxicity and immunogenicity, thus underscoring the potential of targeted drug-carrying nanomedicine platform for further development.[25],[26] Related studies by other scientific groups in support reported the in vivo and in vitro demonstration of bacteriophage binding to the cancer cells. Studies relating to the binding mechanism of bacteriophage T4 to melanoma cells and their possible interaction between the phage capsid protein and also the β1 and β3 integrin receptors on the target cancer cells confirmed the potential of bacteriophage as an ideal drug delivery platform.[27],[28],[29]

Bacteriophage interaction in antitumor therapies

The bacteriophage capability of affecting the mammalian defense immune system has been explored in developing a link between microbial strategies versus cancer targeting. The pioneer study in this regard was conducted by Bloch,[30] suggesting that bacteriophage possessed certain anticancer activities and was reported to have the preferential accumulation in tumor tissues for the suppression of tumor growth. A confirmatory study in this regard was forwarded by Kantoch and Mordarski, demonstrating that phages expressing Fab fragments of antibody, selectively assembled in the tumor cells, induce both humoral and cellular immune responses, resulting in the regression of solid tumor in mice.[31]

In similar related studies conducted subsequently by Dabrowska et al.,[32],[33],[34] it was confirmed that T4 bacteriophage interacting with β3-integrins receptors at the surface of cancer cells, capable of modulating the function of human T-cell, and delayed tumor growth was observed.

Bacteriophage interaction with reactive oxygen species in the suppression of cancer cells

The reactive oxygen species (ROS) is reported to be the cause for the initiation and progression of cancer. High level of oxidative stress in the microenvironment of cancer cells results in the promotion of cell proliferation and tumor progression. ROS suppression may, therefore, be helpful in regulating many undesirable effects relating to the progression of cancer cells. The studies supporting the interaction between bacteriophage and mammalian cell provide sufficient evidence for the inhibition of ROS formation by bacteriophage.[35],[36] It was reported that bacteriophage has the ability to reduce the production of ROS by phagocyte in the presence of bacteria.[37],[38] The mechanism of this process is quite complex and involves both the phage–phagocyte interaction and phage–lipopolysaccharide interaction. The role of bacteriophage in the suppression of ROS production seems to be important in contributing to the beneficial effects of phage-mediated therapy, especially in patients suffering from a sepsis disease, where a high level of ROS production plays a crucial role.[39],[40]

Bacteriophage immune response

Bacteriophage is responsible for inducing strong antiphage humoral responses in the body, recognized as foreign exogenous antigens. Circulation of phages in the blood is inactivated by macrophages of the reticuloendothelial cells, thus synergizing with antiphage antibodies.[41]

Continuous use of a phage as a therapy vehicle causes stimulation of memory cells with subsequent generation of antibodies. It is reported that utilization of phage either for the production of new therapeutic drugs, as gene delivery vehicle, as tumor targeting agents, or for other clinical purpose, demands consideration on phage immunogenicity and its retention time while developing its efficacious biological route. Similarly, there are questions arising on the capabilities of bacteriophage while entering into the blood circulatory system of higher organisms, behaving like highly immunogenic foreign antigenic particles and can interact with the integral immune system, inducing both humoral and cellular responses [Table 1].[42],[43]
Table 1: Effects of bacteriophage interaction against tumor targeting

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 > Phage Display Concept Top


The phage display technology of bacteriophage has been reported to play an important part both in the diagnostic and therapeutic applications for treating cancer, by helping in finding the appropriate receptors on the target cells. The tumor targeting peptides exhibiting on the surface of the bacteriophage particle is an effective approach for targeting drugs on to cancer cells with promising results.[44],[45]

The therapeutic potential of bacteriophages lies in their structure itself. Its homogeneous and nanosize diameter makes it the most promising and ideal candidate suited for drug delivery vehicle as well as for other therapeutic purposes. The development of phage display technology has proven out to be a revolutionary step in the world of MoAbproduction and have open the way for new innovations.[46],[47] The strength of the technology is based on a simple fact that a peptide emerging on the surface of a filamentous bacteriophage is physically connected to that particular DNA which encodes it. The concept that a polypeptide fused on the surface of a phage coat protein enabled the development of phage display technology.[48],[49]

Phage display technology is a useful technology that provides a format for obtaining libraries containing a large number (millions or billions) of different peptides and proteins, including antibodies.[50],[51] Smith working on filamentous bacteriophage reported that the location, domain structure, and flexibility of the pIII bacteriophage minor coat protein might allow insertion of foreign polypeptides as fusion proteins to pIII. The display of the protein on the phage surface would make it accessible to antibodies, thus allowing the screening of a large library of pIII fusions against a specific antibody.[52],[53] Thus, using a recombinant DNA technology, large peptide libraries could thus be built, with every phage displaying a unique random peptide. A direct physical linkage is created between the displayed protein and its encoding gene. The phage display technology has been suggested to use for screening of peptide libraries, identifying peptide receptor ligands, identifying epitopes for MoAbs, selecting enzyme substrates, and in screening of cloned antibody repertoires. The most successful use of phage display technology reported has been in the isolation of MoAbs and its fragments using large phage antibody libraries.[54],[55]

Construction of antibody libraries and their selection

The advent of the phage display technology provides an excellent means for the construction and selection of antibody libraries. Antibody genes can be inserted into a phagemid, a plasmid containing a phage-derived origin of replication.[56] The phagemid is then introduced into competent E. coli cells, which will express the antibody in the form of a fusion protein to the bacteriophage coat, thus providing a direct physical linkage between phenotype (antibody specificity) and genotype (sequence of the variable regions).[57] Selection of specific antibodies can be achieved by a panning procedure where phage particles expressing the antibody fragment are selected against an appropriate antigen and the phage particles carrying nonspecific antibodies are culled, thereby enriching only for those expressing specific antibodies.[58],[59] Culling the initial population of phage particles through several rounds of selection gives rise to a subpopulation with increased fitness.[60] In vitro, selection can be performed either on a solid phase or on an antigen in solution.[61],[62] Alternatively, antibody displaying phage particles can be directly selected against markers on cell surfaces. Such cell panning selects antibodies that are more likely to recognize epitopes accessible in vivo and is important for the selection of therapeutic antibodies.

In vivo panning, where phage repertoires are directly injected into animals, allows the selection of peptides that home to target organs [Figure 3].
Figure 3: The recognition of target-specific peptides through bioscreening or panning process. Screening of combinatorial peptide libraries has been carried out to identify ligands for peptide receptors. The phage particles are selected against an appropriate antigen, and the specific phages are eluted and amplified repeatedly allowing the selection of phage clones, identified as an appropriate diagnostic and therapeutic agent

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 > Applications of Bacteriophage as An In Vitro And In Vivo Imaging and Targeting Agent (Using Phage Display Library-Based Screening Methods) Top


The use of surface display bacteriophage technology for displaying proteins or polypeptides on the surface, in combination with the in vitro and in vivo selection techniques, has paved the way to scientists in generating and manipulating ligands, viz., enzymes, antibodies, and peptides. The technology is based on the ability to express proteins and peptides on the phage coat of bacteriophage. Libraries of phage-displayed polypeptides and proteins in this way are physically liked to their encoding nucleic acids allowing the selection of binding partners to the target site.

The phage display can further be translated for various bacteriophage applications such as in studying protein–ligand interaction, in identifying receptor binding sites, and also in modifying the affinity of proteins for their binding partners. The corresponding section deals with the advancement in the therapeutic applications of bacteriophage and phage display concept through the work by different scientist groups globally, demonstrating the potential of bacteriophage as a futuristic drug/gene delivery platform and also as an ideal screening tool.

Imaging using bacteriophages (phages)

The phage library-related screening methods can be implemented into the field of in vivo screening of various targets. The designing of peptides and proteins can bind various targeting and imaging agents and has opened the way to in vivo screening and in monitoring of specific targets using the whole phage body as a targeting as well as an imaging agent.[63]

A bi-functional peptide ligand system involving the use of bacteriophage has been developed for targeting of receptors.[64] The peptide or protein ligands selectively home onto tissue-specific cell receptors can effectively be used as targeted therapeutic or imaging agents to the selective cells both in vitro and in vivo. The authors in their reported study explained that despite extensive advances, such constructs have been limited to use only for in vitro applications.[65] Taking a step forward into an in vivo application, the concept has been expanded by constructing and validating a more precise bifunctional ligand phage display system with a dual binding affinity. Finally, they developed a targeting application in vivo and observed a preferential homing of the targeted phages to the tumor site, with four times higher accumulation of targeted phage in tumors in comparison to control, nontargeted phages. The main achievement of this study supports the proof of in vivo application of targeted phages as imaging agents.[66]

A study supporting the use of bacteriophage as a potential targeting and imaging agent has been reported by developing a comparative in vivo screening tool of higher value over in vitro identified clones.[67] Direct labeling of phage clones with far-red fluorochromes was reported, imaging them by a multichannel fluorescence imaging system in mouse tumor models. As a model targeting moiety, secreted protein acidic rich in cysteine, and as a target, vascular cell adhesion molecule-1 were used. It has been demonstrated that how novel targeted peptide sequences presented on phages can rapidly be selected against a particular target and how a fluorescently labeled phage retained target specificity on labeling.[68],[69] Finally, it was concluded that the fluorescently labeled phage can itself act as a rechargeable imaging agent. The ease of preparation of the phage-imaging agent compared favorably with peptide-modified magneto-fluorescent nanoparticles and was evaluated using the same model system.[70]

The use of bacteriophage for in vivo imaging of bacterial infection has been reported involving the use of radiolabeled technetium (99mTc).[71]

Radiolabeling of M13 phage with 99mTc via mercaptoacetyltriglycine (MAG3) was carried out both with a target bacterial strain and with a nontarget control bacterial strain 25922 (E. coli) and strain 29213 of Staphylococcus aureus. The results obtained from the study revealed that in the early hours of dose delivery, the organs related to reticuloendothelial system (RES), i.e. liver, lungs, and spleen, show higher percentage of phage accumulation, with about 30% accumulation in liver, 8%–10% in lungs, and 2% in spleen after 30 min. The radioactivity in almost all organs gradually decreases over time, and after 6 h of delivery, only 1% content of the injected dose was reported to be present in the kidneys, spleen, and lungs. It was finally concluded from the study that the M13 phage when labeled with Tc-99m using MAG3 shows no such sign of in vitro instability both in saline and serum and was reported that the radiolabeled phage shows equal binding affinity both with live and heat-killed bacteria and that once bound, the phage is surprisingly stable to dissociation.

The application of targeted phages as a new tool for magnetic resonance imaging (MRI) imaging has been demonstrated.[72] The term “magnetophage” has been coined to describe the particles they developed. They had isolated peptide displaying phages that specifically bind phosphatidylserine (PS), a marker of apoptosis. Magnetophages were prepared by reacting the phages with ultra-small particles of iron oxide (USPIO), in a way that the USPIO reacted with amine groups on the phage coat. The magnetophages injected to BALB/c mice were mostly sequestered by the liver. To overcome the nonspecific liver uptake, “stealthy magnetophages” were prepared using polyethylene glycol (PEG)-modified USPIO that were linked to the PS-specific phages. These stealthy magnetophages no longer accumulate in the liver and other organs of RES.[73],[74] The fact that phages are taken up by RES cells is well documented and considered as an obstacle for their potential as therapeutics. It was shown that the biodistribution of phages in mice can be modulated by conjugating sugar groups to the phage coat.[75] Preparation of stealthy magnetophages with PEG by Laumonier et al. presented a useful insight to the unfavorable biodistribution of phages.[76]

Bacteriophage (as internalizing phages) for in vivo gene delivery

The application of phage display technology has turned out to be an exploring approach in identifying and selecting internalizing antibodies from phage library and which in fact laid the foundation of their application as a gene delivery vehicle. Antibodies that can bind itself on the surface of cell receptor are useful molecules for delivering drug or DNA into the cytosol of mammalian cell. The resulting work in this regard was reported by Poul and Marks at UCSE,[77] involving the use of an anti-ErbB2 (anti-human epidermal growth factor [EGF] receptor-2) antibody for determining the possibility of a direct selection of an internalizing antibodies and also in identifying the most efficient display format from the phage libraries. They used ErbB2 antibody C6.5, in a ScFv format, displayed monovalently on phage as a model and demonstrated that anti ErbB2-phage antibodies can undergo receptor-mediated endocytosis. The same group went on and isolated internalizing phages by selecting antibody phage library on cultured tumor cells.[78]

The possible use of bacteriophage as an internalizing gene delivery vehicle has been explored by researchers at selective genetics.[79] An example for this was set by them where an M13 bacteriophage when linked with targeted EGF receptor is capable of delivering a green fluorescent protein gene to EGF receptor cells.

Similar approach could then also be applied to select genetically modified phages that can be selectively designed and emerge out as gene therapy vectors. Selective genetics patented the technology of methods using genetic package display for selecting internalizing ligands for gene delivery (US patent-US-6451527B1). Two years later, the same group reviewed the technology for efficient selection of internalizing phages and compared them to viral and synthetic vectors used for gene therapy. A similar related study at selective genetics reported the additional advantage of using a phagemid system over phage vector and was demonstrated successfully in terms of high vector stability and efficient cell binding and internalizing capacity. The use of multivalent phagemid system was suggested to work more efficiently for a targeted ligand, selectively designed for targeted mammalian cell transduction.[80]

Gene therapy is a technique in which gene is delivered to the target cell to restore, over-express, or inhibit desired gene product that can further be used to treat various types of cancers. It is reported that the potential of bacteriophage can successfully be harnessed in delivery of gene to eukaryotic cells, through toxic genes transaction to cancer cells. Such type of delivery of gene will have a great prospective in the near future. Similarly, identification of tumor-homing peptides can be helpful for targeting cancer cells and antigen detection and in drug and gene delivery.[19]

Bacteriophage as a targeted drug delivery agent

The bacteriophages are reported to be used as a successful delivery agent for a large number of cyto toxic drugs to the target cells. The drugs can be linked to a genetically modified bacteriophage by means of a chemical conjugation. The phages are modified genetically to exhibit a targeting species on their phage coat, demonstrating the potential of using a multiengineered phage as a universal nanodrug carrier. The main achievement of this approach is the transformation of drug selectivity itself to target selectivity. Apart from this, a large number of therapeutic drugs including antibiotics, anticancer drugs (doxorubicin), radionuclides, and cytokines, which on account of having higher toxicity and less sufficient quantity earlier have been excluded from the list of therapeutics, can now successfully be evaluated for their therapeutic efficacy using phage-assisted drug delivery approach, by making a chemical modification in their groups including amino (-NH2), carboxylic (-COOH), and phenolic group, which can act as a linker for drug fabrication for its successful delivery.[13]

The chemical conjugation of biotin (Vitamin H) with phage nanoparticle to form a biotinylated phage was demonstrated.[81] The extent of labeling was detected by a confocal fluorescence microscopy using an avidin-biotin System. The avidin-biotin system has been advocated for the successful delivery of large number of radioimmune drugs. On account of having high affinity between avidin and biotin (highest among the biological system), the approach has been successfully explored by us (Hazra et al.) both for direct and for indirect targeting of radionuclides to the tumor cells following the prereported pretargeting strategies.[82],[83]

The approach of using bacteriophage as a drug delivery platform was successfully evaluated by Benhar for retardation of tumor cell growth. Antibodies such as anti-ERGR and anti-ErbB2 used as targeting agents were chemically attached to a drug hygromycin by means of a covalently linked amide bond. Successful release of a nanoconjugate drug with significant inhibition in tumor cell growth with over 1000 times more than the corresponding free drug release was reported, revealing an important feature of filamentous phage as a drug delivery platform and also recommends the application of drug-carrying phage nanoparticle as an ideal antibody–drug nanoconjugate.[84]

Polymeric-encapsulated drugs can be another alternative for conjugation with phage nanoparticles. Nanoassemblies of a polymer conjugated with phage particle were developed with a name FA-M13-Poly caprolactone-b-2-vinyl pyridine coated with folate conjugated M13 bacteriophage (PCL-PLVP) composed of two functional units. The results from the study showed that polymeric-loaded drug with phage nanoparticle has significantly higher tumor/nontumor ratio uptake compared to free doxorubicin drug.[85] Similar therapeutic agents such as photosensitizer and radionuclides through fabrication with phage nanoparticles via 1-ethyl-3-(3-dimethylaminocarbodiimide) chemistry can be used for selective binding of SKBR3 cancer cells.[86] The phage nanoparticle proved to be useful for targeting cancer cells, antigen detection, and drug delivery through the identification of tumor and organ homing peptides. Such approach facilitates the selective targeting of cancerous cells, through the use of bacteriophage, and can further be optimized for selective targeted treatment and as drug delivery vehicle.[87]

Antibody, peptide engineering has proven its importance in developing tumor-targeted therapies and diagnostics. However, the efficacy of this treatment is limited due to nonspecific uptake of drugs by the RES uptake. Peptides are much smaller molecule reported to be best suited for specific targeting of cancer cells. Combinatorial bacteriophage-displayed peptide libraries do offer a good source of potential ligands in developing various cancer-related molecular targets. Several peptides are derived from phage-displayed screening methods and can be translated into effective therapeutic agent. Therefore, the current clinical trials validate the potential of peptide targeting and also the importance of phage display technique to identify cancer screening and as a drug delivery tool, which has been further explored by scientist through their relevant scientific studies reported.[22],[88],[89] The tabular summarization of all the mentioned applications of bacteria has been collectively summarized in a separate self-explanatory [Table 2].
Table 2: Tabular summarization of bacteriophage application as imaging, gene, and drug delivery agent

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 > Conclusion Top


The current review article has been framed with an aim of demonstrating the potential of filamentous bacteriophage as a targeted therapeutic agent, especially for cancer cells delivery agent. The fact that phages can be used to identify internalizing antibodies and peptides can successfully be translated into using the phage as a gene delivery vehicle. Similarly, the chemical modification on the phage coat, to load it with different imaging agents and chemotherapeutic drugs, exploited its role in the development of a new targeted drug delivery system. A wealth of new targeting moieties such as imaging agents, radioisotopes, quantum dots, MRI contrast agents, and cytotoxic drugs of therapeutic importance which earlier has been considered as an obstacle, either to their high toxicity effect or uptake by RES cells or immunogenicity, can now be an active participant in the phage-mediated cancer therapy. To conclude, we can say that although phages are being considered as an ideal for therapeutic applications in phage therapy with their unique structural features, high drug-carrying capacity, and diversification in displaying targeting moieties, with a potential of becoming an additional advantage to the fast-evolving modalities of nanomedicine; however, still, a more intensive and thorough research is needed so that many remaining questions relating to the possibility of altering the pharmacokinetic and pharmacodynamic properties of phages by chemical modification and also about the safety of using phages in vivo limiting the immune system reactivity can evidently be explored out.

Future prospective

The direct or indirect application of bacteriophage plays an important role in suppressing cancerous tumor growth. Since phages can be used to display polypeptides, which can regulate different peptides, mRNAs, and micro-RNA that are interfering in the cancer cell mechanism, modulating the useful constituent of extracellular matrix is responsible for regulating the anticancerous activities in the cellular mechanism. The another futuristic application of phage can be for the detection of biomarkers, which can be used to detect bacterial infection in living host and also for detecting cancerous tissues and organs in humans. Thus, it is hoped that bacteriophage can be used as an efficient cancer research tool, which can provide us with new futuristic, innovative options for the treatment of cancer.[90]

Acknowledgment

Ww would like to acknowledge the support of our esteemed teacher and guide Prof. D. K. Hazra, Emeritus Scientist and Professor, S. N. Medical College, Agra, for his technical help and support in designing and reviewing this manuscript.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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