Bacteriophages as Therapeutic and Diagnostic Vehicles in Cancer

Abstract

Evolution of nanomedicine is the re-design of synthetic and biological carriers to implement novel theranostic platforms. In recent years, bacteriophage research favors this process, which has opened up new roads in drug and gene delivery studies. By displaying antibodies, peptides, or proteins on the surface of different bacteriophages through the phage display technique, it is now possible to unravel specific molecular determinants of both cancer cells and tumor-associated microenvironmental molecules. Downstream applications are manifold, with peptides being employed most of the times to functionalize drug carriers and improve their therapeutic index. Bacteriophages themselves were proven, in this scenario, to be good carriers for imaging molecules and therapeutics as well. Moreover, manipulation of their genetic material to stably vehiculate suicide genes within cancer cells substantially changed perspectives in gene therapy. In this review, we provide examples of how amenable phages can be used as anticancer agents, especially because their systemic administration is possible. We also provide some insights into how their immunogenic profile can be modulated and exploited in immuno-oncology for vaccine production.

Keywords: biopanning; drug delivery; gene therapy; phage display; targeting.

Figure 1

M13-based applications. Examples of therapeutic and diagnostic approaches exploiting M13 phage display-derived peptides [40,42], capsid proteins [44,45], and whole phages [46,48,50] as carriers for tumor-targeted delivery of drugs (e.g., Dox, antisense oligonucleotides, photosensitizers) or imaging dyes (e.g., fluorescein, NIR-SWNTs). Figure created with BioRender.com.

Figure 2

Theranostic applications of the hybrid AAVP vector. AAPVs can be ligand-targeted to a tumor-specific cell surface molecule such as α_vβ₃ integrin [53] or GRP78 [59], followed by internalization of DNA and production of AAVP-coded proteins. The HSVtk transgene codes for TK, an enzyme that adds phosphate groups to thymidine analogues and converts (i) the prodrug GCV in the cytotoxic drug GCV triphosphate and (ii) [¹⁸F]FEAU in [¹⁸F]FEAU phosphate, which is retained intracellularly, allowing detection by PET imaging. Figure created with BioRender.com.

Figure 3

Bacteriophage-based platforms to deliver therapeutic and diagnostic agents via RNA technology. (a) Reintroduction of MEG3 lncRNA in cancer cells via an EGFR-targeted MS2 phage—upon binding to EGFR, the phage is internalized by endocytosis and releases MEG3, thus inducing apoptosis and inhibiting proliferation of cancer cells [63]. (b) VNPs derived from Φ29 bacteriophage pRNA are suitable nanocarriers for the delivery of RNAs (aptamer, ribozyme, siRNA), small molecules (drug, dye), or proteins (targeting moiety) to cancer cells [64,65]. Figure created with BioRender.com.