Paradigm shift in bacteriophage-mediated delivery of anticancer drugs: from targeted ‘magic bullets’ to self-navigated ‘magic missiles’

Abstract

Introduction New phage-directed nanomedicines have emerged recently as a result of in-depth study of the genetics and structure of filamentous phage and evolution of phage display and phage nanobiotechnology. This review focuses on the progress made in the development of the cancer-targeted nanomaterials and discusses the trends in using phage as a bioselectable molecular navigation system. Areas covered The merging of phage display technologies with nanotechnology over the past years has proved promising in different areas of medicine and technology, such as medical diagnostics, molecular imaging, vaccine development and targeted drug/gene delivery, which is the focus of this review. The author used data obtained both in his research group and sourced using Science Citation Index (Web of Science) and NCBI PubMed search resources. Expert opinion First attempts of adapting traditional concepts of direct targeting of tumor using phage-targeted nanomedicines has shown minimal improvements. With discovery and study of biological and technical barriers that prevent anti-tumor drug delivery, a paradigm shift from traditional drug targeting to nanomedicine navigation systems is required. The advanced bacteriophage-driven self-navigation systems are thought to overcome those barriers using more precise, localized phage selection methods, multi-targeting “promiscuous” ligands and advanced multifunctional nanomedicine platforms.

Landscape Phage: Evolution from Phage Display to Nanobiotechnology

“…Landscape-phage probes have been discovered for a range of organic and inorganic materials that comprise widespread complexity [ 8 , 20 ]. They efficiently serve as substitutes for antibodies against bacterial and cancer cells in biosensors and targeted drug/gene delivery vehicles [ 49 , 52 , 53 , 54 , 55 , 56 ], as is exemplified below.…”

Autonomous self-navigating drug-delivery vehicles: From Science Fiction to Reality

“…Phage extravasation and migration through tumor microenvironment are controlled by a set of motifs accommodated in promiscuous phage proteins, serving as 'feelers', which navigate phage vehicles through collecting discrete hubs during their traveling toward destination tumor cells. These navigating phages can be selected from landscape phage libraries using a procedure called 'Micro-Biopanning', which combines in vivo selection, laser capture microdissection and next-generation sequencing [21,63,87]. Since 'navigation selection' in combination with 'Micro-Biopanning' analysis results in discovery of entirely unexpected motifs and their combinations that could not be revealed by other means, it may have a strong advantage in comparison with rational design of multifunctional compositions with desired characteristics, such as capacity to programmed navigation in the tumor future science group www.futuremedicine.com microenvironment.…”

“…We suggest a novel paradigm exploring 'self-navigating drug-delivery' model, based on the modern understanding of tumor microenvironment composition and function [21]. The paper introduces also landscape phages and their fusion proteins as potentially invaluable versatile tools -'explorers' for the study of tumor microenvironment, and universal construction material for development of the third generation of 'autonomous self-navigating' cancer nanomedicines [22].…”

“…For example, heptapeptide EVNGRGD accommodates three overlapping motifs targeted to distinct receptors: NGR -aminopeptidase N (CD13) [42]; RGD -integrins [7] and EVN -unknown, ( Figure 2D). Analyzing homology of multi-thousand population of tumor-binding peptides, selected as described below, we identified 3-4 amino acid residues motifs, which are assembled in the phage-displayed peptides during consecutive circles of affinity selection [21,32,43]. Discovery of motifs serving as hypothetical 'elementary binding units' [8,[44][45][46][47] inspired us to suggest the 'addressed drug navigation' concept based on the use of phages, phage proteins and distinct 'molecular navigating motifs,' identified from billion-clone landscape phage libraries used as a variety of 'explorers' in the tissue-migrating selection assay.…”

“…This consideration led us to a novel selection strategy -the selection through migration. We suggested the distinctive 'addressed self-navigating drug' approach, in which peptides selected using traditional principles of affinity [30] are substituted for 'promiscuous phage' particles discovered through 'migration selection' exploring their intrinsic capacity to extravasate from the blood stream to the tumor tissue, migrate through the tumor microenvironment, invade into the tumor and penetrate into the target tumor cells [21]. We hypothesized that phages and their proteins discovered through migration selection in the specific tumor environment, under low pH and distinct medium composition, would serve as navigating 'feelers', or 'sensors' without any modification, or can be used as a reservoir of 'elementary binding units' that can help as 'molecular LEGO' in construction of proteins with expected tissue migrating propensity.…”