In Situ Delivery and Production System (iDPS) of Anti-Cancer Molecules with Gene-Engineered Bifidobacterium

Abstract

To selectively and continuously produce anti-cancer molecules specifically in malignant tumors, we have established an in situ delivery and production system (iDPS) with Bifidobacterium as a micro-factory of various anti-cancer agents. By focusing on the characteristic hypoxia in cancer tissue for a tumor-specific target, we employed a gene-engineered obligate anaerobic and non-pathogenic bacterium, Bifidobacterium, as a tool for systemic drug administration. This review presents and discusses the anti-tumor effects and safety of the iDPS production of numerous anti-cancer molecules and addresses the problems to be improved by directing attention mainly to the hallmark vasculature and so-called enhanced permeability and retention effect of tumors.

Recent Development of Probiotic Bifidobacteria for Treating Human Diseases

“…B. longum HB25 expressing the antibacterial peptide LL-37 was used for treating bacterial diarrhea (Guo et al, 2017). Additionally, since Bifidobacteria can germinate and proliferate in the hypoxic regions of solid tumors (Yazawa et al, 2000;Yazawa et al, 2001;Cronin et al, 2010), Bifidobacteria are currently widely applied as an in situ delivery and production of various anticancer agents for treating tumors (Taniguchi, 2021). For example, B. longum 105-A was used to deliver cytosine deaminase that catalytically converts the non-toxic prodrug 5-fluorocytosine to the anticancer drug 5fluorouracil, to the rat mammary tumors (Taniguchi et al, 2016) or mice metastatic breast tumors (Fujimori, 2006).…”

Intestinal Engineered Probiotics as Living Therapeutics: Chassis Selection, Colonization Enhancement, Gene Circuit Design, and Biocontainment

“…With the development of synthetic biology, various genetic tools can be used to carry out targeted modifications of traditional probiotics and convert them into smart drugs, to overcome the shortcomings of traditional probiotic treatment and achieve personalized treatment. , These engineered probiotics are predicted to colonize the afflicted region, specifically detect abnormal signals from the host, respond promptly, produce the desired drugs in situ within a preset period, and die after completing the treatment; these engineered probiotics are expected to be living therapeutics. While retaining the advantages of previous probiotic therapies, this approach can make treatment less expensive, and more patient-friendly, while maintaining the stability of specific therapeutic molecules. , Therefore, engineered probiotics are expected to elicit preventive or therapeutic effects and participate in the treatment process for various diseases, including metabolic disorders, − tumors, ,− and chronic inflammatory infections. − …”

Poly(Styrene-Co-Maleic Acid)-Conjugated 6-Aminofluorescein and Rhodamine Micelle as Macromolecular Fluorescent Probes for Micro-Tumors Detection and Imaging

“…Furthermore, a prolonged retention time of the macromolecules or nanoparticles delivered to the tumor, for instance, several days in mice, will be attained in vivo, which is a great contrast to the low molecular weight drugs that will disappear in a few minutes or hours [ 18 , 19 , 20 , 25 ]. The EPR effect is not only applied to targeted anticancer therapy [ 26 ] but it is also applicable to photodynamic therapy (PDT) [ 15 , 27 ], radiation therapy [ 28 ], bacterial therapy of cancer [ 29 ], as well as nucleic acid medicine [ 30 ].…”