E. coli Phagelysate: A Primer to Enhance Nanoparticles and Drug Deliveries in Tumor

Abstract

The tumor microenvironment (TME), where cancer cells reside, plays a crucial role in cancer progression and metastasis. It maintains an immunosuppressive state in many tumors and regulates the differentiation of precursor monocytes into M1 (anti-tumor)- and M2 (pro-tumor)-polarized macrophages, and greatly reduces anticancer drug and nanoparticle delivery. As a result, the effectiveness of recently developed chemo- and/or nanotechnology-mediated immune and magnetic nanoparticle hyperthermia (mNPH) therapies is inhibited significantly. One of the ways to overcome this limitation is to use E. coli phagelysate as a primer to modify the tumor microenvironment by switching tumor-associated M2 macrophages to anti-tumor M1 macrophages, and initiate the infiltration of tumor-associated macrophages (TAMs). Recently, bacteriophages and phage-induced lysed bacteria (bacterial phagelysates—BPLs) have been shown to be capable of modifying the tumor-associated environment. Phage/BPL-coated proteins tend to elicit strong anti-tumor responses from the innate immune system, prompting phagocytosis and cytokine release. It has also been reported that the microenvironments of bacteriophage- and BPL-treated tumors facilitate the conversion of M2-polarized TAMS to a more M1-polarized (tumoricidal) environment post-phage treatment. This paper demonstrates the feasibility and enhanced efficacy of combining E. coli phagelysate (EcPHL) and mNPH, a promising technology for treating cancers, in a rodent model. Specifically, we illustrate the EcPHL vaccination effect on the TME and mNP distribution in Ehrlich adenocarcinoma tumors by providing the tumor growth dynamics and histology (H&E and Prussian blue) distribution of mNP in tumor and normal tissue.

Oncolytic bacteria VNP20009 expressing IFNβ inhibits melanoma progression by remodeling the tumor microenvironment

“…Numerous studies in bacterial-mediated tumor therapy effectively reverse tumor immunosuppression and significantly enhances the effect of tumor immunotherapy by polarizing TAMs to the M1 type. 17 , 28 , 29 Therefore, we examined the polarization phenotype of RAW264.7 cells after VNP-IFNβ stimulation via flow cytometry in vitro , and the results showed that the expression level of CD86 in RAW264.7 cells was much higher than that in the PBS group (11.8% vs. 2.9%) and the VNP group (11.8% vs. 8.9%) ( Figures 2 C and 2D), which suggests that VNP-IFNβ can promote the macrophage polarization to M1 antitumor phenotype. Next, we examined the expression levels of different polarization markers of RAW264.7 cells after VNP-IFNβ stimulation via RT-PCR in vitro .…”

Delivery of Therapeutics Using Bacteriophage Vectors

“…E. coli phage lysate can modify the TME, transforming tumor-associated M2 macrophages into anti-tumor M1 macrophages. Bacterial phage lysates (BPLs) and phage/BPL-coated proteins can also modify the TME, eliciting robust anti-tumor responses and facilitating the conversion of M2-polarized TAMs to a more M1-polarized environment [156].…”