Bacteriolytic therapy with Clostridium ghonii for experimental solid tumors.

Clostridium ghonii (C. ghonii) is a non-pathogenic Clostridium species and a strictly anaerobic, spore-forming bacterium. However, its bacterial oncolytic capabilities and applications have not yet been reported. This study aimed to determining the bacterial oncolytic capability of C. ghonii for the treatment of experimental solid tumors. C. ghonii secreted collagenase IV and phospholipase c and significantly promoted apoptosis and necrosis in cultured A549 cells. C. ghonii spores specially germinated and were distributed in the tumors, and elicited the immune responses after intratumoral injection in tumor-bearing mice. C. ghonii spores decreased tumor volumes and increased tumor necrosis and inhibition rates in tumor-bearing mice. Furthermore, the combination of radiation and C. ghonii exerted additive anti-tumor effects. Taken together, our data indicate that C. ghonii is a bacteriolytic therapeutic agent against solid tumors. Given the proven natural safety of C. ghonii, it is attractive as a potential novel bacteriolytic therapy for solid tumors.

Treating cancer with infection: a review on bacterial cancer therapy.

There is an increasing need for new cancer therapies. The antitumour effect of bacterial infection has been well observed and practiced throughout history. Bacteria are well-suited to serve as anticancer agents due to their intrinsic mobility, cell toxicity, immunogenicity, and preferential accumulation within the anoxic tumour environment. Furthermore, advances in biotechnology and molecular techniques have made it easier than ever to engineer bacteria as both therapeutic agents themselves and as therapeutic vectors. Here, we review bacteriolytic therapy and immunotherapy strategies, and examine the development of bacteria as vehicles for cell- and tissue-targeted delivery of genetic cancer therapeutics.

Acid-Directed Electrostatic Self-Assembly Generates Charge-Reversible Bacteria for Enhanced Tumor Targeting and Low Tissue Trapping.

Despite recent preclinical progress with oncolytic bacteria in cancer therapy, dose-limiting toxicity has been a long-standing challenge for clinical application. Genetic and chemical modifications for enhancing the bacterial tumor-targeting ability have been unable to establish a balance between increasing its specificity and effectiveness while decreasing side effects. Herein, we report a simple, highly efficient method for rapidly self-assembling a clinically used lipid on bacterium and for reducing its minimum effective dose and toxicity to normal organs. The resultant bacteria present the ability to reverse-charge between neutral and acidic solutions, thus enabling weak interactions with the negatively charged normal cells, hence increasing their biocompatibility with blood cells and with the immune system. Additionally, the lipid-coated bacteria exhibit a longer blood circulation lifetime and low tissue trapping compared with the wild-type strains. Thereby, the engineered bacteria show enhanced tumor specificity and effectiveness even at low doses. Multiple visualization techniques are used for vividly demonstrating the time course of bacterial circulation in the blood and normal organs after intravenous administration. We believe that these methods for biointerfacial lipid self-assembly and evaluation of bacterial systemic circulation possess vast potential in exquisitely fabricating engineered bacteria for cancer therapy in the future.

Novel insights into the role of Clostridium novyi-NT related combination bacteriolytic therapy in solid tumors.

Several solid tumors (for example leiomyosarcoma, melanoma and hepatocellular carcinoma) possess areas of hypoxia, which underlies one of the primary reasons of failure of conventional anticancer therapies. The areas of poor vascularization are insensitive to radiotherapy and chemotherapeutic drugs. Conversely, the hypoxic regions of tumors provide an ideal environment for anaerobic bacteria. The attenuated anaerobic bacterium, Clostridium novyi-NT (C. novyi-NT), is highly sensitive to oxygen and can target the destruction of hypoxic and necrotic areas of tumors, inducing oncolysis and characteristics indicative of an immune response. Theoretically, chemotherapy, radiotherapy and immunotherapy combined with bacterial therapy can be used as a novel means of treating solid tumors, promoting tumor regression and inhibiting metastasis formation with a notable beneficial effect. The present review discusses the molecular mechanisms of combined bacteriolytic therapy, predominantly focusing on C. novyi-NT, and summarizes the findings of previous studies on experimental animal models, including its efficacy and safety via different drug delivery routes. This strategy has great potential to overcome the limitations of conventional cancer therapy, resulting in improved treatments, and thus potentially improved outcomes for patients.

Tumor Microenvironment Targeting Nano-Bio Emulsion for Synergistic Combinational X-Ray PDT with Oncolytic Bacteria Therapy.

Various cancer therapies have been developed, but tumor recurrence with incomplete tumor killing and remaining tumor cells/tissues is frequent in monotherapies. Herein, a nano-bio therapeutic emulsion formulated with multifunctional nanoscintillators and anaerobic Clostridium novyi-NT spores for synergistic image-guided combinational cancer therapy is reported. MRI visible nanoscintillators (NSs) are synthesized with a NaGdF4 :Tb,Ce@NaGdF4 core/shell structure for an image-guided X-ray photodynamic therapy (PDT) of the normoxic peripheral tumor. An anaerobic oncolytic bacterium (C. novyi-NT) therapy is combined to treat the hypoxic central tumor tissues. Photosensitizer-coated NSs (PS-NSs) and C. novyi-NT spores are emulsified with clinically available ethiodized oil (Lipiodol) to be the nano-bio therapeutic emulsion and injected into the tumor with computed tomography image guidance. The distribution of nano-bio therapeutic emulsion, including PS-NSs and anaerobic C. novyi-NT spores in the tumor site, is confirmed by both X-ray and T1 -weighted magnetic resonance imaging. Following the image-guided X-ray PDT and anaerobic C. novyi- NT combination treatment, apoptotic cell death in cancer tissues, including both peripheral and central tumor regions, is significantly higher than in the control groups. This combination therapy approach using a nano-bio therapeutic emulsion is expected to overcome the limitations of conventional cancer therapy, resulting in increased cancer-therapeutic efficacy.

Learning from Clostridium novyi-NT: How to defeat cancer.

Side effects associated with conventional anticancer therapies have prompted the new idea of solid tumor treatment strategy. One of them is using bacteria explored as potential antitumor agents over more than one century. Notably, the ideal therapy is a specifical target to tumors with limited toxicity. Here, we take "Clostridium novyi" for the search keyword in the PubMed from 2000 to 2015 and describe that C. novyi-NT spores act as "Trojan horse" for bacteriolytic therapy. This therapy is based on the fact that the live and attenuated obligate anaerobic bacteria are capable of binary fission selectively in anoxic areas of solid tumors and direct tumoricidal effects. Our succinct review mainly concentrates on the potential mechanisms of combination bacteriolytic therapy, an effective and safe tumor therapy with the help of C. novyi-NT. Importantly, C. novyi-NT spores were shown to induce solid tumor regression and exhibit the property to initiate an immune response. Therefore, C. novyi-NT spores should be an effective and safe tumor therapy.