Due to the abnormal hyperplasia of the vascular system in tumor tissue, a specific anaerobic, acidic microenvironment is formed in tumors. Over the past decades, targeting delivery of therapeutic drugs into cancer with reduced side effects still remains a challenge in cancer therapy. Researchers have made a series of attempts in the drug delivery systems; various viral vectors (e.g., adenovirus, adeno-associated virus), abiotic carriers (e.g., micelles, liposomes, carbon materials, inorganic structures, self-assembled peptide and protein nanostructures) and cell carriers (e.g., bacteria, red blood cells) were developed to achieve active or passive targeting to tumor tissue.1–4 Among the cell carriers, bacteria have been explored in cancer therapy for more than a century, including Salmonella, Listeria monocytogenes and Bifidobacterium. Compared with other synthetic carriers, bacteria exhibit multiple advantages, such as (1) the unique ability to preferentially penetrate and colonize anaerobic tumors by an aerotaxis or chemotaxis pathway;5 (2) their intrinsic genetic system, which is easily engineered to deliver antitumor agents such as genes or proteins;6 and (3) their own immune-stimulating activity,7 which allows them to act as adjuvants in tumor immunotherapy. Despite the above advantages, several challenges in bacteria-mediated delivery still exist, such as (1) the risks and safety of bacteria and their derivatives;8–10 (2) the active targeting efficiency remains to be enhanced; and (3) expanding the types of drug carried by bacteria.11 To address these concerns, a nanotechnology-employed bacteria-based delivery strategy is considered to be an effective strategy to improve bacteria-mediated tumor therapy. In this review, the current developments and their deficiencies of bacteria as therapeutic agents or delivery system are first introduced. Then, we focus on the design strategy of a nanotechnology-employed bacteria-based drug delivery system (e.g., bacteria-derived nano-hybrid, bacteria-derived outer membrane vesicles based nano-platforms) and highlight the interaction between bacteria and nanomaterials and the modification strategies to complement or enhance their therapeutic applicability in cancer field. This review can provide more perspectives for the practical medicinal application for a nanotechnology-employed bacteria-based drug delivery system in the future.
Bacteria Used as Carriers in Anticancer Therapeutics
In the design of a bacteria-based drug-delivery system, the most important thing is the selection of a bacterial strain with specific characteristics to target the tumor area. Until now, various bacterial strains have been used to combat tumors, including Escherichia coli, Clostridium, Listeria monocytogenes, Serratia marcescens, magnetotactic bacteria (MTB) and Salmonella typhimurium.12 It is noted that the above bacteria are mainly divided into two types according to application. One is that pathogenic or attenuated bacteria themselves act as therapeutic agents alone, relying on the strong immune stimulation. The other is attenuated or non-pathogenic bacteria mainly acting as a carrier to assist other antitumor therapy.
In 1891, W Busch surprisingly found significant tumor reduction after infection of Streptococcus pyogenes in sarcoma patients. Inspired by this phenomenon, physician W. B. Coley firstly purified and prepared mixed bacteria vaccine (inactivated Serratia marcescens and Streptococcus pyogenes), which has treated thousands of patients with various tumors and mostly exhibited effective tumor suppression. Therefore, attributed to physiological colonization differences between normal and neoplastic tissues, the pathogenic anaerobes were initially developed as immune-stimulating vaccines. The unusually successful case is Mycobacterium bovis BCG, which had been clinically used in postsurgical bladder cancer to prevent cancer recurrence …….