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A Synergistic Integration of Bacteria and Nanomaterials in Cancer Therapy

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A Synergistic Integration of Bacteria and Nanomaterials in Cancer Therapy Mini Review Nanobiohybrids: A Synergistic Integration of Bacteria and Nanomaterials in Cancer Therapy Yuhao Chen1, Meng Du1, Jinsui Yu1, Lang Rao2, Xiaoyuan Chen2 and Zhiyi Chen1,* Abstract 1Department of Ultrasound Medicine, Laboratory of Cancer is a common cause of mortality in the world. For cancer treatment modalities such as chemotherapy, photothermal therapy and immunotherapy, the concentration of therapeutic agents in tumor tissue is the key Ultrasound Molecular Imaging, factor which determines therapeutic efficiency. In view of this, developing targeted drug delivery systems are The Third Affiliated Hospital of of great significance in selectively delivering drugs to tumor regions. Various types of nanomaterials have Guangzhou Medical University, been widely used as drug carriers. However, the low tumor-targeting ability of nanomaterials limits their Guangzhou 510150, China clinical application. It is difficult for nanomaterials to penetrate the tumor tissue through passive diffusion due to the elevated tumoral interstitial fluid pressure. As a biological carrier, bacteria can specifically colonize 2Laboratory of Molecular and proliferate inside tumors and inhibit tumor growth, making it an ideal candidate as delivery vehicles. In Imaging and Nanomedicine, addition, synthetic biology techniques have been applied to enable bacteria to controllably express various National Institute of Biomedical functional proteins and achieve targeted delivery of therapeutic agents. Nanobiohybrids constructed by the Imaging and Bioengineering, combination of bacteria and nanomaterials have an abundance of advantages, including tumor targeting National Institutes of Health, ability, genetic modifiability, programmed product synthesis, and multimodal therapy. Nowadays, many Bethesda, Maryland, USA different types of bacteria-based nanobiohybrids have been used in multiple targeted tumor therapies. In this review, firstly we summarized the development of nanomaterial-mediated cancer therapy. The mechanism and advantages of the bacteria in tumor therapy are described. Especially, we will focus on introducing different therapeutic strategies of nanobiohybrid systems which combine bacteria with nanomaterials in cancer therapy. It is demonstrated that the bacteria-based nanobiohybrids have the potential to provide a *Correspondence: targeted and effective approach for cancer treatment. Zhiyi Chen, MD, PhD E-mail: zhiyi_chen@gzhmu. Keywords edu.cn Bacteria, cancer therapy, nanocatalytic therapy, nanomaterial, targeted delivery. Received: February 19 2020 Revised: May 22 2020 Accepted: May 26 2020 Published Online: June 9 2020 Introduction kill tumor cells through cytotoxicity or immune activation. However, the acidic, Available at: Cancer has emerged as one of the main hypoxic and hypo-vascular tumor microen- https://bio-integration.org/ causes of death in the world and poses a vironment affects the delivery of various serious threat to human health. Although therapeutic agents, resulting in treatment conventional therapies, including surgery resistance of tumor cells. Systemic injec- and radiation, remain as the standard treat- tion of therapeutic agents cannot specif- ment for cancer, the limitations of these ically act on tumor cells and may cause treatment options are becoming increas- toxic effects on normal tissues. Therefore, ingly apparent [1]. Surgery is an effective many studies focus to improve the targeted treatment method for tumors, but postop- delivery of therapeutic agents in order to erative metastasis and recurrence renders enhance the tumor therapeutic effect and tumor treatment more difficult. The ther- reduce toxic effects. apeutic effect of radiotherapy is limited In the past decade, the rapid devel- by the hypoxic and necrotic region of the opment of nanomaterials has become a tumor. On the other hand, many promising powerful thrust for the advancement of therapeutic methods such as drug therapy, tumor treatment. Nanomaterials such as photothermal therapy, photodynamic ther- liposomes, metal particles, polymers and apy and immunotherapy are developing micelles are widely used as targeted deliv- rapidly. All of these treatments rely on ery carriers of therapeutic agents and play therapeutic agent such as chemotherapeu- important roles in the treatment of tum- tic agents, photosensitizers, and immuno- ors. Tumors are more permeable to nano- adjuvants to reach the tumor region and particles (NPs) than normal tissue due to BIOI 2020, Vol 1, No. 1, 25–36 25 https://bio-integration.org doi: 10.15212/bioi-2020-0008 BIOI 2020 the sifted vascular structure [2]. NPs can enter and remain nanobiohybrids that combine bacterial therapy with nano- in tumor tissue through leaky tumor blood vessels to exert technology can better realize treatment potential and reduce therapeutic roles. This phenomenon is called the enhanced their respective limitations, which may result in a new tar- permeability and retention (EPR) effect, which is the basic geted cancer therapy modality. In this review, we summarized Mini Review mechanism by which NPs deliver drugs to solid tumors [3]. the development of nanomaterial-based therapy. The mecha- Various nanomaterial-based treatments, including chemo- nism, advantages and research progress of bacteria-mediated therapy, photothermal therapy (PTT), photodynamic therapy tumor therapy were also described. Furthermore, different (PDT) and immunotherapy, have been proven to have good therapeutic strategies for nanobiohybrids based on bacteria tumoral inhibitory effects in preclinical studies. Despite and nanomaterials in cancer treatment were also discussed. the great success of nanomaterial-based cancer treatments Nanobiohybrids could improve the targeting of nanoma- in preclinical studies, many difficulties still remain in the terials and enhance the nanocatalytic reaction to achieve clinical application of nanomaterials [2]. Only a few nano- increasingly efficient cancer therapy. materials were able to reach the tumor compartment due to the poor permeation and retention in the tumor site, where the pathological microenvironment is characterized by high interstitial fluid pressures, acidity, hypoxia and immuno- suppression [4–6]. Therefore, it is still an important unmet Nanomaterial-mediated requirement to effectively improve the tumor targeting of therapeutic agent delivery nanomaterials. Recently, biological carriers such as cells, bacteria and Nanomaterials can have both the ability to diagnose and viruses have become the focus of tumor targeted ther- treat tumors based on their inherent physical and chemical apy due to their unique characteristics of active targeting. properties or the ability to load therapeutic agents or contrast Environmental sensing and autonomous propulsion abilities agents. The rapid development of nanotechnology has ena- are the basis for biological vectors to actively target tumor bled the integration of various therapeutic agents into NPs, regions, which are not possessed by nanoparticles. Among such as polymeric systems, micelles, silica-based porous them, bacteria-mediated tumor therapy is developed as a materials, and liposomes [11]. potential biologic therapy against tumors. The unique tumor Nanomaterials are widely used in the treatment of tumor microenvironment is an ideal breeding site for some fac- chemotherapy because of their high drug loading capacity, ultative and obligate anaerobic bacteria [7]. Bacteria such facile preparation and biological safety. Organic NPs are the as Bifidobacterium, Clostridium, Salmonella typhimurium most popular nanocarriers for drug delivery because of their (S. typhimurium) and Escherichia coli (E. coli) preferen- broad range of favorable properties such as biocompatibil- tially proliferate in the hypoxic, eutrophic and immuno- ity, biodegradability and flexibility. The first nanodelivery suppressive tumor tissue. Bacteria activate the suppressed system approved for cancer therapy was a liposome about immune function of the tumor microenvironment, and 100 nm in diameter that encapsulated doxorubicin (DOX). induce a strong immune response to inhibit tumor growth Nanomaterials passively accumulated in the tumor via the [8]. With the development of genetic engineering and syn- EPR effect to improve the pharmacokinetic and biolog- thetic biological technology, genetically engineered bacte- ical distribution of the encapsulated drug. Compared with ria can achieve targeted delivery of therapeutic drugs by free drugs, drug-loaded NPs demonstrated higher tumoral expressing special therapeutic proteins, such as cytotoxic accumulation and lower systemic toxicity. Other benefits drugs, antibodies, antigens, enzymes and cytokines [9]. As a of nanomedicine include specific binding of NPs with can- promising antitumor therapeutic carrier, bacteria can fill the cer cells, prolonged drug circulation, and controlled release gap in the treatment of hypoxia and necrotic areas of tum- kinetics [12]. ors. However, bacterial therapy is limited by dose depend- Many NPs which are currently under development ence toxicity in clinical trials. In order to ensure minimal focus on improving local drug concentration and the phar- toxicity and side effects, low bacterial injection volume is macokinetics of anti-tumor drugs through targeted mod- used, which leads to limited treatment effects. It is difficult ifications [13, 14]. One way to accomplish this is to have to achieve satisfactory tumor therapeutic effects by relying ligands attached to their surfaces,
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