bims-mricoa 2023-04-02 papers

Issue of 2023–04–02
five papers selected by
Merve Yavuz, Bilkent University

Acta Pharm Sin B. 2023 Mar;13(3): 1014-1027

Recent advances in bacterial therapeutics based on sense and response.

Zhuo Feng, Yuchen Wang, Haiheng Xu, Yunfei Guo, Wen Xia, Chenxuan Zhao, Xiaozhi Zhao, Jinhui Wu.

Intelligent drug delivery is a promising strategy for cancer therapies. In recent years, with the rapid development of synthetic biology, some properties of bacteria, such as gene operability, excellent tumor colonization ability, and host-independent structure, make them ideal intelligent drug carriers and have attracted extensive attention. By implanting condition-responsive elements or gene circuits into bacteria, they can synthesize or release drugs by sensing stimuli. Therefore, compared with traditional drug delivery, the usage of bacteria for drug loading has better targeting ability and controllability, and can cope with the complex delivery environment of the body to achieve the intelligent delivery of drugs. This review mainly introduces the development of bacterial-based drug delivery carriers, including mechanisms of bacterial targeting to tumor colonization, gene deletions or mutations, environment-responsive elements, and gene circuits. Meanwhile, we summarize the challenges and prospects faced by bacteria in clinical research, and hope to provide ideas for clinical translation.

Keywords: Bacterial drug delivery system; Cancer therapy; Gene circuits; Intelligential delivery; Responsive elements; Synthetic biology

DOI: https://doi.org/10.1016/j.apsb.2022.09.015

J Mater Chem B. 2023 Mar 31.

Ultrasmall superparamagnetic iron oxide nanoparticles for enhanced tumor penetration.

Xue Feng, Yuxiang Xue, Sevil Gonca, Kunlang Ji, Mei Zhang, Francisco R García-García, Quan Li, Yi Huang, Konstantin V Kamenev, Xianfeng Chen.

The intrinsic pathological characteristics of tumor microenvironments restrict the deep penetration of nanomedicines by passive diffusion. Magnetophoresis is a promising strategy to improve the tumor penetration of nanomedicines aided by the external magnetic propulsive force. However, the research thus far has been focused on large nanoparticles, while ultrasmall superparamagnetic iron oxide (Fe3O4) nanoparticles (<∼20 nm) exhibit better performance in many applications such as cancer diagnosis and treatment. Herein, we aim to determine and understand the penetration of ultrasmall Fe3O4 nanoparticles with various sizes, shapes, surface charges and magnetizations in a 3D tumor spheroid model. The behaviour of the nanoparticles of three sizes (10, 15 and 21 nm), two shapes (spherical and octahedral), and opposite surface charges (negative and positive) was investigated. The results demonstrate that magnetically directed penetration works effectively on ultrasmall Fe3O4 nanoparticles. In the absence of a magnetic field, the shape and the surface charge of the ultrasmall magnetic nanoparticles have a more pronounced effect on their penetration compared to their dimensions. While in the presence of a magnetic field, the advantage of larger magnetic nanoparticles was obvious because they experience higher magnetic driving force due to their higher magnetic moments. Overall, relatively large (21 nm), spherical, and positively charged ultrasmall Fe3O4 nanoparticles showed greater penetration in tumors under a magnetic field. Furthermore, our findings suggest that the penetration efficiency of Fe3O4 nanoparticles is closely related to their cellular internalization ability. Therefore, optimization of the cellular uptake and of the magnetization of magnetic nanoparticles should be considered simultaneously for maximizing their penetration in tumor tissue through magnetophoresis.

DOI: https://doi.org/10.1039/d2tb02630a

Biotechnol Adv. 2023 Mar 26. pii: S0734-9750(23)00049-6. [Epub ahead of print] 108142

Synthetic bacterial therapies for intestinal diseases based on quorum- sensing circuits.

Zhuoce Dang, Mengxue Gao, Lina Wang, Jiahao Wu, Yufei Guo, Zhixin Zhu, He Huang, Guangbo Kang.

Bacterial therapy has become a key strategy against intestinal infectious diseases in recent years. Moreover, regulating the gut microbiota through traditional fecal microbiota transplantation and supplementation of probiotics faces controllability, efficacy, and safety challenges. The infiltration and emergence of synthetic biology and microbiome provide an operational and safe treatment platform for live bacterial biotherapies. Synthetic bacterial therapy can artificially manipulate bacteria to produce and deliver therapeutic drug molecules. This method has the advantages of solid controllability, low toxicity, strong therapeutic effects, and easy operation. As an essential tool for dynamic regulation in synthetic biology, quorum sensing (QS) has been widely used for designing complex genetic circuits to control the behavior of bacterial populations and achieve predefined goals. Therefore, QS-based synthetic bacterial therapy might become a new direction for the treatment of diseases. The pre-programmed QS genetic circuit can achieve a controllable production of therapeutic drugs on particular ecological niches by sensing specific signals released from the digestive system in pathological conditions, thereby realizing the integration of diagnosis and treatment. Based on this as well as the modular idea of synthetic biology, QS-based synthetic bacterial therapies are divided into an environmental signal sensing module (senses gut disease physiological signals), a therapeutic molecule producing module (plays a therapeutic role against diseases), and a population behavior regulating module (QS system). This review article summarized the structure and function of these three modules and discussed the rational design of QS gene circuits as a novel intervention strategy for intestinal diseases. Moreover, the application prospects of QS-based synthetic bacterial therapy were summarized. Finally, the challenges faced by these methods were analyzed to make the targeted recommendations for developing a successful therapeutic strategy for intestinal diseases.

Keywords: Gene module; Intestinal diseases; Quorum sensing; Synthetic bacterial therapy

DOI: https://doi.org/10.1016/j.biotechadv.2023.108142

Colloids Surf B Biointerfaces. 2023 Mar 23. pii: S0927-7765(23)00155-8. [Epub ahead of print]225 113277

Probiotic Escherichia coli Nissle 1917 propelled micro-robot with pH sensitivity for hypoxia targeted intestinal tumor therapy.

Ting Wang, Qiong Yin, Hao Yang Huang, Zhenyu Wang, Haixing Song, Xiaoming Luo.

Poor drug penetration in hypoxia area of solid tumor is a big challenge for intestinal tumor therapy and thus it is crucial to develop an effective strategy to overcome this challenge. Compared with other bacteria used for construction of hypoxia targeted bacteria micro-robot, the Escherichia coli Nissle 1917 (EcN) bacteria are nonpathogenic Gram-negative probiotic and can especially target and identify the signal molecules in the hypoxic region of tumor, and thus, in this study, we choose EcN to construct a bacteria propelled micro-robot for targeting intestinal tumor therapy. Firstly, the MSNs@DOX with average diameter of 200 nm were synthesized and conjugated with EcN bacteria using EDC/NHS chemical crosslinking method to construct a EcN propelled micro-robot. The motility of micro-robot was then evaluated and the motion velocity of EcN-pMSNs@DOX was 3.78 µm/s. Compared with pMSNs@DOX without EcN driven, EcN bacteria propelled micro-robot transported much more pMSNs@DOX into the inner of HCT-116 3D multicellular tumor spheroids. However, the EcN bacteria are non-intracelluar bacteria which lead to the micro-robot can not directly enter into tumor cells. Therefore, we utilized acid-labile linkers of cis-aconitic amido bone to link EcN with MSNs@DOX nanoparticles to achieve the pH sensitive separation of EcN with MSNs@DOX from the micro-robot. At 4 h of incubation, the isolated MSNs@DOX began to enter into the tumor cells through CLSM observation. In vitro live/dead staining results show that EcN-pMSNs@DOX induced much more cell death than pMSNs@DOX at 24 and 48 h of incubation with HCT-116 tumor cells in acid culture media (pH 5.3). For the validation of the therapeutic efficacy of the micro-robot for intestinal tumor, we established the HCT-116 subcutaneous transplantation tumor model. After 28 days of treatment, EcN-pMSNs@DOX dramatically inhibit tumor growth with tumor volume was around 689 mm3, induce much more tumor tissues necrosis and apoptosis. Finally, the toxicity of this micro-robot was investigated by pathological analysis the liver and heart tissues. We expect that the pH sensitive EcN propelled micro-robot here we constructed may be a safe and feasible strategy for intestinal tumor therapy.

Keywords: Escherichia coli Nissle 1917(EcN); Hypoxia targeting; Micro-robot; Tumor treatment; pH sensitive

DOI: https://doi.org/10.1016/j.colsurfb.2023.113277

Front Cell Infect Microbiol. 2023 ;13 1120995

A comprehensive review of the application of probiotics and postbiotics in oral health.

Aziz Homayouni Rad, Hadi Pourjafar, Esmaeel Mirzakhani.

Oral diseases are among the most common diseases around the world that people usually suffer from during their lifetime. Tooth decay is a multifactorial disease, and the composition of oral microbiota is a critical factor in its development. Also, Streptococcus mutans is considered the most important caries-causing species. It is expected that probiotics, as they adjust the intestinal microbiota and reduce the number of pathogenic bacteria in the human intestine, can exert their health-giving effects, especially the anti-pathogenic effect, in the oral cavity, which is part of the human gastrointestinal tract. Therefore, numerous in vitro and in vivo studies have been conducted on the role of probiotics in the prevention of tooth decay. In this review, while investigating the effect of different strains of probiotics Lactobacillus and Bifidobacteria on oral diseases, including dental caries, candida yeast infections, periodontal diseases, and halitosis, we have also discussed postbiotics as novel non-living biological compounds derived from probiotics.

Keywords: dental caries; functional foods; microbiome; microbiota; postbiotic; probiotic; tooth decay

DOI: https://doi.org/10.3389/fcimb.2023.1120995