Over 100 years! Bacterial cancer is reviving.

The 1966 film Fantastic Voyage tells the fantasy story of a group of scientists who are scaled down into a small submarine and then injected into a colleague's veins to remove deadly blood clots from their brainsThis classic film is one of many imaginative creatures of the past few decadesAt the same time, scientists have been working to make a similar idea a reality: to create tiny robots that can roam the human body to detect and treat diseasesAlthough nanomotors and autonomous navigation on-board computing systems are still fictitious materials, researchers have designed and built a number of micro-nanosystems for diagnostic and therapeutic applications, especially in cancer, which can be considered early prototypes of nanorobotsSince 1995, the FDA has approved more than 50 nanodrugs (largely a nanodevice containing the drug)Such drugs can be called nanobots if they have one or more robot characteristics, such as sensing, on-board computing, navigation, or self-supplyThey are directed or prioritized to the tumor site and are released only under certain trigger conditionsthe first approved nanodrug was doxil®, a liposome nanoshell that carries the chemotherapy drug amycinIntravenous nanoshells are preferred to accumulate in tumors and slowly release the drug over timeIn this sense, the basic form of nanorobots has been used clinicallyscientists can improve tumor targeting by controlling the shape, size and composition of nanoparticles, while newer systems use strategies that specifically identify cancer cellsStill, accurate tumor location is the "holy grail" of nano-robot developmenta meta-analysis in 2016 assessed the effectiveness of nano-delivery vehicles tested in animal studies over the past 10 years, and found that the median number of nano-delivery vehicles that actually reached the tumor site was less than 1%, which could only be slightly improved by active targeting mechanisms such as surface modification of specific antibodies or peptides to bind to tumor-specific receptorshow canmake these nanobots better direct themselves to the tumor site? Wireless energy transmission remains a huge challenge, and nanoscale batteries are inefficientResearchers have used external forces such as ultrasound or magnetic fields to promote the accumulation of nanodrugs into tumor tissue, but the fluid dynamics of the circulatory system have an effect on nano-transmission tools, which may travel in the liquid environment of the vascular system as if they were moving in honeybut as always, nature may have a solution: bacteria Microbes can be driven by spiral-shaped molecular motors that rotate cilia or whiplash, an effective propulsion mechanism that has stimulated the interest of many nanobotists trying to mimic this function For example, researchers have created a spiral-shaped magnetic swimming robot that can rotate forward under the action of a rotating magnetic field But bacteria are not just a good example of swimming, some bacteria are therapeutic in themselves In addition, microorganisms can sense biochemical signals and adjust their trajectories accordingly, similar to the envisaged on-board calculations the idea of using bacteria to treat cancer is not new One of the first reports of bacteria as a treatment for cancer came from immunotherapy pioneer William Coley, who realized in the late 19th century that some cancer patients with skin infections were more likely to get better He began injecting bacterial toxins, hot inactivated microbes, and even streptococcus live cultures into patients with incapacitated bone and soft tissue cancers, often relieving symptoms This is a bold approach, as these bacterial preparations can cause uncontrollable infections before antibiotics are widely used To a large extent, the clinical application of bacteria as a cancer treatment drug has not developed because of this danger and the rise of radiotherapy and chemotherapy Today, the idea is being revived William Coley (Photo: The Scientist) a fusion of everything from biology and chemistry to materials science, engineering and computer science, opening up new avenues for the development of cancer bacterial therapies anti-cancer-carrying bacteria
kamyum, a detoxified live seedling, commonly used to prevent tuberculosis, has been reapplied to localtreatment of bladder cancer over the past few decades The rationale behind this approach is similar to Coley's hypothesis that it fights cancer by injecting the patient with bacteria that stimulates the patient's immune system even more encouraging is that, despite Coley's knowledge, many bacteria can selectively grow in solid tumors, bladders and elsewhere This is because the tumor's hypoxia and acidic environment have reduced immune monitoring, providing a safe haven for the growth and reproduction of anaerobic bacteria Inside the tumor, some bacteria produce toxins and compete with cancer cells for nutrients Eventually, the build-up of bacteria in the tumor induces immune cell immersion, which in turn leads to an anti-cancer response However, despite testing many naturally occurring and laboratory-made bacterial strains in animal models of cancer, and human trials of bacteria to treat cancer, the researchers observed little effect other than the benefits observed in patients with bladder cancer therefore, the field has shifted to genetic design of bacteria to serve as a recombinant drug carrier Selective targeting and subsequent growth of bacteria in tumors, as well as local therapies promoted by microorganisms themselves, can minimize collateral damage to healthy cells common in systemic cancer treatment Some research groups have modified bacteria to produce a variety of substances, including anti-cancer toxins, cytokines and apoptotic inducing factors The production of potentially toxic therapeutic drugs means that bacteria must be further controlled to prevent them from "landing" where they should not be As a result, researchers are now moving toward designing the next generation of bacterial systems to sense physiological signals and respond by making therapeutic drugs at local disease sites Image source: The Scientist to help achieve this goal, the field of synthetic biology has developed a set of gene circuits to control microbial behavior over the past two decades These circuits consist of positive and negative feedback bases to regulate dynamic cell function and act as a tool for switching switches, oscillators, counters, biosensors, and recorders that have been used by researchers to design anti-cancer microorganisms an example of gene control for anticancer bacteria, Jeff Hasty's team at the University of California, San Diego, in collaboration with the Sangeeta Bhatia Laboratory at the Massachusetts Institute of Technology, developed the "Synchronous Lysis Circuit" in 2016 In this circuit, the bacteria are positioned in the tumor and grow to a critical density, which then bursts synchronously, releasing the therapeutic compounds it produces This approach takes advantage of bacterial population sensing, as bacteria reach critical density only within tumors, which self-destruct and release their therapeutic drugs, leading to a reduction in microbial populations that prevent uncontrolled growth of tumors or bacteria elsewhere bacterial bomb (Photo: The Scientist) several research groups have developed this method In 2019, for example, scientists created a bacterium that produces molecules that block immune checkpoints, such as CD47 or PD-L1, that typically suppress immune cells, thereby reducing antitumor activity By blocking these pathways in tumors, bacteria can stimulate T cells in mouse models of lymphoma and promote tumor removal Most surprisingly, untreated tumors in treated animals also shrink, suggesting that local treatments may trigger long-lasting far-end anti-tumor immunity 's use of bacteria to treat cancer is beginning to attract the attention of biotech companies A company called BioMed Valley Discoveries has been experimenting with injections of specialized anaerobic clostium novyi NT spores in several clinical trials According to a 2014 report, the treatment showed precise, powerful and repeatable anti-tumor responses in rats, dogs and the first patient another company, Synlogic, is developing injecting bacteria into the tumor, which is designed to produce a interferon gene stimulator (STImulator of INterferon Genes, STING) that acts as an innate immunoactivizer These bacteria are penetrated into the antigen-transmitting cells in the tumor, where they activate the STING pathway, leading to interferon release and tumor-specific T-cell response Relevant Phase I clinical trials are under way to assess the therapeutic effect of the treatment on refractory solid tumors, as well as in combination with checkpoint inhibitors these trial results will help guide further innovations in the safety and efficacy of engineered bacterial cancer therapies For example, these studies will reveal not only the therapeutic effect, but also the level and distribution of bacteria in a patient's tumor, shedding, and the stability of genetic modification over time These factors are currently only studied in detail in mouse models, and once the principles are validated in humans, they can greatly contribute to the establishment of the best bacterial strains, effective loads (drugs), circuits, and appropriate clinical environments for the use of these therapies remotely guide bacteria to tumors
Although researchers are successfully modifying bacteria to carry or produce anti-cancer compounds, less than 1% of these microbes reach the tumor on their own Since most tumors cannot be reached by direct injection, clinicians need to be able to effectively direct bacterial therapies to the tumor site, where they can reliably and controlally release the drugs they encode this is where synthetic biology is influenced by the principles of micro-robots E coli, for example, can be modified using the genes of marine microorganisms to perceive and utilize light energy In 2018, Jochen Arlt of the University of Edinburgh and colleagues demonstrated that the modified E coli could be guided by a space-mode light field In response to the light, the bacteria move to a specific location, track their location, and inform the next light source input to guide them along a predetermined path In the same year , scientists at Wuhan University in China used light to enhance the metabolic activity of E coli by attaching semiconductor nanomaterials to the surface of bacteria and producing photoelectrons under light, triggering a reaction with the bacteria's endogenous nitrate molecules, increasing the formation and secretion of nitric oxide in the form of cytotoxicity by 37 times In mouse models, the therapy reduced tumor growth by 80% image source: The Scientist Although light-touch navigation and control have great potential, the limited capacity of light penetration tissue has hindered the development of this approach One form of use of a wider range of external energy is ultrasound, which has a long-term application for medical diagnosis and monitoring recently, gas-containing microbubbles have been used to enhance the contrast of tissue ultrasound images due to their strong and obvious acoustic response Special forms of high-power focused ultrasound are used in treatment to advance the nanobubbles that fill the drug deep in tumor tissue by using acoustic pressure waves as external energy This method has achieved particularly promising results in glioblastoma, where drugs are particularly difficult to overcome the blood-brain barrier image source: The Scientist other common external energy sources that can be applied safely and remotely to the human body are magnetic fields Although magnetic resonance imaging systems have been used clinically for decades, the development of magnetic navigation and control systems is still quite new So far, researchers have applied this method to magnetic catheter guidance in high-precision surgery The most famous example is from St Louis's NIOBE system based on stereotactic cardiac arrhythmia therapy The tip of a magnetic catheter moves precisely along abnormal heart tissue, accompanied by electrical impulses to heat or cool the device to remove invalid cells use similar magnetic instruments to guide bacteria in the context of cancer treatment, which was proposed by scientists who study magnetic bacteria In the 1970s, Richard Blakemore of the Woods Hole Oceanographic Institution in Massachusetts first discovered that marine microbes could naturally synthesize iron oxide nanoparticles wrapped in lipid shells, a trait that has evolved to help them navigate the water by sensing the Earth's magnetic field About 40 years , Sylvain Martel of polygent's Mandr?al Nanorobotics Laboratory and his colleagues combined these magnetometers with the Doxil ® Martel's team also took advantage of the low-oxygen environment of the tumor to become anaerobic host, combining this natural nesting mechanism with an external directional magnetic field to find an increased build-up and permeability of the therapy in mouse tumors image source: The Scientist Although the use of this magnetic species in the human body may appear in the coming decades, coding magnetic induction in other, more clinically transformative or tested bacteria may be achievable in the near future Some of the proteins involved in the complex biomineralization process of forming magnetic compounds in magnetized bacteria have been identified, and in a preprint edging published earlier this year, researchers reported that engineered E coli forms magnetite particles and controls them through external magnetic fields another way to keep non-magnetic bacteria under magnetic control is simply to attach magnetic material to the bacteria Researchers have combined one or more bacterial strains with magnetic or nanoparticles When exposed to an external magnetic field, these magnetic particles are oriented with the magnetic field, and the bacteria are directed, and then the bacteria move in that direction 2017, Metin Sitti and colleagues at the Max Planck Institute for Intelligent Systems in Stuttgart, Germany, attached E coli to particles made up of the chemotherapy drug amycin and tiny magnetic nanoparticles Using cancer cells in a petri dish, the researchers demonstrated that they could use magnets to remotely control these drug-carrying bacterial robots to improve the targeting of tumor cells in any case, genetically engineered bacteria triggered, controlled and guided by external energy sources are an attractive new direction in the field Driven by a fusion of synthetic biology, mechanical engineering and robotics, these new approaches may bring us closer to the wonderful vision of creating micro-robots that can find and eliminate multiple types of cancer References: 1 s Bacteria as Living Microrobots to Fight Cancer (Source: The Scientist)