Researchers at Université de Montréal, Polytechnique Montréal, and McGill University have developed a new way to carry anti-cancer drugs to a target site in the body – using bacteria. The technique (recently featured on Medgadget) involves using bacteria covered with anti-cancer drugs. The bacteria also contain magnetic iron oxide crystals and can be injected into the bloodstream like any other drug, but can then be guided specifically to the tumor using a magnetic field. Once there, the bacteria are attracted to areas of the tumor that traditional cancer drugs find difficult to penetrate. These hard to reach places are called hypoxic regions, and arise because tumors possess areas of poor blood flow. Since one of the major limitations of anti-cancer drugs delivered in the blood stream is that they can’t easily penetrate the hypoxic regions of tumors, this technology could be a leap forward in cancer targeting.
Medgadget had the opportunity to ask the senior author on the study, published in Nature Nanotechnology, Professor Sylvain Martel of Polytechnique Montréal, some questions about the research.
Conn Hastings, Medgadget: The bacteria used in this study are attracted to and tend to stay in hypoxic regions. Was this the main motivation for using this live therapeutic payload?
Prof. Sylvain Martel, Polytechnique Montréal: In their natural environment, these specific bacteria have an internal chain of magnetic nanoparticles that acts like a microscopic compass needle. They use this microscopic compass to swim in the direction of the geomagnetic field to help them go deeper, in order to more effectively find regions of low oxygen concentration. They seek these regions of low oxygen concentration because they are microaerophilic, meaning that they survive in a low-oxygen environment. Luckily, the level of oxygen that they seek corresponds to the oxygen concentrations at regions of fast duplicating cancer cells inside tumors, which are also believed to be the sources of tumor metastasis.
So, for this approach, we attached the therapeutic drug payload to the bacteria, and used a special platform to create a magnetic field directed towards the tumor to indicate its location to the bacteria so that they can swim towards it. When the bacteria reach the tumor, we make sure that the magnetic field is null so that the bacteria will rely on their oxygen sensors instead of the magnetic field. The bacteria then seek the hypoxic areas of the tumor that correspond to the regions of active cancer cells (fast duplicating cells), delivering their drug payload to the areas of the tumor which need it most.
Medgadget: How did you conceive of this strategy?
Prof. Martel: We could not build microscopic nanorobots as sophisticated as these bacteria, with all their sensors, propulsion systems, etc. and with an overall size sufficiently small to penetrate inside a tumor. Therefore, the strategy that we adopted was to find bacteria that would have the right size with the characteristics and functionalities required to deliver therapeutic payloads to hypoxic regions in tumors. We needed to find a way to harness them to behave as futuristic artificial nanorobots that are currently well beyond technological feasibility.
Medgadget: Why is there a need for two targeting mechanisms, magnetic fields and the attraction to hypoxia?
Prof. Martel: Because we can visualize the tumor and then know its location with regards to the injection point. But we cannot know the exact location of the hypoxic regions inside the tumor. To achieve maximum therapeutic efficacy, we must target these hypoxic regions, and that requires two targeting mechanisms. The first mechanism relies on magnetotaxis, where a directional magnetic field indicates the location of the tumor to the bacteria. If we used only magnetotaxis, then the tumor would be targeted but not necessarily the hypoxic zones. The magnetotaxis method allows the bacteria to come sufficiently close for them to detect the change in oxygen levels inside the tumor. When the bacteria are inside the tumor, magnetotaxis is switched off and they rely on oxygen concentrations to find the hypoxic zones. The latter aerotactic targeting happens autonomously, and requires that the bacteria are already close to the tumor, and so would not be as effective if used alone without magnetotactic targeting.
Medgadget: Are there any potential safety issues associated with delivering these bacteria into the bloodstream? Could they cause sepsis or blood clots?
Prof. Martel: We are more concerned about immune system responses. Safety is certainly a big issue. We have performed extensive tests in rats and mice to assess potential safety issues and everything looks very promising so far for future application in humans. However, before we can proceed to human trials, more safety tests need to be performed using animal models that are closer to humans, such as those with primates. This is our next step in safety tests.
Medgadget: Has anyone previously attempted to deliver bacteria directly into the bloodstream to produce a therapeutic effect?
Prof. Martel: Yes, bacteria have been injected in humans before but the results were not very encouraging since they were swimming without any guidance in terms of the location of the tumor. The targeting sophistication of these previous approaches was relatively low. In our case, the high targeting ratio obtained with a good delivery approach is the key to success and differentiates us from previous attempts.
Medgadget: Could the technique be used to deliver drugs to treat other disease states involving hypoxic tissues, such as the heart following a heart attack, or the brain following a stroke?
Prof. Martel: Potentially yes, in some cases it would need to be complemented with other techniques that we have developed in our laboratory, such as the use of a clinical MRI (Magnetic Resonance Imaging) scanner to visualize larger blood vessels and for delivery to the brain, our recent technique using magnetic nanoparticles combined with hyperthermia could be useful.
Related study in Nature Nanotechnology: Magneto-aerotactic bacteria deliver drug-containing nanoliposomes to tumour hypoxic regions…