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trojan horse

Tiny robots can now smuggle drugs into brain tumors

The future of cancer treatment may be robot-delivered.

Jay Sprogell / GIPHY

The future of medicine is going to be hand-delivered — but not by mail carriers. Instead, life-saving drugs will be parceled, smuggled, and transported in the body via tiny, self-propelled microbots.

In a study published Wednesday in the journal Science Robotics, a research team in China designed a new kind of bio-hybrid microbot that uses clever biological disguises to get even closer to the source of disease in the body in order to provide the most targeted (and effective) treatment.

The target of choice? Hard to treat illness epicenters like brain tumors.

What’s new — Tiny microbots are nothing new. The same goes for disguising a robot as a bacteria or using magnets to move them through the bloodstream. But what makes this microbot design stand apart from the crowd is that it can cross one of the body’s toughest biological barriers: the blood-brain barrier (BBB.)

Designed to keep pathogens out and nutrients in, it has historically been difficult for microbots (which the body often recognizes as a foreign invader) to pass this last line of defense and get closer to potential tumors beyond it.

Zhiguang Wu, an author on the study and a professor at the Harbin Institute of Technology focusing on nanotechnology, says that the new microbots can overcome obstacles that have hindered many more conventional lines of medical treatment.

“Such passive diffusion suffers from the long diffusion time, ineffectiveness, and block of biological barriers, which could result in strong side effects,” Wu tells Inverse. “The swimming micro/nanorobots, able to navigate into hard-to-reach tissues utilizing their active propulsion, hold considerable expectations for loading various drugs and actively swim toward the diseased sites for targeted drug transportation.”

Using a Trojan Horse approach, the team disguised their drug delivery microbot as a white blood cell to sneak by the body’s blood-brain barrier.Zhang et al., Sci Robot. 6, eaaz9519 (2021)

Why it matters — When it comes to fighting off cancer, the more targeted the treatment the better. This is especially true when it comes to glioblastomas, or brain tumors. Because of the delicate location in the brain and the strong defense of the BBB, drug treatment can be difficult, and removing the tumor can require dangerous brain surgery. Even then, often only 90 percent of the tumor can actually be removed.

Using self-propelled, drug-delivering microbots like these could open a door for scientists to get even more up close and personal when treating tumors than pills or injections have previously allowed — all while being minimally invasive.

Here’s the background — Previous microbots drew inspiration from the way a microbe or sperm moves through the body. Light, acoustics, and magnetic fields have all been used to propel them along an animal host’s body. Through this, a wide range of biomedical tasks can be accomplished, including cutting a cell membrane, retaining delivered drugs in the gastrointestinal tract, and delivering drugs via an eye-dropper.

But even though researchers have more control over the movement of these microbots than they do typical drugs in the body, most microbot designs have still faced a big obstacle: the body's immune system.

To move their neutrobots through the body, the team used a rotating magnetic field to propel the bots through the mouse’s bloodstream.Zhang et al., Sci Robot. 6, eaaz9519 (2021)

The BBB is one of the body's toughest lines of defense. Like a stone battlement surrounding a castle, the BBB is an incredibly selective, semi-permeable defense layer that allows nutrients, like oxygen or even caffeine molecules, to flow into the brain while keeping pathogens out.

In order to spoof the BBB’s defense systems, the team set out to design a Trojan Horse-like microbot that would rely on some biological camouflage to sneak through the barrier undetected.

What they did — To disguise their microbots, the team took a three-pronged approach:

  • Creating a drug-loaded, magnetic nanogel to act as the base of their drug-delivery microbot
  • Coating his nanogel-bot in an E. coli membrane to make it look like an especially dangerous, foreign threat
  • Exposing their coated nanogel to a neutrophil — a type of white blood cell that fights infection — so that their microbot would be gobbled up and hidden inside enemy ranks

And voila, the microbot masquerading as E. coli, masquerading as a neutrophil was born. Appropriately, the team dubbed it a “neutrobot.”

To test out how well these neutrobots would actually perform, the team used a mouse brain tumor model. The nanogels were loaded up with the cancer drug paclitaxel, and the entire neutrobot contraption was injected into the mouse via its tail.

In order to control the movement of the neutrobots, the mouse was housed within a rotating magnetic field.

With fine-tuning of the surrounding magnetic field, the team can precisely control the movement of their neutrobots. Zhang et al., Sci Robot. 6, eaaz9519 (2021)

“By combining the capabilities of real-time position tracking, autonomous path planning, and vision-based feedback, our system enables self-navigation of neutrobots along a programmed path,” write the authors.

In their trials, the team reports that their neutrobots were able to successfully navigate and even permeate the mouse’s BBB in order to reach and deliver drugs to its brain tumors.

What’s next — But despite these successes, there’s still much left to be done before such a treatment could be used in humans as well.

One problem to still be overcome, explain the authors, is how to keep a better eye on the individual neutrobots as they make their way through the body. Right now MRI and fluorescence imaging can track groups of the neutrobots as they move, but not individuals.

In the future, working to improve real-time, in-body imaging systems will be essential for improving the dynamic movement of these tumor-targeting bots, write the authors.

“Our research has verified the treatment of the neutrobots can extend the survival time of glioma-bearing mice,” Wu says. “So it may not too long to translate the micro/nanorobots stories in science fiction into the reality.”

Abstract: Swimming biohybrid microsized robots (e.g., bacteria- or sperm-driven microrobots) with self-propelling and navigating capabilities have become an exciting field of research, thanks to their controllable locomotion in hard-to-reach areas of the body for noninvasive drug delivery and treatment. However, current cell-based microrobots are susceptible to immune attack and clearance upon entering the body. Here, we report a neutrophil-based microrobot (“neutrobot”) that can actively deliver cargo to malignant glioma in vivo. The neutrobots are constructed through the phagocytosis of Escherichia coli membrane-enveloped, drug-loaded magnetic nanogels by natural neutrophils, where the E. coli membrane camouflaging enhances the efficiency of phagocytosis and also prevents drug leakage inside the neutrophils. With controllable intravascular movement upon exposure to a rotating magnetic field, the neutrobots could autonomously aggregate in the brain and subsequently cross the blood-brain barrier through the positive chemotactic motion of neutrobots along the gradient of inflammatory factors. The use of such dual-responsive neutrobots for targeted drug delivery substantially inhibits the proliferation of tumor cells compared with traditional drug injection. Inheriting the biological characteristics and functions of natural neutrophils that current artificial microrobots cannot match, the neutrobots developed in this study provide a promising pathway to precision biomedicine in the future.
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