Who knew that idea of shrinking people into a microbe size in the science fiction movie to fight disease will become a near reality with the advent of micro/nano bots. In the movie based on Isaac Asimov's novel, a submarine was shrunk to the size of a microbe and injected into a scientist's brain to cure a life-threatening clot. Fantastic Voyage (1966) Something similar is a practical reality today thanks to microbes and synthetic biology. Biological microbes ( ) are attached to cargo-carrying apparatus and could deliver disease-fighting drugs, attack tumors, or perform other helpful functions. micro/nano bots Introduction to Targeted Drug Delivery Targeted drug delivery (TDD) is one the most popular healthcare applications of the Internet of Bio-Nano Things. TDD is the process of carrying the drug directly to the diseased organ and releasing it at that site (tumor tissue) only locally. Targeted drug delivery is primarily effective in cancer patients when other medical procedures like taking pills orally, injections, and chemotherapy procedures have potential side effects on healthy cells of the body. Targeted drug delivery aims to protect healthy cells of the body by only targeting tumor cells by providing localized medicine on the tumor site only. Nanotechnology for Targeted Drug Delivery Research in is playing an important role in realizing TDD, as it enables (1-100nm) to traverse the cardiovascular system of the body and reach the tumor site through blood vessels. is an edge to many therapeutic applications as nanorobots can reach hard-to-access areas like deep inside human tissue. Nanomedicine nanorobots The nanosize The blood vessels around the body provide a well-founded casing for blood cells to ensure blood does not leak into other parts of the body. However, blood vessels around the tumor site have tiny holes which allow only nano-sized particles to enter the tumor site and target tumor cells through . In TDD drugs are encapsulated inside the nanomachines which traverse the blood vessel network. ligand-receptor phenomena Nanotechnology-based delivery systems are making a significant impact on cancer treatment and the polymers play a key role in the development of nanoparticulate carriers for cancer therapy. These nanomachines are fabricated with biological material so that they are bio-compatible for the human body. For a successful TDD in cancer patients, nanobots can be programmed in a way that they carry drugs directly to the tumor site. A bacterial bot can be coated with a material (e.g., Streptavidin) that has a high affinity with biotin, which is a vitamin found in abundance at tumor tissue. This way the bacteria/nano bot will find its way to the tumor site. Internet of Bio Nano Things for Targeted Drug Delivery (IoBNT) systems comprise biological nanonetworks that sense biological and chemical changes in the environment (i.e., human body) and send the collected data over the Internet to data centers for further processing. Internet of Bio-Nano Things In an Internet-enabled TDD medical scenario, a cancer patient is injected with therapeutic nanodevices. The actions of injected therapeutic devices are continuously monitored by healthcare providers remotely through the internet. The health care provider can interact with the therapeutic devices in two ways: He can send commands to release the regulated amount of drug dose at the targeted site. He receives the biological parameters of the body sent by these nanodevices. The therapeutic devices traverse the blood vessel network and reach the targeted site, due to high-affinity nanodevices being anchored at the site. TDD in IoBNT can be performed through in two ways Active transport and passive transport. Active transport in molecular communication for TDD has usually been realized through the use of molecular motors and bacteria. While passive transport can be done through a particle diffusion-based approach with or without drift. Molecular Communication (MC) To present a proof-of-concept of TDD, researchers present a that presents a profile of physiological parameters of the body. cardiovascular system model After analyzing the body profile, this model can be employed to make the drug delivery more efficient by identifying injection points to get maximized treatment benefits while minimizing the drug effects on other parts of the body. The aim is to control and monitor the drug release amount from the initial release. Apart from monitoring and control of drugs through feedback messages and other mechanisms, real-time monitoring is also very important, where nanomachines can make decisions by sensing the concentration of molecules. The nanosensors can even send messages to external sources (healthcare providers) if the concentration of drug molecules increases the threshold value. The three main functions an IoBNT based TDD system performs are and . delivery, monitoring, control 1. Delivery Drug delivery is the process of releasing drugs into the target site. The process of drug delivery is performed by complex proteins called liposomes. Liposomes have the characteristics of targeting, long circulation, and stimuli responsiveness. The drug contained inside liposomes is in the form of specific molecules and can be released only upon pH, and light. These liposomes are used as drug delivery nanomachines in healthcare applications Internet of Bio-nano things. external stimulation from factors like temperature, Drug delivery can be performed systematically, where the drug delivery system is configured to regulate the amount of drug or localized where real-time monitoring and control to regulate the amount of drug release is performed. Localized drug delivery requires other entities like monitoring and control nodes, to ensure real-time control of drug release. Targeted Drug Delivery model In the above image, DD is the drug delivery nanomachine. The red particles are drug molecules traveling towards the target site. MN is the monitoring nano node that emits molecules (colored blue) towards DD to send dosage regulation signals. CN is the control nanomachine that is in charge of starting and terminating the drug release process by emitting specific molecules (colored green) towards DD. 2. Monitoring Once the drug is released in the case of a localized drug delivery system, the dosage amount must be regulated by other entities (nanosensors, nano actuators). Specialized nanomachines are assigned the task of monitoring the concentration level of the drug, and taking appropriate actions upon sensing the increased amount of drug after evaluating the MC channel. An excessive amount of drug must be avoided due to its possible side effects and to avoid drug wastage which happens during . receiver/channel congestion 3. Control The control node is responsible for starting the drug release and is in charge of terminating the drug release operation in case of specific local conditions. The control node is an actuator that can be deployed as part of a monitoring node or can be implemented as a separate node depending upon application requirements. This node can send feedback messages by releasing specific molecules different from drug molecules to update the external entities (healthcare providers) about the abnormal rate of drug release. The monitoring and control nodes used for TDD application are genetically engineered biological cells, bacterium, or artificial cells. The nano sensing devices must have high sensitivity for detecting specific molecules and must be able to respond by emitting certain molecules. Such nanosensors can be designed using whole-cell or sensor molecules captured in a chemically inert matrix. Wrapping up Although the TDD technology seems promising, there are some shortcomings to it. Firstly, there is an issue of bioethics and phagocytosis. There is a possibility that the inherent immune system might attack the drug carrying microbots, thinking of them as invaders and eat(eliminate) them up. To cater to this, the design of these bots has to be envisioned in a way that the immune system doesn't treat these drug carriers as invaders. To this aim, these bots can be coated with immune system-friendly material such as a CD47 biomarker, which carries a signal “Don’t eat me”. This way the injected drug-carrying bots will not undergo phagocytosis and will successfully reach the target site. Secondly, there is a chance that the TDD is used with malicious intent to harm the patient. The attacker can take control of the TDD system through the internet and can release inappropriate drug dosage which may be fatal for the patient.

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Isaac Asimov's 'Fantastic Voyage' in Real Life: IoBNT for Targeted Drug Delivery

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