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Medicine's Fantastic Voyage

Constructing a Medical Nanobot - Biomimetic Enzyme Nanocomplexes (Nanobots)

James Robb, MD, Pathology, 08:15PM Apr 10, 2013

Nanobots to the rescue before you consume too much ethanol! Yes, our Good Health Nanobot Patrol will include this type of very useful and specific multienzymatic nanobot. The one described below is a definite plus for inebriated mice! If you suspect that your hepatic response to ethanol ingestion is a tad bit slower than your brain's consumption, you might want to consider signing up for a bunk in the guinea pig cage!

Liu, Du, Yan, et al., have created an alcohol oxidase - catalase nanocomplex (nanobot) that is both prophylactic and antidotal in an ethanol-intoxicated mouse model (Nature Nanotechnology, 2013;8:187-192). These nanobots are physiologically stable and resistant to protease degradation in the blood stream and organs. Furthermore, this nanobot design can be generalized for many types of coupled enzyme systems and the nanobot surface can be functionalized for programmable targeting of appropriate cells and/or tissues. Figure 1 below demonstrates the synthesis of a typical triple-enzyme nanobot.

Figure 1: Schematic illustration of the synthesis of a model triple-enzyme nanocomplex by DNA-directed assembly and nano-encapsulation. Spontaneous assembly of invertase (Inv, A), glucose oxidase (GOx, B) and horseradish peroxidase (HRP, C) with an inhibitor-DNA scaffold containing their respective competitive inhibitors—lactobionic acid (a), glucosamine (b) and 4-dimethylaminoantipyrine (c)—leading to the formation of a triple-enzyme architecture (I). Confinement and stabilization of the triple-enzyme architecture by in situ growth of a thin network polymer around the enzyme nanocomplex (II). Removal of the DNA scaffold leading to the formation of triple-enzyme nanocomplexes with significantly enhanced stability and close-proximity definition. Such a close-proximity architecture enables active transport of their reaction intermediates among the enzymes, leading to significantly enhanced reaction efficiency and complementary function, such as the capability to eliminate toxic intermediates (III).

This type of nanobot begins to resemble in function what nature has created over evolutionary time: coupled enzymatic systems that are spatially defined within subcellular organelles or co-localized within the cytoplasm, nucleus, mitochondria, endoplasmic reticulum, etc.. Previous attempts at achieving spatially localized multienzymatic synthetic systems have significant barriers for achieving high product throughput with blood/tissue stability and low toxicity. Such systems are based on four primary architectures: co-entrapment, co-immobilization, template assembly, or fusion-protein methodology.

The liver is the primary location for the metabolism of ethanol. The nanobots, after intravenous administration, but not after gavage, rapidly left the blood and localized primarily in the liver. The nanobots reached a peak concentration in the kidney at about 40 minutes after injection. 

This novel nanobot's multienzyme architecture was less toxic (epidermal blistering and altered liver function [elevated alanine aminotransferase, ALT]) than the PBS and single enzyme controls. The nanobot, after gavage administration, was significantly more prophylactic (nanobot injection before ethanol administration) than the controls, as demonstrated by a more rapid lowering of the blood alcohol concentration. The nanobot, used as an intravenous antidote for the ethanol-intoxication, was a significantly better antidote than the controls at reducing the blood alcohol concentration. These positive effects were dose dependent.

Acetaldehyde, the toxic byproduct of this ethanol intoxication process, was not degraded, because a suitable aldehyde dehydrogenase or aldehyde oxidase with sufficient activity was not available. If available, either of these enzymes could have been easily incorporated into a tri-enzymatic nanobot for the complete non-toxic oxidation of ethanol.

I predict that many specialized nanobots will be developed and clinically implemented, using this type of highly versatile, multienzymatic architecture. Both natural and synthetic enzymes will be used in these programmable, targeted nanobots.

Thanks, Jim.

About This Blog

This blog will discuss new technologies that are entering the diagnostic and treatment arenas. Information given here is intended to help pathologists and laboratory technicians anticipate, understand, tolerate, accept, and subsequently implement these new technologies into their work.

Disclosure: James A. Robb, MD, has disclosed the following relevant financial relationships: Served as a director, officer, partner, employee, advisor, consultant, or trustee for: Biomatrica, Inc.; Strategic Visions, Inc.
Received income in an amount equal to or greater than $250 from: Leidos Biomedical Research, Inc. (formerly SAIC-Frederick) Consulting Pathologist to the National Cancer Institute, NIH and The Research Institute at Nationwide Children's Hospital (NCI-TCGA).
Poll: Which of the following logic-gates is not used in this extracellular biocomputing platform? 1) YES|2) NOT|3) HALF ADDER|4) AND|5) OR|

  • James Robb

    Dr. Robb is board certified in anatomic pathology, clinical pathology, cytopathology, and dermatopathology. Dr. Robb is currently aLeidos Biomedical Research, Inc. (formerly SAIC-Frederick, Inc)consulting pathologist to the National Cancer Institute, NIH, HHS, and a consulting pathologist for Strategic Visions, Inc. and Biomatrica, Inc.. He has been Senior Surgeon at NIH, Professor of Pathology at University California at San Diego; staff pathologist at Scripps Clinic, La Jolla, California; Director of Anatomic and Molecular Pathology, Cedars MC, Miami, Florida; and Medical Director of the HCA East Florida Divisions Integrated Regional Laboratories system, and College of American Pathologists governor.

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