Nanomedicine, Volume I: Basic Capabilities

© 1999 Robert A. Freitas Jr. All Rights Reserved.

Robert A. Freitas Jr., Nanomedicine, Volume I: Basic Capabilities, Landes Bioscience, Georgetown, TX, 1999 Ideal Messenger Molecule

The ideal chemical messenger molecule will have several important characteristics. First, its structure will contain a distinctive "head" or "flag" that permits easy recognition and binding by nanorobot molecular receptor systems such as molecular pumps or sorting rotors (Section 3.4), so that the entire message need not be read in order to identify the intended recipient. Second, it will be relatively bioinactive, thus not readily broken down by natural processes before the message is likely to be received. Third, it should be easily eliminated from the body, thus preventing potentially toxic accumulations; however, the molecule and any likely breakdown products should also be inherently nontoxic in anticipated maximum concentrations.* Finally, the molecule should be capable of easy extension to larger sizes, permitting significant entire messages to be written on the molecule, as the statistical nature of the transport process implies a relatively long time between assured detections of the messenger molecule.

* M. Krummenacker notes that if a common standard format is established for design economy, then any stray messenger molecules that are released intact into the environment could trigger unwanted action in other bodies, and at inappropriate times, if inhaled or ingested by someone other than the original patient. Such "information toxicity" can be reduced by judicious degradation and deflagging of all messenger molecules prior to final excretion, by recycling, and by employing validity-checking security protocols (Chapter 12) before permitting any action to be stimulated or influenced by received messenger molecules.

One possible candidate messenger is the partially fluorinated polyethylene molecule originally suggested by Drexler10 for nanocomputer tape bulk memory systems, although others have been investigated.1200 Such molecules can store one bit per carbon atom using an H atom to represent a "0" and an F atom to represent a "1" on one side of the carbon-chain backbone, with all H atoms occupying the other side of the backbone to facilitate easy reading. The message may be a single linear chain or may include branching structures representing conditionals or prioritizations embedded in the message. Assuming molecules (averaging 50%/50% H/F atoms on the read side) are of the form CH3(CHX)nCH3 (with X = H or F atoms) and can store 1 bit per unit (with n units/molecule), then message molecule density rmessage ~ 1000 kg/m3 and message molecule volume Vmessage ~ (3.82 x 10-29)n (meter3), giving an information density of Dmessage ~ 26 bits/nm3 (~3 bits/nm of linear message molecule length). (By comparison, linear DNA achieves ~1 bit/nm3.) Message molecule molecular weight MWmessage ~ n MWunit (kg/mole) for n >> 1, where MWunit = 0.023 kg/mole for (CHX), ignoring the end caps and again assuming 50%/50% H/F atoms.

Hydrofluorocarbon message molecules with n > 20 may be strategically crosslinked in a standardized pattern across the all-H backbone and folded into a maximally compact spheroidal configuration in preparation for transmission. Alternatively, the polymer could be wound up onto a bobbin or reel, allowing more convenient reading and a high packing density.10 The read-write mechanism may require ~104 nm3 of nanomachinery, providing a readout rate of 'Iread ~ 109 bits/sec by scanning the message molecule at a ~30 cm/sec read rate,10 although the complete tape-handling mechanism may require up to 105 nm3 of nanomachinery. Two-dimensional information-bearing fluorinated hydrocarbon molecules have also been considered.2182

Are hydrofluorocarbon molecules biocompatible? Fluorinated hydrocarbon perfusants with n < 20 such as Fluosol-DA or the commercial solvent polyfluoro-octobromide (Perflubron) are FDA-approved and have been used as reversible oxygen carriers in artificial blood formulations for years.704,705 Such fluorocarbons are characterized by high chemical and biochemical inertness, absence of metabolism, and rapid excretion.704 The rate of excretion has been shown to decrease exponentially with increasing molecular weight, with the exception of fluorocarbons containing a lipophilic substituent such as Br (e.g., Perflubron) or a hydrogenated fragment in their molecular structure.704 These water-insoluble compounds usually consist of 8-10 carbon atoms with molecular weights of ~450-500 daltons; clinical administrations typically reach maximum bloodstream concentrations of 70-400 gm/liter.705 (cf. LD50 ~ 700 gm/liter estimated from acute single-dose toxicity studies707), many orders of magnitude in excess of the levels anticipated for nanodevice chemical communication applications. Interestingly, mice survive immersion in fluorocarbon through which oxygen is bubbled,2183 and rats breathing 95% oxygen have survived total blood replacement with fluorocarbon fluid.2184 The boiling point of perfluoropentane (C5F12) is 29.2C, but is >37C for n>5 -- e.g., 56.6C for perfluorohexane (C6F14).

Fluorocarbons and fluorocarbon moieties have very strong intramolecular bonds and very weak intermolecular interactions,2940 hence should display low particle aggregation. Fluorinated surfactants are less hemolytic and less detergent than their hydrocarbon counterparts,2940 and fluorosurfactants appear unable to extract membrane proteins.2940 The stability and permeability of fluorinated liposomes has been widely studied.2941-2944 For example, anionic double chain glycophospholipids with either two hydrocarbon or two perfluorocarbon chains, or a mixed double chain (one fluorinated, one hydrogenated), readily give vesicles 30-70 nm in diameter when dispersed in water, with maximum tolerated IV doses up to 0.5 gm/kg body weight in mice (~5 gm/liter blood volume); hemolytic activity sharply decreases with increasing degree of fluorination.2943 Many fluorinated surfaces such as Teflon are simultaneously hydrophobic and lipophobic.2940

Fluorocarbons are typically administered in the form of emulsions of 0.1-0.2 micron droplets dispersed in a physiologic solution, similar to fat emulsions routinely used for parenteral nutrition. A compact folded messenger molecule of spherical radius rmessage can store approximately

{Eqn 7.2}

and may display Isurface ~ (3 p1/2 Imessage/4)2/3~1.2 Imessage2/3 (bits) on a compact spherical packet surface. For rmessage = 0.2 micron, Imessage ~ 109 bits/molecule (e.g., "genome packets") with Isurface ~ 106 bits. Of this number, at most ~1000 bits may be required for recipient identification, time stamping, "destroy by" dating, or other message packet flagging or header information. For the (CHX)n core fragment, Imessage = n (bits).

Hydrofluorocarbon messenger molecules will not be readily metabolized. The smaller molecules are cleared rapidly from the circulation with brief retention in the mononuclear phagocyte system,706 mainly in the liver, spleen and bone marrow. They are then reintroduced into the circulation by lipid carriers in the blood at a rate that appears to depend on the fluorocarbon's solubility in fat, with some concentration in adipose tissues. Eventually, they are excreted through the lungs with the expired air709 as a vapor (for short message segments of low molecular weight), with an intravascular persistence of 4-12 hours for present oxygen-carrying emulsions.704 (Linear mixed fluorocarbon-hydrocarbon amphiphiles have demonstrated at least some bloodstream persistence in vivo of up to 4 months.712) Massive single doses or repeated administration can cause saturation and transient blockade of the reticuloendothelial system (RES), temporarily depressing this component of the host-defense system.710 Message-carrying fluorocarbons should be extremely inert, although there is some evidence that macrophages which have ingested perfluorocompounds show loss of phagocytic function and possible release of cytokines and other immune mediators.708 Fluosol has been found to elicit anaphylactoid-type reactions in a small percentage of patients at blood concentrations as low as ~0.1 gm/liter.711 Irregular Teflon (CF2)n granules measuring 4-100 microns (equivalent to n = 106-1010) employed clinically in periurethral injection 944 have produced granulomatous reaction, embolization, and migration to the lungs.945,946 This implies a maximum size limit on large naked messenger molecules and a possible requirement for encapsulation in a biocompatible shell prior to release. R. Bradbury suggests that such a shell might include a lipid membrane with "docking tags" similar to viral attachment proteins. These tags should be engineered to be incapable of binding by antibodies, to have minimal affinity for common cell receptors, and to be indigestible by the regular cellular protein breakdown and recycling machinery (and thus be incapable of generating long-term immunity).

A hydrofluorocarbon messenger molecule with a lengthy stretch of exposed hydrogens might display increased toxicity, as some short-chain linear paraffin hydrocarbons (CnH2n+2) are considered "poisonous"2945 with an official NFPA Health Hazard Rating of 1 or "slightly toxic" (scale 0-4).2947 Animal toxicity of pure propane (C3H8) occurs with inhalation exposures to concentrations >10% and includes mild respiratory tract irritation and irregular respiration, cardiac sensitization to catecholamine-induced arrhythmias, analgesia and hypotension,2947,2948 although the principal risk is simple asphyxia and cold burn during bulk exposures. Typical OSHA workplace air exposure concentration limits for propane and butane are 0.06%-0.1%.2946,2947 Inhalation toxicity to pentafluoroethane (C2F5H) in rats is 70.9% (4-hour ALC), with no significant toxicological effects under <5% concentration.2948 Toxicity mechanisms may differ for short-chain and long-chain hydrocarbon molecules. (For more on fluorocarbon biocompatibility, see Section 15.3.4.)

This entire area deserves an indepth toxicology study. If long-term toxicity is found to be unacceptable, the solution may be to engineer "digestible" but nonimmunogenic packages, reducing bit density but increasing the available molecular pool of raw materials for building messenger molecules in vivo. As a possible alternative to hydrofluorocarbons, R. Bradbury suggests using unusual protein or polysaccharide chains (which can compactly encode large quantities of data; Section that are easily read by nanorobots but also are easily digestible by cells as "food." If patient immunotype is known, then protein sequences can be designed which cannot be bound by MHC molecules (Section, preventing the patient from developing an immunity to them, and which look like self-shapes or are nonbinding to antibodies.


Last updated on 18 February 2003