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

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

7.2.1.1 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 r_message ~ 1000 kg/m³ and message molecule volume V_message ~ (3.82 x 10^-29)n (meter³), giving an information density of D_message ~ 26 bits/nm³ (~3 bits/nm of linear message molecule length). (By comparison, linear DNA achieves ~1 bit/nm³.) Message molecule molecular weight MW_message ~ n MW_unit (kg/mole) for n >> 1, where MW_unit = 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 'I_read ~ 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 29.2°C, but is >37°C for n>5 -- e.g., 56.6°C 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 r_message can store approximately

{Eqn 7.2}

and may display I_surface ~ (3 p^1/2 I_message/4)^2/3~1.2 I_message^2/3 (bits) on a compact spherical packet surface. For r_message = 0.2 micron, I_message ~ 10⁹ bits/molecule (e.g., "genome packets") with I_surface ~ 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, I_message = 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 (C_nH_2n+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 8.5.2.2)³¹²² 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 8.5.2.1), 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