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
126.96.36.199 Cytovehicular Behavioral Control
Besides simple steering and chemotaxis, many stereotypical cell behaviors may be triggered biochemically as well. Diapedesis, ECM brachiation with a preference for a particular ECM ligand, particle engulfment, transitions between migratory and profibrotic phenotypes in fibroblasts,1537 cell volume and shape changes, cell cycling and growth, and epithelial-mesenchymal transformations1547 may be initiated, amplified, or suppressed by regulating the flows and distributions of various cytoplasmic signal molecules which may include proteins or nonproteins (such as Ca++ or GTP). Motility-stimulating factors such as autocrine stimulating factor1548 and migration stimulating factor1549 are produced by fibroblasts and act in an autocrine (Section 188.8.131.52) fashion. Leukocytes keep rolling over vascular endothelium until a neutrophil activator (e.g., a selectin) is encountered, whereupon they stick tightly and undergo the shape change characteristic of neutrophil diapedesis978 -- a process that nanorobotic pilots should be able to monitor and control. Mammary epithelial cells receive mechanical signals from the ECM via a tyrosine kinase (biochemical) signal transduction pathway through the b1 integrin receptor leading to the activation of elements in the promoter region of the b-casein gene.1550 Release of Sr++ inside cytolytic T lymphocytes induces degranulation -- the emission of cytotoxic granules containing granulysin that can inhibit growth in a broad spectrum of pathogens, including bacteria, fungi, and parasites, and can directly kill the tuberculosis bacterium.2165
Most integrins bind to their ECM ligands via the tripeptide RGD (Arg-Gly-Asp), so the nanorobotic pilot can release RGD as an antagonist to moderate or to prevent cell-ECM interactions.1551 Alternatively, ECM-integrin binding can be enhanced by specific cytoplasmic molecules such as the cell adhesion regulator (CAR), a myristoylated protein that can connect the plasma membrane to the cytoskeleton.1552 ECM molecules interact with their receptors at the cell surface, transmitting signals directly or indirectly to second messengers which in turn unravel a cascade of events leading to the coordinated expression of a variety of genes involved in cell adhesion and release, migration, proliferation, differentiation, and death.1553 By intercepting and regulating specific second messenger pathways, or by artificially triggering them mechanically, the pilot can exercise considerable control over cell behavior.
The nanorobotic pilot must inhibit certain natural cell behaviors that might distract the cytovehicle from its imposed mission. For example, emission of Rap1-GTP protein into the cytoplasm of a Jurkat T cell renders the cell anergic (unresponsive) and incapable of transcribing the gene encoding interleukin-2 when stimulated with antigen.1562 Intracellular kinesin molecular motors (Fig. 9.32) are inhibited by adociasulfate-2 (AS-2; MW = 738 daltons), a molecule that targets the kinesin motor domain.1563 Activated macrophages themselves secrete chemoattractant factors that may draw a crowd of leukocytes, fibroblasts, and other macrophages toward the flight path, impeding mobility and possibly triggering a natural granulomatous (encapsulation) reaction. These processes may be desirable to stimulate at the destination, but they should be suppressed en route.
Unwanted cytovehicular responses due to nanorobot intrusion should also be suppressed, much as pathogens such as M. tuberculosis resist or inhibit oxidative killing, attack by defensins, phagosome-lysosome fusion, and formation of the electron-transparent zone that impairs lysosomal enzyme diffusion, thus ensuring their survival inside macrophages for long periods of time.1558,1559
Cell behavior can also be mechanically regulated by altering cell shape, because cells can detect when a mechanical strain is placed upon them.942,1020 In one experiment, stretching a fibroblast by 1% for 180 sec triggered large-scale changes in cell shape, including retraction of pseudopods and cell elongation.1557 Other experiments show that very flat cells, with their cytoskeletons stretched, sense that more cells are needed to cover the surrounding substrate (as in wound repair) and that cell division is needed. A rounded shape indicates that too many cells are competing for space on the matrix and that cells may be excessively proliferating; some must die to prevent tumor formation. Normal tissue function is established and maintained between these two extremes.1021 Certain mechanical stresses on cells, such as might be generated by a nanorobotic pilot inside the cytovehicle or dense cytovehicular traffic near the destination, may trigger unwanted reactions that should be avoided.
Last updated on 22 February 2003