ABSTRACT
While more details can be found in Chapter 1, we brie§y provide the salient features of tumor biology that are relevant for the present chapter.
Solid tumors are composed of cancer cells that divide at an accelerated pace and that do not (typically) naturally undergo apoptosis. šis is a tremendous advantage over neighboring normal cells, as cancer cells are able to proliferate more e—ciently, eventually outgrowing, invading, and even replacing normal tissues. šese processes require energy, which is obtained from nutrients in the blood stream. šose nutrients are available to the œrst few layers of cells around a blood vessel, which would in principle limit the development of tumors. However, cancer cells have the ability to recruit new blood vessels (neovasculature) that allow them to develop further [2]. šese neovessels are grown rapidly and imperfectly, resulting in a “leaky” vasculature (see Figure 21.1). še epithelium of normal blood vessels is smooth and relatively impermeable to exogenous contrast agents. However, the tumor neovessels are characterized by a higher permeability. še fenestration of tumor neovessels has diameters in the micrometer range [3], such that compounds present in the vasculature, such as glucose, amino acids, or contrast agents, can readily escape the vasculature and enter the interstitium, where they can interact with tumor cells. še size of the fenestration is an upper limit for molecular imaging agents designed to target cancer cells, which may be located several micrometers away from a blood vessel. Here, di›usion can be a rate-limiting step
21.3 Summary .................................................................................................................................. 285 Acknowledgments .............................................................................................................................. 285 References ............................................................................................................................................ 285
in the delivery of a contrast agent to the desired target, as is the case for the delivery of therapeutic agents [4]. še di›usion coe—cient decreases as a function of the molecular weight and size (Figure 21.2) such that smaller agents can di›use further than larger agents for a given time. For example, the time constant for an antibody to di›use over 100 μm in a tumor is around 1 h [4]. In the same interval, a low-molecular-weight compound would have di›used over 1 mm. šere is, however, a trade-o›; small compounds can easily extravasate and di›use over several hundred micrometers, but they may also be rapidly eliminated by the kidneys. Larger contrast agents typically have a longer blood circulation time, and this
can improve the total quantity of compound delivered to a tumor [3]. However, it may become more di—cult to determine whether the accumulation of a contrast agent in a tumor is due to a speciœc event or due to an unspeciœc e›ect such as the “enhanced permeability and retention” for macromolecules and lipids [5]. Elimination of a compound (and its degradation products) from a tissue is normally either due to lymphatic drainage or the return of the compound or its degradation products to the bloodstream. Tumors lack a fully functional lymphatic drainage system, and this has contradictory consequences. First, this contributes to an elevated interstitial pressure, which decreases the transport of molecules from the vasculature to the tumor tissue; second, this prolongs the retention and favors the accumulation of a molecule that did reach the tumor interstitium. While it is certainly desirable to obtain the largest concentration possible of a drug in a tumor, the design of a speciœc contrast agent may require a di›erent approach in order to optimize the speciœcity of the agent. Finally, it must be noted that once inside the cytosol, the di›usion of compounds is reduced in relation to their molecular weight [6].
