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Editorials |
Edwin L. Steele Laboratory, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114
In this issue of Clinical Cancer Research, Lankelma et al. (1) report on doxorubicin gradients in biopsies of breast tumors from patients. The gradients are pronounced 2 h after i.v. injection and become negligible 24 h later. Gradients of anthracyclins in tumor spheroids (2 , 3) , in animal tumors (4) and in human tumors (5 , 6) have been reported previously. Gradients of other low MW2 agents in animal tumors have also been reported previously (7, 8, 9) . Thus, these results are not surprising. What is different, however, is that Lankelma et al. have stained microvessels in the same regions so that gradients from the vessel wall can be discerned. In this editorial, I will address three questions: Why are these data important? What mechanisms create these gradients? How can these mechanisms be discerned?
For any therapeutic agent to be effective, it must accumulate in target cells in optimal concentrations for a required duration of time. Unfortunately, physicochemical and physiological barriers can lead to heterogeneous accumulation of various therapeutic molecules, particles, and cells in solid tumors (10 , 11) . In a disease such as cancer, failure to treat a small fraction of cells can result in tumor regrowth. Thus, it is crucial to know which cells have been successfully treated and which have not. To determine this, high-resolution imaging of drug distribution and its physiological determinants is essential. Only with this knowledge can we improve drug delivery to all regions of a tumor.
Physiological Barriers
There are at least four known physiological barriers to delivery of a blood-borne agent. The first barrier is the heterogeneous angiogenesis and blood flow in tumors. The second barrier is the heterogeneous permeability of tumor vessels. Tumor vessels are generally hyperpermeable, supporting the use of high MW therapeutic agents (12)
. However, tumor vascular permeability exhibits tremendous spatial and temporal heterogeneity, and, thus, extravasation of drugs from hypopermeable regions of tumor vessels may be reduced (13)
. The interstitial compartment poses a third barrier. Movement through this compartment occurs by diffusion and convection. Diffusion coefficient (D) decreases with increasing MW of drug (D 
MW-n, n 
1). Thus, one would expect high MW drugs to penetrate the interstitium slowly. This movement can be further retarded if the drug binds to relatively immobile molecules. Because of uniformly elevated pressure throughout the tumor, convection is negligible in tumors except in the periphery, where there may be steep pressure gradients (14)
. The fourth barrier to drug delivery is the cell membrane and the cytoplasm. Each of these barriers varies from one region of the tumor to the next, from one day to the next, and yet again when a tumor metastasizes to a different organ. Thus, heterogeneous distribution of a therapeutic agent in a tumor is not unexpected.
Need for High Resolution in Vivo Imaging
The question now is to what extent each of the physiological barriers outlined above contributes to the gradients reported by Lankelma et al. Is the heterogeneous blood supply partly responsible for these gradients? Certainly. How about heterogeneous vascular permeability and interstitial diffusion? Probably yes. Doxorubicin is known to bind plasma proteins and, thus, may behave as a macromolecule with respect to transport properties. Can plasma pharmacokinetics after i.v. injections contribute to gradients? Probably. When the plasma concentration is higher than the interstitial concentration, the drug will accumulate in the tumor. When the plasma concentration is lower than that in the interstitial compartment, the drug will be cleared. This reversal of concentration gradients has been measured for both low and high MW agents and has been referred to as the "reservoir effect" (9 , 14) . How about cell membrane permeability? On the basis of our recent data, probably not (15) . Do pH gradients in the tumor modify fluorescence intensity of doxorubicin and, thus, influence measurement of gradients? Not known. Finally, how do these gradients change as a function of time in a given location? This cannot be determined from these studies.
All of these are very important questions. Answers will require the ability to monitor drug pharmacokinetics and physiological parameters simultaneously and continuously with high spatial resolution (1–10 µm). Invasive methods such as those used by Lankelma et al. can provide the desired spatial resolution, but do not provide temporal dynamics. Hence, several of these questions remain unanswered. Although useful for functional imaging, positron emission tomography, computed tomography, nuclear magnetic resonance, and ultrasound currently do not have the desired spatial resolution required to monitor events at the cellular level. Nuclear magnetic resonance microscopy can provide high resolution structural information, and limited functional imaging. The only noninvasive method currently available that satisfies these prerequisites is in vivo microscopy (16) . This approach has provided powerful insight into angiogenesis and blood flow (17, 18, 19, 20) , leukocyte adhesion in vessels (21) , vascular permeability (22) , interstitial diffusion, convection and binding (23 , 24) , interstitial pH and pO2 (25) , and, most recently, gene expression (26) . A major limitation of this method is that the imaging is surface weighted (<40 µm). With the availability of multiphoton microscopy (27) and novel probes (28) , it is now possible to image deeper in tissue (<400 µm) without significant loss of spatial resolution. It is also possible to adapt some of these techniques to the clinical setting (29) . Until technology for deeper imaging without loss of spatial resolution is developed, these techniques should provide useful insight into mechanisms that contribute to heterogeneous distribution of drugs in tumors. With this microscopic information in hand, we should be able to devise strategies to overcome or exploit these barriers. If getting there is half the problem, we certainly must invest greater effort and resources to improving drug delivery.
ACKNOWLEDGMENTS
The author thanks B. Stoll, T. Padera, S. Ramanujan, R. Weissleder, and J. Samson for their helpful input.
FOOTNOTES
1 To whom requests for reprints should be addressed, at Department of Radiation Oncology, Massachusetts General Hospital, Boston, MA 02114. Phone: (617) 726-4083; Fax: (617) 726-4172; E-mail: jain{at}steele.mgh.harvard.edu 
2 The abbreviations used are: MW, molecular weight; n, exponent measured experimentally or estimated theoretically.
Received 4/28/99; accepted 5/ 4/99.
REFERENCES
in hypoxia-mediated apoptosis, cell proliferation and tumor angiogenesis. Nature (Lond.), 394: 485-490, 1998.[Medline]
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