Determinants of drug delivery and transport to solid tumors

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Abstract

This presentation addresses the barriers and determinants and the importance of drug-induced apoptosis in drug transport and delivery to organs and solid tumors. In particular, we examined the roles of interstitial space, drug removal by capillaries, tissue structure and tissue composition on drug distribution. Drug transport in bladder tissues is described by the distributed model which combined monodimensional Fickian diffusion and first order removal of drug by the perfusing blood. Microscopic evaluation of the spatial drug distribution in bladder, prostate and tongue indicates heterogeneous drug distribution with large and erratic concentration gradient. In general, drug distribution favors interstitial space and vasculature, with little penetration in muscles. Drug penetration into 3-dimensional solid tumors is typically 5- to 10-fold slower than in monolayer cultures. The transport of highly protein-bound drugs such as paclitaxel and doxorubicin in a solid tumor is retarded by a high tumor cell density and enhanced by drug-induced apoptosis. Accordingly, the delivery of a highly protein-bound drug to cells in a solid tumor is affected by its apoptotic effects and is therefore determined by the drug concentration and the treatment duration, i.e. treatment schedule. Under in vitro and in vivo conditions, the delivery of highly protein-bound drugs to tumor can be enhanced by using a pretreatment that induces apoptosis and reduction in cell density, and by using treatment schedules designed to take advantage of these drug-induced changes in tumor tissue composition. In conclusion, in addition to the usual processes involved in drug transport such as distribution through vascular space, transport across microvessel walls, and diffusion through interstitial space in tumor tissue, other factors including tissue structure and composition and alteration by drug-induced apoptosis are important determinants of drug distribution in organs and solid tumors.

Introduction

Systemic and regional chemotherapy are used in the management of cancer patients. Following a systemic intravenous injection, drug delivery to the tumor core involves three processes, i.e. distribution through vascular space, transport across microvessel walls, and diffusion through interstitial space within the tumor tissue [1]. When the drug is directly injected into a tumor such as by intratumoral injection or by direct instillation into peritumoral space such as in intravesical therapy of superficial bladder cancer and in intraperitoneal dialysis of ovarian cancer, drug delivery to tumor cells is primarily by diffusion through interstitial space [2], [3], [4], [5].

An earlier presentation in this symposium discussed the importance of interstitial pressure in drug delivery after a systemic treatment. The present presentation addresses the barriers and determinants and the importance of drug-induced apoptosis in drug transport and delivery to solid tumors. The roles of interstitial space, drug removal by capillaries, tissue structure and tissue composition on drug distribution in organ and solid tumors are discussed.

Section snippets

Drug distribution in organs

We have completed a series of studies that evaluated the drug distribution on an organ level. We first studied the penetration of several drugs into bladder tissues during intravesical therapy or after the drug is instilled directly into the bladder cavity [5], [6], [7], [8]. These drugs, i.e. mitomycin C, doxorubicin, 5-fluorouridine and paclitaxel, have different physicochemical properties. These compounds show similarities as well as differences in their ability to penetrate the bladder. The

Barriers to drug distribution in organs

Confocal microscopy was used to evaluate the sub-organ barriers to drug distribution in several organs including bladder, prostate and tongue. Fig. 3 shows the distribution of doxorubicin in a dog bladder, after an intravesical dose. The results show uneven drug distribution throughout the bladder, with high drug concentration localized in the interstitial space adjacent to the blood vessels. In comparison, the remaining bladder tissues showed 3- to 5-fold lower drug concentrations. These data

Determinants of drug distribution in solid tumors

Many anticancer drugs exert their action by binding to macromolecules. Earlier studies using tumor cell spheroids have shown that penetration of protein-binding drugs such as doxorubicin and paclitaxel is limited to the periphery [9], [10], [11], [12], [13]. To identify the determinants of distribution of these protein-binding drugs, we used in vitro systems to study the time course of drug penetration, so that the results are not confounded by the effect of blood flow on drug transfer. Most of

Methods to improve drug delivery to tumors

Based on the above observations, we hypothesize a strategy where an apoptosis-inducing pretreatment is used to enhance the delivery of a protein-bound drug to solid tumors. This hypothesis was tested by in vitro and in vivo studies, using paclitaxel as the model drug. Three in vitro studies were performed using histocultures of human pharynx FaDu tumor xenograft. The first study evaluated the importance of apoptosis on paclitaxel penetration. This study used two concentrations of [3H]paclitaxel

Conclusions

With respect to drug distribution in organs, our results indicate that the kinetics of drug penetration from urine to bladder tissues, on an organ level, is described by the distributed model. Microscopic evaluation of the spatial drug distribution within several organs, i.e. bladder, prostate and tongue, indicates that drug distribution within these organs is heterogeneous with large and erratic concentration gradient. In general, drug distribution favors interstitial space and vasculature,

Acknowledgments

The work described in this manuscript is partly supported by research grants R37CA49816, R01CA63363 and R01CA74179 from the National Cancer Institute, NIH, DHHS.

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