Seong Hoon Jang

Drug Delivery and Transport to Solid Tumors

AbstractPurpose. The purpose of this review is to provide an overview of the principles of and barriers to drug transport and delivery to solid tumors. Methods. This review consists of four parts. Part I provides an overview of the differences in the vasculature in normal and tumor tissues, and the relationship between tumor vasculature and drug transport. Part II describes the determinants of transport of drugs and particles across tumor vasculature into surrounding tumor tissues. Part III discusses the determinants and barriers of drug transport, accumulation, and retention in tumors. Part IV summarizes the experimental approaches used to enhance drug delivery and transport in solid tumors. Results. Drug delivery to solid tumors consists of multiple processes, including transport via blood vessels, transvascular transport, and transport through interstitial spaces. These processes are dynamic and change with time and tumor properties and are affected by multiple physicochemical factors of a drug, multiple tumor biologic factors, and as a consequence of drug treatments. The biologic factors, in turn, have opposing effects on one or more processes in the delivery of drugs to solid tumors. Conclusion. The effectiveness of cancer therapy depends in part on adequate delivery of the therapeutic agents to tumor cells. A better understanding of the processes and contribution of these factors governing drug delivery may lead to new cancer therapeutic strategies.

Determinants of drug delivery and transport to solid tumors.

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.

Clinical aspects of drug delivery to tumors

This report describes our experience on enhancement of drug delivery to solid tumors. Results of our preclinical and clinical studies including a randomized prospective phase III trial have validated the concept that enhanced drug delivery can significantly improve the treatment efficacy of intravesical mitomycin C therapy of superficial bladder cancer. The report further describes the roles of interstitial space, drug removal by capillaries, tissue structure and tissue composition on drug distribution. In general, drug distribution favors interstitial space and vasculature, with little penetration in muscles. 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. Results of in vitro studies using solid tumor histocultures and in vivo studies using tumor-bearing animals demonstrate that the delivery of highly protein-bound drugs to tumor can be enhanced using a pretreatment that induces apoptosis and reduces cell density, and by using treatment schedules designed to take advantage of these drug-induced changes in tumor tissue composition.

Determinants of paclitaxel uptake, accumulation and retention in solid tumors

This report addresses the determinants ofthe rate and extent of paclitaxelaccumulation in tumors. In a 2-dimensionalsystem such as monolayers where the drug isdirectly in contact with tumor cells, drugaccumulation is determined by theextracellular-to-intracellularconcentration gradient, the drug binding toextracellular and intracellularmacromolecules, the presence of the mdr1p-glycoprotein (Pgp), and thetime-dependent and drugconcentration-dependent changes in tubulinsand cell density. Intracellularpharmacokinetic models were developed todepict the effects of these parameters.Computer simulation results indicate thatat the clinically relevant concentrationrange of 1 to 1,000 nM, (a) the bindingaffinity and the number of intracellularsaturable drug binding sites are importantfor drug accumulation at low and highextracellular concentrations, respectively,(b) saturation in the drug binding to thehigh affinity intracellular binding sites(e.g., tubulin/microtubule) occurs atextracellular drug concentration above 100nM, (c) treatment with 1,000 nM paclitaxelfor ≥4 hr results in increased levels oftubulin/microtubule and consequentlyincreased intracellular drug accumulation,whereas the continued cell proliferationafter treatment with low drugconcentrations results in reducedintracellular accumulation, and (d)saturation of Pgp in mdr1-transfectedcells occurs at the high end of theclinically relevant concentration range. Ina 3-dimensional system such as the solidtumor histocultures, which contain tumorcells as well as stromal cells, the drugaccumulation into the inner cell layers isdetermined by the unique properties ofsolid tumors, including tumor cell densityand spatial arrangement of tumor andstromal tissues. Most interestingly, drugpenetration is modulated by thedrug-induced apoptosis; the reduced celldensity due to apoptosis results in anenhancement of the rate of drug penetrationinto the inner cell layers of solid tumors.In conclusion, the uptake, accumulation,and retention of paclitaxel in solid tumorsare determined by (a) factors that areindependent of biological changes in tumorcells induced by paclitaxel, i.e., ratio ofextracellular and intracellularconcentrations, and drug binding toextracellular and intracellularmacromolecules, and (b) factors that aredependent on the time- and drugconcentration-dependent biological changesinduced by paclitaxel, i.e., induction ofapoptosis, enhancement oftubulin/microtubule production, andinduction of Pgp expression.

Enhanced Drug-Induced Apoptosis Associated with P-Glycoprotein Overexpression Is Specific to Antimicrotubule Agents

AbstractPurpose. We have reported that overexpression of mdr1 P-glycoprotein (Pgp) is associated with a higher sensitivity to paclitaxel-induced apoptosis (1,2). The present study examined the substrate specificity of this phenomenon. Methods. Two Pgp substrates (vincristine and doxorubicin) and three nonsubstrates (cisplatin, camptothecin, and 5-fluorouracil) were studied. Serum deprivation, known to induce apoptosis, was used as a comparison. Results. The Pgp nonsubstrates and serum deprivation showed similar overall cytotoxicity and apoptosis in human breast MCF7 cells (with negligible Pgp expression) and its mdr1-transfected subline BC19 cells (with nine-fold higher Pgp expression). In contrast, the overall cytotoxicity and apoptosis of the two Pgp substrates was higher in MCF7 cells. Cotreatment with a Pgp inhibitor, verapamil, abolished the difference in intracellular accumulation of doxorubicin as well as the differences in apoptosis between MCF7 and BC19 cells. This finding confirms that the lower apoptosis of doxorubicin in BC19 cells, in the absence of verapamil, was a result of lower intracellular drug accumulation secondary to high Pgp expression in BC19 cells. In contrast, abolishing the difference in intracellular vincristine concentration by verapamil cotreatment resulted in significantly higher apoptosis in BC19 cells. This finding is identical to our previous finding with paclitaxel, where equal intracellular drug concentration resulted in greater apoptosis in the Pgp-rich BC19 cells. Conclusions. These data, together with the opposite effects of paclitaxel and vincristine on microtubules (i.e., polymerization versus depolymerization), indicate that the enhanced apoptosis in Pgp-rich cells is specific for antimicrotubule agents but is not related to the polymerization of microtubules.