Cancer therapy based on tumor-selective macromolecules may fail due to the elevated interstitial fluid pressure (IFP) that reduces the transvascular and interstitial convection in solid tumors. Modulation of the tumor extracellular matrix (ECM) may reduce IFP and enhance transvascular filtration and interstitial transport of macromolecules. We therefore measured the effect of the ECM-degrading enzyme collagenase on IFP and microvascular pressure (MVP) in human osteosarcoma xenografts using the wick-in-needle and micropipette methods, respectively. The tumor uptake and distribution of a systemically administered osteosarcoma-associated monoclonal antibody (TP-3) after i.v. injection of collagenase were analyzed using confocal laser scanning microscopy. Collagenase (0.1%) reduced both IFP (45%) and MVP (60%), but the kinetics of the recoveries differed, because MVP had recovered by the time IFP reached its minimum level. Thus, collagenase increased the transcapillary pressure gradient, inducing a 2-fold increase in the tumor uptake and improving the distribution of the monoclonal antibody, which was localized further into the tumor. To study the mechanism of the reduction in MVP, mean arterial blood pressure was measured and found not to be affected by the collagenase treatment. The reduction in MVP was rather due to reduced vascular resistance because microvascular-associated collagen was totally or partially disintegrated. Although collagenase may favor metastasis and thus not be clinically relevant, this study shows proof of principle that degradation of the ECM leads to a favorable change in the transvascular pressure gradient, thereby increasing antibody penetration and binding to tumor cells.

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Purpose: To evaluate manganese (Mn 2ϩ )-enhanced MRI in a longitudinal study of normal and injured rat visual projections. Materials and Methods:MRI was performed 24 hours after unilateral intravitreal injection of MnCl 2 (150 nmol) into adult Fischer rats that were divided into four groups: 1) controls (N ϭ 5), 2) dose-response (N ϭ 10, 0.2-200 nmol), 3) time-response with repeated MRI during 24 -168 hours post injection (N ϭ 4), and 4) optic nerve crush (ONC) immediately preceding the MnCl 2 injection (N ϭ 7). Control and ONC animals were reinjected with MnCl 2 20 days after the first injection, and MRI was performed 24 hours later. Results:In the control group, the optic projection was visualized from the retina to the superior colliculus, with indications of transsynaptic transport to the cortex. There was a semilogarithmic relationship between the Mn 2ϩ dose and Mn 2ϩ enhancement from 4 to 200 nmol, and the enhancement decayed gradually to 0 by 168 hours. No Mn 2ϩ -enhanced signal was detected distal to the ON crush site. In the control group, similar enhancement was obtained after the first and second MnCl 2 injections, while in the ONC group the enhancement proximal to the crush site was reduced 20 days post lesion (20dpl). Conclusion:Mn 2ϩ -enhanced MRI is a viable method for temporospatial visualization of normal and injured ON in the adult rat. The observed reduction in the Mn 2ϩ signal proximal to the ONC is probably a result of retrograde damage to the retinal ganglion cells, and not of Mn 2ϩ toxicity.

Liposomal drug delivery appears to improve the antitumor effect and reduce toxicity compared with the free drug. The therapeutic index may be improved further by combining cytotoxic drugs and radiotherapy. Successful therapy requires that the cytotoxic agents reach the tumor cells. Therefore, we studied tumor growth and the microdistribution of liposomal doxorubicin (Caelyx) with and without additional ionizing radiation in human osteosarcoma xenografts in athymic mice. Caelyx was injected i.v. 1 day before single or fractionated radiotherapy. Both chemoirradiation regimens induced significant tumor growth delays and worked synergistically. Confocal laser scanning microscopy showed that intact liposomes were located in close proximity to endothelial cells, and the distribution of released doxorubicin was heterogeneous. Before radiotherapy, hardly any doxorubicin was localized in the central parts of the tumor. Radiotherapy increased the tumor uptake of doxorubicin by a factor of two to four, with drug being redistributed farther from the vessels in the tumor periphery and located around vessels in the central parts of the tumor. Colocalization of doxorubicin and hypoxic cells showed no distribution of drug into hypoxic areas. Dynamic contrastenhanced magnetic resonance imaging (MRI) 1 day before the injection of Caelyx and 2 days after treatment start showed that the combined treatment reduced the vascular volume and the vascular transfer rate of the MRI tracer. The results show that chemoirradiation with Caelyx induces synergistic treatment effects. Improved intratumoral drug uptake and distribution are responsible to some extent for the enhanced antitumor effect.