Abstract
Certain solid tumours (e.g., P388 murine leukaemia) regress completely when treated with soluble polymer-based prodrugs such as doxorubicin-N-(2-hydroxypropyl) methacrylamide (HPMA) copolymer conjugates, while others (e.g., B16F10 murine melanoma, LS174T human colorectal carcinoma xenografts) show only transient growth inhibition (Duncan et al., J. Control. Release, 19 (1992) 331-346). Here we have examined physiological factors potentially influencing responsiveness to such macromolecular prodrugs. Tumour uptake of drug probably contributes to response and a radiolabelled HPMA copolymer probe (297 kDa) showed passive accumulation up to 6.6%/g (P388), 10.4%/g (B16F10) and 6.1%/g (LS174T) after 24-48 h. Vascular permeability is thought to influence passive targeting, although levels of mRNA encoding the permeability-controlling vascular endothelial growth factor (VEGF) were similar in P388 and B16F10 tumours. Epifluorescence microscopy using FITC-dextran (70 kDa) showed macromolecular extravasation within all tumours, with accumulation at the periphery of B16F10 and LS174T and throughout the interstitium of P388 tumours. The greater chemosensitivity to doxorubicin of P388 cells (IC50 120 nM) compared with B16F10 (688 nM) and LS174T (723 nM) probably contributes to responsiveness, although the amount of prodrug reaching the tumour may be less important than its localisation, resulting from the distribution of hyperpermeable tumour vasculature.