INTRATUMORAL DISTRIBUTION AS A DETERMINANT OF TUMOR RESPONSIVENESS TOTHERAPY USING POLYMER-BASED MACROMOLECULAR PRODRUGS

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 carcinom a xenografts) show only transient growth inhibition (Duncan et al., J. Control, Release, 19 (1992) 331-346). Here we have examined physiolog ical factors potentially influencing responsiveness to such macromolec ular prodrugs. Tumour uptake of drug probably contributes to response and a radiolabelled HPMA copolymer probe (297 kDa) showed passive accu mulation up to 6.6%/g (P388), 10.4%/g (B16F10) and 6.1%/g (LS174T) aft er 24-48 h. Vascular permeability is thought to influence passive targ eting, although levels of mRNA encoding the permeability-controlling v ascular endothelial growth factor (VEGF) were similar in P388 and B16F 10 rumours. Epifluorescence microscopy using FITC-dextran (70 kDa) sho wed macromolecular extravasation within all tumours, with accumulation at the periphery of B16F10 and LS174T and throughout the interstitium of P388 rumours. 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, resu lting from the distribution of hyperpermeable tumour vasculature.