Polymer-peptide conjugates for angiogenesis targeted tumor radiotherapy.

ABSTRACT

INTRODUCTION: New methods of delivering radiotherapy to sites of occult or disseminated cancer are needed to control the disease and address the failure of conventional therapy. Because tumor cells rely on angiogenesis for survival, we assessed the effectiveness of beta-emitter radiotherapy delivered by polymer-peptide conjugates that target tumor neovasculature. This molecularly targeted radiation is intended to damage both the endothelial bed and surrounding neoplastic cells. METHODS: N-(2-Hydroxypropyl) methacrylamide (HPMA), a biocompatible and water-soluble copolymer, was derivatized to incorporate side chains for (99m)Tc and (90)Y chelation and was further conjugated to a alpha(V)beta(3) integrin-targeting peptide (RGD4C). The HPMA copolymer-RGD4C conjugate was characterized by its side-chain contents, in vitro endothelial cell adhesion assay and its biodistribution and antitumor effectiveness in a SCID mouse xenograft model of human prostate carcinoma. RESULTS: The conjugate contained about 16 RGD4C moieties per polymer backbone. Tumor accumulation significantly increased (P < .01) over time from 1.05 +/- 0.03 % injected dose (%ID)/g tissue at 1 h to 4.32 +/-0.32% at 72 h. The activity in major normal tissues significantly decreased (P < .05) during that period. At 21 days, the control tumors increased 442% in volume from baseline. In contrast, a 7% and a 63% decrease of tumor volume were observed for the 100- and 250-microCi (90)Y treatment groups, respectively. Histopathological examination revealed increased apoptosis in the treated tumors with no acute signs of radiation-induced toxicity to other organs. CONCLUSION: This copolymer-peptide conjugate targets tumor angiogenic vessels and delivers sufficient radiotherapy to arrest tumor growth.