Losartan inhibits collagen I synthesis and improves the distribution and efficacy of nanotherapeutics in tumors

TLDR

Tumor stroma rich in collagen impedes nanotherapeutic penetration and effectiveness. The study examined whether losartan, an angiotensin II receptor blocker with antifibrotic properties, could improve nanomedicine delivery and efficacy. Losartan suppressed collagen‑I synthesis by carcinoma‑associated fibroblasts, reduced stromal collagen in breast, pancreatic, and skin tumor models, and enhanced the distribution and therapeutic activity of intratumoral oncolytic HSV and intravenously administered pegylated liposomal doxorubicin, indicating its promise for desmoplastic tumors.

Abstract

The dense collagen network in tumors significantly reduces the penetration and efficacy of nanotherapeutics. We tested whether losartan--a clinically approved angiotensin II receptor antagonist with noted antifibrotic activity--can enhance the penetration and efficacy of nanomedicine. We found that losartan inhibited collagen I production by carcinoma-associated fibroblasts isolated from breast cancer biopsies. Additionally, it led to a dose-dependent reduction in stromal collagen in desmoplastic models of human breast, pancreatic, and skin tumors in mice. Furthermore, losartan improved the distribution and therapeutic efficacy of intratumorally injected oncolytic herpes simplex viruses. Finally, it also enhanced the efficacy of i.v. injected pegylated liposomal doxorubicin (Doxil). Thus, losartan has the potential to enhance the efficacy of nanotherapeutics in patients with desmoplastic tumors.