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

Authors: Benjamin Diop-Frimpong, Vikash P. Chauhan, Stephen Krane, Yves Boucher, and Rakesh K. Jain

Published in: PNAS 2010, Volume 108 No. 7

Introduction

The newly developed nanotherapeutics exhibit modest efficiency in treating cancers. Studies showed that penetration of these molecules is hindered in fibrotic tumors, in which the interfibrillar spacing in the interstitium slows down the particles that are larger than 10nm.

Matrix modifiers (e.g. bacterial collagenase, relaxin, MMP-1/-8) was shown to improve the efficacy of intratumorally injected oncolytic viruses. The drawbacks are the associated toxicity to normal tissues and risk of tumro progression/metastasis (when matrix is loosen)

About Losartan

• Used to control hypertension
• Antifibrotic agent - reduce incidence of cardiac and renal fibrosis
  • Suppression of active Transforming Growth Factor-<math>\beta</math>1 (TGF-<math>\beta</math>1) levels
    • Angiotensin-II type I receptor (AGTR1)-mediated down-regulation of TGF-<math>\beta</math>1 activators (e.g. thrombospondin-1 (TSP-1) )
• At the dose, which has minial effects on mean arterial blood pressure (MABP), losartan reduces collagen I levels in tumor models, and thus improves penetration of nanoparticles

Now, the authors looked at how losartan affect distribution and efficacy of oncolytic herpes simplex viruses administered intratumorally, and Doxil administered intravenously.

Results

Effect on expression and activation of TGF-<math>\beta</math>1 and resulting collagen I production

• In mammary carcinoma-associated fibroblasts (CAFs)
• Losartan not affect levels of total TGF-<math>\beta</math>1
• Significantly reduced active TGF-<math>\beta</math>1 (90%)
• Reduced in vitro synthesis of collagen I (27%)

How about in tumors?...

Dose response

• Second-harmonic generation (SHG) signaling