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Liposomal Nω-hydroxy-l-norarginine, a proof-of-concept: Arginase inhibitors can be incorporated in liposomes while retaining their therapeutic activity ex vivo

Abstract

Cancer immunotherapy has evolved significantly over the last decade, with therapeutics targeting the adaptive immune system showing exciting effects in clinics. Yet, the modulation of the innate immune system, particularly the tumor-associated innate immune cells which are an integral part of immune responses in cancer, remains less understood. The arginase 1 (Arg1) pathway is a pivotal metabolic pathway that tumor-associated innate immune cells exploit to create an immunosuppressive tumor microenvironment, leading to the evasion of immune surveillance. The inhibition of Arg1 presents a therapeutic opportunity to reverse this immunosuppression, and Nω‑hydroxy-l-norarginine (nor-NOHA) has emerged as a potent arginase inhibitor with promising in vivo efficacy. However, the rapid systemic clearance of nor-NOHA poses a significant challenge for its therapeutic application. This study pioneers the encapsulation of nor-NOHA in liposomes, aiming to enhance its bioavailability and prolong its inhibitory activity against Arg1. Historically, the extensive interaction between innate immune cells and nanoparticles has been one of the biggest drawbacks in nanomedicine. Here we seek to utilize this effect and deliver liposomal nor-NOHA to the arginase 1 expressing innate immune cells. We systematically investigated the effect of lipid composition, acyl chain length, manufacturing and loading methodology on the encapsulation efficiency (EE%) and release profile of nor-NOHA. Our results indicate that while the manufacturing method and lipid acyl chain length do not significantly impact EE%, they crucially influence the release kinetics of nor-NOHA, with longer acyl chains demonstrating a more sustained release of nor-NOHA from liposomes enabling continuous inhibition of Arg1. Our findings suggest that liposomal nor-NOHA retains its functional inhibitory activity and could offer improved pharmacokinetic properties, making it a compelling base for iterations for further innovative cancer immunotherapeutic strategies in preclinical and clinical evaluations.
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Category

Academic article

Language

English

Author(s)

  • Elena Markova
  • Camilla Izabel Wolowczyk
  • Aly Mohamed
  • Alexandros Marios Sofias
  • Montserrat Martin-Armas
  • Rune Sundset
  • Jens Berndtsson
  • Sjoerd Hak
  • Natasa Skalko Basnet

Affiliation

  • SINTEF Industry / Biotechnology and Nanomedicine
  • University of Gothenburg
  • RWTH Aachen University
  • UiT The Arctic University of Norway
  • University Hospital of North Norway
  • Norwegian University of Science and Technology

Year

2025

Published in

European Journal of Pharmaceutical Sciences

ISSN

0928-0987

Volume

204

View this publication at Norwegian Research Information Repository