Polymerized Albumin Receptor of Hepatitis B Virus for Evading the Reticuloendothelial System.

Kurumi Takagi,Shun’Ichi Kuroda,Joohee Jung,Masumi Iijima,Masaharu Somiya

doi:10.3390/ph14050408

Abstract

Various strategies, such as optimization of surface chemistry, size, shape, and charge, have been undertaken to develop nanoparticles (NPs) as DDS (drug delivery system) nanocarriers for evading the reticuloendothelial system (RES) in vivo. We previously developed a hollow NP composed of hepatitis B virus (HBV) surface antigen L proteins and lipid bilayers, hereinafter referred to as bio-nanocapsule (BNC), as a nonviral DDS nanocarrier. Such a BNC harbors the HBV-derived human hepatic cell-specific infection mechanism, and intravenously injected BNCs by themselves were shown to avoid clearance by RES-rich organs and accumulate in target tissues. In this study, since the surface modification with albumins is known to prolong the circulation time of nanomedicines, we examined whether the polymerized albumin receptor (PAR) of BNCs contributes to RES evasion in mouse liver. Our results show that NPs conjugated with peptides possessing sufficient PAR activity were captured by Kupffer cells less efficiently in vitro and were able to circulate for a longer period of time in vivo. Comparing with polyethylene glycol, PAR peptides were shown to reduce the recognition by RES to equal content. Taken together, our results strongly suggest that the PAR domain of BNCs, as well as HBV, harbors an innate RES evasion mechanism. Therefore, the surface modification with PAR peptides could be an alternative strategy for improving the pharmacodynamics and pharmacokinetics of forthcoming nanomedicines.

Highlights

We found that BNCs showed strong and weak avidity to polymerized human serum albumin (pHSA) and polymerized mouse serum albumin (pMSA), respectively, did not bind to monomeric albumins (HSA or mouse serum albumin (MSA))
Through the surface modification with hepatitis B virus (HBV)-derived polymerized albumin receptor (PAR) peptides, we demonstrate that NPs were able to escape from the uptake by Kupffer cells efficiently in vitro and show a reticuloendothelial system (RES) evasion in vivo
We show that hepatocytes incorporated fewer NPs displaying PAR peptides than albumin-modified NPs, both in vitro and in vivo

Summary

Introduction

Phagocytosis of NPs is known to be regulated by two major mechanisms: opsonization-dependent and opsonization-independent mechanisms [2] The former is triggered by the opsonization of the NP surface, and NPs that are modified with opsonins (e.g., antibodies, complements, and fibronectins) in the bloodstream are recognized by either Fcγ receptors or complement receptor 3 on phagocytes and promptly excluded from the bloodstream [3]. The latter mechanism is triggered by negative charges of NPs and mediated by scavenger receptors [4]

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Discussion

Conclusion