Optimization of Liposomes for Antigen Targeting to Splenic CD169+ Macrophages.

Maarten K Nijen Twilhaar,Cornelus F Van Nostrum,Joanna Grabowska,Chun Yin Jerry Lau,Katarzyna Olesek,Alsya J Affandi,Hakan Kalay,Joke M.M Den Haan,Lucas Czentner,Gert Storm,Yvette Van Kooyk

doi:10.3390/pharmaceutics12121138

Maarten K Nijen Twilhaar, Cornelus F Van Nostrum + Show 9 more

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https://doi.org/10.3390/pharmaceutics12121138

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Abstract

Despite promising progress in cancer vaccination, therapeutic effectiveness is often insufficient. Cancer vaccine effectiveness could be enhanced by targeting vaccine antigens to antigen-presenting cells, thereby increasing T-cell activation. CD169-expressing splenic macrophages efficiently capture particulate antigens from the blood and transfer these antigens to dendritic cells for the activation of CD8+ T cells. In this study, we incorporated a physiological ligand for CD169, the ganglioside GM3, into liposomes to enhance liposome uptake by CD169+ macrophages. We assessed how variation in the amount of GM3, surface-attached PEG and liposomal size affected the binding to, and uptake by, CD169+ macrophages in vitro and in vivo. As a proof of concept, we prepared GM3-targeted liposomes containing a long synthetic ovalbumin peptide and tested the capacity of these liposomes to induce CD8+ and CD4+ T-cell responses compared to control liposomes or soluble peptide. The data indicate that the delivery of liposomes to splenic CD169+ macrophages can be optimized by the selection of liposomal constituents and liposomal size. Moreover, optimized GM3-mediated liposomal targeting to CD169+ macrophages induces potent immune responses and therefore presents as an interesting delivery strategy for cancer vaccination.

Highlights

Cancer development is started by the malignant transformation of cells caused by the successive accumulation of mutations that alter protein expression and the behavior of cells [1]
We have evaluated the effects of the amount of incorporated GM3, the presence of surface-exposed PEG and particle size on liposomal targeting and conclude that small (i.e., 200 nm) liposomes with 3 mol% GM3 and without PEG are the most optimal for targeting splenic CD169+ MΦ
Splenic metallophilic marginal zone and lymph node subcapsular sinus MΦ express high levels of CD169 and are known for their capacity to capture particles such as viruses and extracellular vesicles (EVs), which are enriched in gangliosides, including GM3 [31,32,33,34,35,36]

Summary

Introduction

Cancer development is started by the malignant transformation of cells caused by the successive accumulation of mutations that alter protein expression and the behavior of cells [1]. The power of the immune system is illustrated by the effectiveness of checkpoint inhibitor immunotherapies in patients with melanoma, which can lead to the significant prolongation of survival and sometimes even to complete tumor regression [5]. These beneficial responses are only observed in a minority of patients and can be linked to the presence of a pre-existing immune response [6,7]. Classical vaccines that consist of protein, peptide, RNA or DNA and are supplemented with an adjuvant do not always result in robust antigen presentation by DCs and lead to suboptimal CD8+ T-cell responses [9]. An alternative approach is to design a vaccine that consists of a tumor antigen and adjuvant and has an enhanced capacity to be taken up by DCs [13,14]

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