Reconstituted high-density lipoprotein as a potential delivery vehicle for TAMs re-polarization agents

Date

2019-03-05

Authors

Sabnis, Nirupama
Dossou, Akpedje
Raut, Sangram
Lacko, Andras G.

ORCID

Journal Title

Journal ISSN

Volume Title

Publisher

Abstract

Purpose: As part of the tumor microenvironment, tumor-associated macrophages (TAMs) form a functionally heterogeneous population where the pro-inflammatory M1 type macrophages exert anti-tumoral function by enabling the activation of cytotoxic immune cells while immunosuppressive M2 type macrophages support tumor progression, angiogenesis, immune system evasion and metastasis. However, TAMs display a high ratio of M2 to M1 macrophages, and this polarization is promoted by tumor secretions. Thus, their presence in tumor microenvironment is associated with poor prognosis. Because the reversal from M2 to M1 constitutes an attractive cancer immunotherapy strategy, there is a need for targeted selective delivery carriers for reversal agents to avoid off-target effects. Reconstituted high density lipoprotein (rHDL) nanoparticles (NPs) are biocompatible with various administration routes, and they have been confirmed to deliver their cargo to targeted cells via a scavenger receptor class B type 1 (SR-B1)-mediated uptake. In addition, Apolipoprotein A1 (ApoA1), one of the components of the rHDL NP, has been shown to promote a M2 to M1 reversal of TAMs. Hence, we propose that rHDL NPs are particularly appropriate to deliver specific re-polarizing agents to TAMS to achieve a predominately M1 type TAM population, and thus enhance the effectiveness of tumor immunotherapy. Methods: The rHDL NPs were prepared using egg yolk phosphatidylcholine, free cholesterol, cholesterol oleate and the ApoA1 protein. The size, polydispersity index and zeta potential of the NPs were assessed by dynamic light scattering. Transmission electron microscopy confirmed size and uniformity of the rHDL NP preparation. Raw 264.7 macrophages were polarized to M1, M2a and M2c by using respectively lipopolysaccharide + interferon-gamma, interleukin-4, and interleukin-10. Protein expression was confirmed via immunoblot. Results: The rHDL NPs show a sub-50 nm size and form a fairly homogeneous preparation. M2 type macrophages display a higher SR-B1 expression than the M1 type (Raw 264.7 macrophages). Conclusions: Findings of these and earlier studies show that the rHDL NPs may be particularly suited to deliver reversal (re-polarizing) agents to M2 macrophages.

Description

Keywords

Citation

Rights

License

Collections