Sesquiterpene-Loaded Co-Polymer Hybrid Nanoparticle Effects on Human Mast Cell Surface Receptor Expression, Granule Contents, and Degranulation.

Narcy Arizmendi,Yiming Li,Hui Qian,Marianna Kulka

doi:10.3390/nano11040953

Abstract

Biodegradable polymeric nanoparticles (NPs) such as poly(lactic-co-glycolic acid) (PLGA) and polyvinyl alcohol (PVA) have been used as drug delivery systems for natural and synthetic compounds and are designed to control the loading and release of biodegradable materials to target cells, tissues, and organs. Eremophilane-type sesquiterpenes have anti-inflammatory properties but are lipophilic, cytotoxic, and not biocompatible with many cells. To determine whether biodegradable PLGA/PVA could improve the biocompatibility of sesquiterpenes, sesquiterpene-loaded NPs were synthesized and their effects on human mast cells (LAD2), the major effector cells of allergic inflammation, were determined. NPs composed of PLGA/PVA and two types of sesquiterpenes (fukinone, PLGA/PVA-21 and 10βH-8α,12-epidioxyeremophil-7(11)-en-8β-ol, PLGA/PVA-22) were produced using a microfluidic synthesis method. The NPs’ size distribution and morphology were evaluated by dynamic light scattering and cryogenic transmission electron microscopy (TEM). PLGA/PVA-21 and PLGA/PVA-22 were 60 to 70 nm and were readily internalized by LAD2 as shown by flow cytometry, fluorescence microscopy, and TEM. While unencapsulated sesquiterpenes decreased LAD2 cell viability by 20%, PLGA/PVA-21 and PLGA/PVA-22 did not alter LAD2 viability, showing that encapsulation improved the biocompatibility of the sesquiterpenes. PLGA/PVA-21 and PLGA/PVA-22 decreased the expression of genes encoding the subunits of the high affinity immunoglobulin E receptor (FcεR1α, FcεR1β, FcεR1γ) and the stem cell factor receptor (Kit,), suggesting that hybrid NPs could alter mast cell responses to antigens and shift their maturation. Similarly, PLGA/PVA-21 and PLGA/PVA-22 inhibited tryptase expression but had no effect on chymase expression, thereby promoting a shift to the tryptase-positive phenotype (MCT). Lastly, PLGA/PVA-21 and PLGA/PVA-22 inhibited mast cell degranulation when the LAD2 cells were activated by IgE crosslinking and FcεRI. Overall, our results suggest that PLGA/PVA-21 and PLGA/PVA-22 alter human mast cell phenotype and activation without modifying viability, making them a more biocompatible approach than treating cells with sesquiterpenes alone.

Highlights

Licensee MDPI, Basel, Switzerland.Drug-delivery of lipophilic payloads to specific intracellular compartments is challenging
Eremophilane-type SQs used in these studies are bicyclic terpenes and are referred to as SQ, and SQ (10βH-8α, 12-epidioxyeremophil-7(11)-en8β-ol, SQ22, Figure 1B)
To determine whether SQ21 or SQ22 were biocompatible with human LAD2 cells, we measured the metabolic activity of human LAD2 mast cells exposed to different concentrations (12.5, 25 and 50 μM) of SQ21 (Figure 1C), or SQ22 (Figure 1E) for 1, 3, 48, or 72 h

Summary

Introduction

Drug-delivery of lipophilic payloads to specific intracellular compartments is challenging. The delivery vehicle must allow for the stable incorporation and loading of the constituent components, including the target payload. The delivery vehicle must possess the necessary chemical composition to release the payload in the target organelle or cellular compartment. When targeting complex immune cells such as granulocytes (basophils and mast cells), these conditions are especially challenging.

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