Abstract
This study sought to develop a simple nanoparticle-based approach to enhance the efficiency and tolerability of lipopolysaccharide (LPS), a potent ligand of Toll-like Receptor 4 (TLR4), for immunotherapy in cancer. Despite holding promise within this context, the strong pro-inflammatory properties of LPS also account for its low tolerability given localized and systemic side effects, which restrict the administrable dosage. Herein, we investigated the effect of LPS decoration as a surface-active molecule on a polymeric matrix upon its efficiency and tolerability. The LPS-decorated nanoparticles (LPS-NP) were about 150 nm in size, with slightly negative zeta potential (about −15 mV) and acceptable LPS incorporation (about 70%). In vitro, the particles accounted for a higher induction of apoptosis in tumor cells cultured with murine splenocytes compared to LPS solution. When used for the treatment of a murine syngeneic colorectal tumor model, higher intratumoral deposition of the particle-bound LPS was observed. Furthermore, unlike LPS solution, which accounted for localized necrosis at high concentrations, treatment of tumor-bearing animals with equivalent doses of LPS-NP was well tolerated. We propose that the observed localized necrosis can be Shwartzman phenomenon, which, due to modulated 24-h post-injection systemic TNF-α and LPS concentrations, have been avoided in case of LPS-NP. This has in turn enhanced the therapeutic efficiency and enabled complete tumor regression at concentrations at which LPS solution was intolerable. The findings indicate that nanoparticles can serve as beyond carriers for the delivery of superficially decorated LPS molecules, but impact their overall efficiency and tolerability in cancer therapy.
Highlights
Toll-like Receptor (TLR) agonists have been long since proven promising for reversing the tumor-induced ‘immune-privileged’ attenuation of the body’s immune response (Mellman et al, 2011; Beatty & Gladney, 2015)
The prepared nanoparticles had an effective diameter of 155 ± 20 nm, with an acceptable polydispersity index (PDI) of
The results demonstrated a high level of nanoparticle internalization by the macrophages, as well as a high colocalization of LPS, LPS-decorated nanoparticles (LPS-NP), and blank poly(lactic-co-glycolic acid) (PLGA) nanoparticles with polymer concentrations corresponding to those of LPS-NP
Summary
Toll-like Receptor (TLR) agonists have been long since proven promising for reversing the tumor-induced ‘immune-privileged’ attenuation of the body’s immune response (Mellman et al, 2011; Beatty & Gladney, 2015). Immunotherapy with LPS accounts for the induction of a plethora of pro-inflammatory cytokines and the upregulation of co-stimulatory molecules in antigen presenting cells (APCs). The overall outcome of this turn of events in the presence of the tumor antigens is primarily the generation of a Th1 immune response and the breakage of the tumor-induced immune tolerance (McAleer & Vella, 2008; Awasthi, 2014). Despite having undergone two phases of clinical trials, the anticancer efficiency of intravenously injected LPS has been limited due to significant side effects restricting the administrable dosage (Engelhardt et al, 1991; Otto et al, 1996). Approaches to decrease the LPS-related side effects while maintaining, or even improving, the compound’s pro-inflammatory properties have been long since sought after
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