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Abstract
Porous silicon (pSi) microparticles, in diverse sizes and shapes, can be functionalized to present pathogen-associated molecular patterns that activate dendritic cells. Intraperitoneal injection of MPL-adsorbed pSi microparticles, in contrast to free MPL, resulted in the induction of local inflammation, reflected in the recruitment of neutrophils, eosinophils and proinflammatory monocytes, and the depletion of resident macrophages and mast cells at the injection site. Injection of microparticle-bound MPL resulted in enhanced secretion of the T helper 1 associated cytokines IFN-γ and TNF-α by peritoneal exudate and lymph node cells in response to secondary stimuli while decreasing the anti-inflammatory cytokine IL-10. MPL-pSi microparticles independently exhibited anti-tumor effects and enhanced tumor suppression by low dose doxorubicin nanoliposomes. Intravascular injection of the MPL-bound microparticles increased serum IL-1β levels, which was blocked by the IL-1 receptor antagonist Anakinra. The microparticles also potentiated tumor infiltration by dendritic cells, cytotoxic T lymphocytes, and F4/80+ macrophages, however, a specific reduction was observed in CD204+ macrophages.
Highlights
The physico-chemical properties of synthetic particles have a major impact on their cellular associations, biodistribution, degradation, and immuno-modulatory properties
For the first time we examine in depth the in vivo immunomodulatory properties of porous silicon (pSi) microparticles and the impact of multivalent presentation of monophosphoryl lipid A (MPL), as well as the combined potential of these agents to augment the immunomodulatory properties of chemotherapeutics
Fabrication of pSi Microparticles Discoidal (D) and rod-shaped (R) pSi microparticles were fabricated by a process that consists of electrochemical etching of silicon films to create pores, photolithographic patterning of microparticle dimensions on pSi films, and reactive ion etch (RIE)
Summary
The physico-chemical properties of synthetic particles have a major impact on their cellular associations, biodistribution, degradation, and immuno-modulatory properties. We previously demonstrated [14] that porous silicon (pSi) microparticles enhance lipopolysaccharide (LPS) and MPL mediated DC secretion of proinflammatory cytokines that are associated with successful cancer immunosurveillance. [15] Direct attachment of the molecule to the particle surface generated a multivalent ligand for TLR-4, with superior activation of downstream pathways compared to free MPL or LPS leading to secretion of IL-1b and proinflammatory cytokines such as TNF-a. [16] pSi presentation of adsorbed MPL led to increased particle uptake by DC; elevated DC expression of costimulatory and major histocompatibility complex (MHC) class I and II molecules; stimulated migration of DC to the draining lymph node; and enhanced associations between DCs presenting the ovalbumin peptide SIINFEKL and T cells from C57BL/6Tg(TcraTcrb) (OT-1) transgenic mice [14] PSi microparticle stimulated IL-1b secretion was caspase-dependent and slightly elevated in the presence of cytochalasin B, [14] which is known to induce frustrated phagocytosis, locking silicon microparticles on the cell surface in actin rings, thereby inducing sustained engagement of surface receptors. [16] pSi presentation of adsorbed MPL led to increased particle uptake by DC; elevated DC expression of costimulatory and major histocompatibility complex (MHC) class I and II molecules; stimulated migration of DC to the draining lymph node; and enhanced associations between DCs presenting the ovalbumin peptide SIINFEKL and T cells from C57BL/6Tg(TcraTcrb) (OT-1) transgenic mice [14]
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