Multivalent Presentation of MPL by Porous Silicon Microparticles Favors T Helper 1 Polarization Enhancing the Anti-Tumor Efficacy of Doxorubicin Nanoliposomes

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.

Co-loaded paclitaxel/rapamycin liposomes: Development, characterization and in vitro and in vivo evaluation for breast cancer therapy

“…These cells are highly tumorigenic, invasive, and can spontaneously metastize to distant sites, including lymph nodes, blood, liver, lung, brain and bone. Therefore, 4T1 tumor has many characteristics that make it an adequate experimental model for human mammary breast cancer and has been employed for the therapeutic efficacy evaluation of drugs and nanoparticles in breast cancer [5,32,52]. …”

“…After injection, the time for tumor appearance was 10–14 days, when the treatment was started [32]. Lyophilized liposomes and negative and positive controls were diluted in PBS buffer, pH 7.4, prior to administration.…”

Tailoring Porous Silicon for Biomedical Applications: From Drug Delivery to Cancer Immunotherapy

“…The surface of these microparticles can also be modified with adjuvants: Meraz et al adsorbed lipopolysaccharide (LPS) or monophosphoryl lipid A (MPLA) on PSi microparticles evaluating first the effect of the particles on the immune system, as shown in Figure , followed by the assessment of the efficacy of a combinatorial therapy based on adjuvant‐modified microparticles administered with DOX‐loaded liposomes . The microparticles alone (presenting a positively charged surface, APTES), despite promoting the secretion of the proinflammatory cytokine interleukin‐1β (IL‐1β) due to activation of the inflammasome, did not induce the maturation of murine bone marrow‐derived dendritic cells .…”

“…The microparticles alone (presenting a positively charged surface, APTES), despite promoting the secretion of the proinflammatory cytokine interleukin‐1β (IL‐1β) due to activation of the inflammasome, did not induce the maturation of murine bone marrow‐derived dendritic cells . On the contrary, the administration of the LPS/MPLA‐modified particles alone or in combination with DOX resulted in maturation of DCs, migration of DCs pulsed with the particles to the lymph nodes, enhanced control over the tumor development in a murine model of breast cancer after intravenous administration, and in a modification of the tumor microenvironment, with the increase in the number of CD8 + T‐cells …”

“…a1–a4) Adapted with permission . Copyright 2014, Elsevier B.V. b) Adapted with permission . Copyright 2014, Public Library of Science.…”