Abstract
Stimulating the patient’s immune system represents a promising therapeutic strategy to fight cancer. However, low immunogenicity of the tumor cells within an immune suppressive milieu often leads to weak anti-tumor immune responses. Additionally, the immune system may be impaired by accompanying aggressive chemotherapies. We show that mitoxantrone, bound to superparamagnetic iron oxide nanoparticles (SPIONs) as the transport system, can be magnetically accumulated in adherent HT-29 colon carcinoma cells, thereby inducing the same cell death phenotype as its soluble counterpart, a chemotherapeutic agent and prototypic inductor of immunogenic cell death. The nanoparticle-loaded drug induces cell cycle stop, apoptosis and secondary necrosis in a dose- and time-dependent manner comparable to the free drug. Cell death was accompanied by the release of interleukin-8 and damage-associated molecular patterns (DAMPs) such as HSP70 and ATP, which fostered chemotactic migration of monocytes and maturation of dendritic cells. We furthermore ensured absence of endotoxin contaminations and compatibility with erythrocytes and platelets and investigated the influence on plasma coagulation in vitro. Summarizing, with magnetic enrichment, mitoxantrone can be accumulated at the desired place, sparing healthy peripheral cells and tissues, such as immune cells. Conserving immune competence in cancer patients in the future might allow combined therapeutic approaches with immune therapies (e.g., checkpoint inhibitors).
Highlights
In recent years, immune therapies have constituted substantial improvements in tumor treatment
SPIONMTO are intended for use in magnetic drug targeting, implying that after intraarterial application, they will come into close contact with components of the blood
Since the used MTO was of pharmaceutic quality and loading was strictly performed under aseptic sterile conditions immediately preceding every experiment, sterility and absence of endotoxins was assumed for SPIONMTO
Summary
Immune therapies have constituted substantial improvements in tumor treatment. We found that cell death induced by MTO loaded onto SPIONs was accompanied by the release of danger signals in Jurkat cells, with concomitant activation of dendritic cells [28] with comparable efficacy, as may be observed with administration of the free drug. Based on these earlier findings, we further investigated the effects of MTO loaded on SPIONs in HT-29 colon carcinoma cells and its biocompatibility in blood. We confirmed that it is possible to magnetically guide MTO to the desired location and to induce tumor cell death with immunogenic features
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