Abstract
Currently, there is a great interest in nanoparticle-based vaccine delivery. Recent studies suggest that nanoparticles when introduced into the biological milieu are not simply passive carriers but may also contribute immunological activity themselves or of their own accord. For example there is considerable interest in the biomedical applications of one of the physiologically-based inorganic metal oxide nanoparticle, zinc oxide (ZnO). Indeed zinc oxide (ZnO) NP are now recognized as a nanoscale chemotherapeutic or anticancer nanoparticle (ANP) and several recent reports suggest ZnO NP and/or its complexes with drug and RNA induce a potent antitumor response in immuno-competent mouse models. A variety of cell culture studies have shown that ZnO NP can induce cytokines such as IFN-γ, TNF-α, IL-2, and IL-12 which are known to regulate the tumor microenvironment. Much less work has been done on magnesium oxide (MgO), cobalt oxide (Co3O4), or nickel oxide (NiO); however, despite the fact that these physiologically-based metal oxide NP are reported to functionally load and assemble RNA and protein onto their surface and may thus also be of potential interest as nanovaccine platform. Here we initially compared in vitro immunogenicity of ZnO and Co3O4 NP and their effects on cancer-associated or tolerogenic cytokines. Based on these data we moved ZnO NP forward to testing in the ex vivo splenocyte assay relative to MgO and NiO NP and these data showed significant difference for flow cytometry sorted population for ZnO-NP, relative to NiO and MgO. These data suggesting both molecular and cellular immunogenic activity, a double-stranded anticancer RNA (ACR), polyinosinic:poly cytidylic acid (poly I:C) known to bind ZnO NP; when ZnO-poly I:C was injected into B16F10-BALB/C tumor significantly induced, IL-2 and IL-12 as shown by Cohen’s d test. LL37 is an anticancer peptide (ACP) currently in clinical trials as an intratumoral immuno-therapeutic agent against metastatic melanoma. LL37 is known to bind poly I:C where it is thought to compete for receptor binding on the surface of some immune cells, metastatic melanoma and lung cells. Molecular dynamic simulations revealed association of LL37 onto ZnO NP confirmed by gel shift assay. Thus using the well-characterized model human lung cancer model cell line (BEAS-2B), poly I:C RNA, LL37 peptide, or LL37-poly I:C complexes were loaded onto ZnO NP and delivered to BEAS-2B lung cells, and the effect on the main cancer regulating cytokine, IL-6 determined by ELISA. Surprisingly ZnO-LL37, but not ZnO-poly I:C or the more novel tricomplex (ZnO-LL37-poly I:C) significantly suppressed IL-6 by >98–99%. These data support the further evaluation of physiological metal oxide compositions, so-called physiometacomposite (PMC) materials and their formulation with anticancer peptide (ACP) and/or anticancer RNA (ACR) as a potential new class of immuno-therapeutic against melanoma and potentially lung carcinoma or other cancers.
Highlights
There is a great deal of current interest in nanoparticle delivery of vaccines and immuno-therapeutics [1,2]
zinc oxide (ZnO) and Co3O4 NP have been evaluated against macrophages (RAW264.7) and transformed lung cells (BEAS-2B) [28]
Complexation of ZnO to immunogenic RNA or anticancer peptide (ACP) such as LL37 had quite distinct effects, in the former case inducing cytokines associated with regulating the metastatic tumor niche (Table 1) and in the latter inhibiting pro-tumor cytokine (Figure 4)
Summary
There is a great deal of current interest in nanoparticle delivery of vaccines and immuno-therapeutics [1,2]. I:C-iron oxide nanoparticle complexes have been used for immune cell targeting [5] Certain cytokines such as interleukin-6 (IL-6) are thought to play a key role in cancer progression and resistance to therapy [6]. Whereas others such as IL-1, IL-4, IL-10 may be involved in cancer tolerogenicity [7]. Other cytokines such as IL-2, IL-2, TNF-α, and IFN-γ are thought to regulate the metastatic tumor niche and play a key role in regulating cells of the immune system recruited into this environment [3]. The effect of inorganic NP such as ZnO and others or their RNA and peptide complexes on tumor associated cytokines is a very important question
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