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.