An Iron Oxide Nanocarrier for dsRNA to Target Lymph Nodes and Strongly Activate Cells of the Immune System

Abstract

The success of nanoparticle-based therapies will depend in part on accurate delivery to target receptors and organs. There is, therefore, considerable potential in nanoparticles which achieve delivery of the right drug(s) using the right route of administration to the right location at the right time, monitoring the process by non-invasive molecular imaging. A challenge is harnessing immunotherapy via activation of Toll-like receptors (TLRs) for the development of vaccines against major infectious diseases and cancer. In immunotherapy, delivery of the vaccine components to lymph nodes (LNs) is essential for effective stimulation of the immune response. Although some promising advances have been made, delivering therapeutics to LNs remains challenging. It is here shown that iron-oxide nanoparticles can be engineered to combine in a single and small (<50 nm) nanocarrier complementary multimodal imaging features with the immunostimulatory activity of polyinosinic-polycytidylic acid (poly (I:C)). Whilst the fluorescence properties of the nanocarrier show effective delivery to endosomes and TLR3 in antigen presenting cells, MRI/SPECT imaging reveals effective delivery to LNs. Importantly, in vitro and in vivo studies show that, using this nanocarrier, the immunostimulatory activity of poly (I:C) is greatly enhanced. These nanocarriers have considerable potential for cancer diagnosis and the development of new targeted and programmable immunotherapies.

An Iron Oxide Nanocarrier Loaded with a Pt(IV) Prodrug and Immunostimulatory dsRNA for Combining Complementary Cancer Killing Effects

“…Recently, we demonstrated that poly (I:C) could be attached noncovalently to IONP‐filled micelles of commercially available PEGlyated phospholipids with different end groups . In this type of construct, the PEG–RNA interaction takes place via the RNA bases and the phosphate backbone through multiple hydrophobic and hydrophilic contacts and the phospholipid hydrocarbon chains form hydrophobic interactions with the hydrophobic groups decorating the IONP . We envisaged that poly(I:C) would, therefore, associate also with Pt(IV) prodrug‐modified PEGylated phospholipids.…”

“…Using poly (I:C) tumor growth inhibition has been achieved via stimulation of DCs, which results in activation and maturation of T‐cells and natural killer (NK) cells to kill the cancer cells ( Scheme ) . A few recent studies have shown the excellent potential and unprecedented advantages of using inorganic NPs functionalized with immunomodulatory molecules to assist in the generation of high immunostimulatory activity while acting as an imaging agent …”

Engineering Nanoparticles to Overcome Barriers to Immunotherapy

“…74 To evaluate the localization and biodistribution of nanoparticle vaccines, evaluation of trafficking to the lymph nodes can be conducted in vivo by magnetic resonance imaging (MRI) or singlephoton emission computed tomography (SPECT) with iron oxide or radioisotope labeling, respectively. 75…”

Development of Drugs Based on High-Polymeric Double-Stranded RNA for Antiviral and Antitumor Therapy

“…dsRNA delivery systems are also developed on the basis of inorganic molecules. For example, iron oxide nanoparticles were used for PolyI:PolyC delivery to lymph nodes and this led to a significant increase in the immune response [93]. Immunization of mice with calcium phosphate particles containing PolyI:PolyC and CpG dinucleotide promoted their intensive uptake by DC and this was accompanied by the expansion of pathogen-specific CD4+ and CD8+ T-lymphocytes [94].…”