Microneedle-Delivered Nanoparticles Boost Antitumor Vaccines
In the quest to develop anti-cancer vaccines that would stimulate the body to destroy tumors and keep them from recurring, researchers continually run into the same problem – the immune-stimulating proteins, known as antigens, are not interacting effectively with the key immune system cells that trigger long-lasting immune responses. Now, using a novel administration system and polymer nanoparticles, a team of investigators led by Adrien Kissenpfennig of Queen’s University Belfast has shown that they can deliver anticancer antigens to dendritic cells and trigger an effective immune system response against melanoma tumors.
There were two keys to the Irish team’s success, which they reported in the journal ACS Nano. First, Dr. Kissenpfennig and his colleagues used an array of dissolving microneedles to deliver antigens into the dermis, the second layer of tissue that forms the skin. In this case, the researchers used a polymeric, water-soluble microneedle array that was just long enough to penetrate the outer layer of skin but not so long as to hit sensory nerves in the dermis.
Once the array penetrates the skin, the biocompatible microneedles break off and remain embedded in the dermis. There, they slowly dissolve and release the second key component – biocompatible polymer nanoparticles loaded with a protein found on the surface of a particular type of melanoma tumor. For this study, the investigators used the protein ovalbumin and tested their system’s ability to attack so-called B16 melanoma cells that express ovalbumin on their surface.
Many studies have shown that antigens released slowly in the dermis trigger a strong immune response. In particular, this route of vaccination appears to promote the development of CD8-positive cytotoxic T cells at higher levels that is achieved using standard intramuscular injection of antigens. The reason for this enhanced response is that the dermis is rich in dendritic cells, which play an essential role in processing foreign proteins and "presenting them" to the immune system.
The results of this study follow that trend, as the nanoparticle-encapsulated antigen triggered the production of specific CD8-positive T cells for ovalbumin. Moreover, this response was indeed mediated by dendritic cells that took up the slowly released ovalbumin protein. In fact, the investigators showed that their microneedle-nanoparticle system was able to maintain high levels of ovalbumin-processing dendritic cells for at least seven days that in turn were able to evoke significantly increased production of ovalbumin-specific CD8-positive T cells.
Given these results, Dr. Kissenpfennig’s team conducted experiments to determine if this immune response would have any effect on ovalbumin-expressing melanoma tumors. Three weeks after immunizing mice one time using microneedles loaded with ovalbumin-containing nanoparticles, the researchers injected ovalbumin-expressing B16 melanoma cells into the inoculated animals. At the end of the16-day test period, none of the immunized animals had any tumors, while tumors grew significantly in animals injected with empty nanoparticles.
This work is detailed in a paper titled, "Skin dendritic cell targeting via microneedle arrays laden with antigen-encapsulated poly-D,L-lactide-co-glycolide nanoparticles induces efficient antitumor and antiviral immune responses." Investigators from the Aix Marseille Université, Institut National de la Santé et de la Recherche Médicale (INSERM), and Centre National de la Recherche Scientifique (CNRS) also participated in this study. An abstract of this paper is available at the journal’s website.View full paper