INNO Indigo, Multilayer Nano-Capsules and targeted DNA vaccines for Immunotherapy of Cancer

Nanotechnology plays an important role in delivery of drugs in various diseases. The Inno Indigo project is an EU/India consortium that wants to develop a multivalent nano-platform to engineer nanoparticles that can selective deploy tumoricidal drugs and cancer DNA vaccines. The UoO partner of the project will develop targeted DNA vaccine against myeloma, a B cell cancer. Nanoparticles are passivly targeting tumors because of the leaky vasculature of the tumors that accumulate the nanoparticles at the tumor site. Natural compounds like curcumin have been suggested to sensitize tumor cells and induce cell apoptosis. The major hurdle in assigning natural compounds like curcumin are in vivo stability, non-specific biodistribution and non-specific targeting properties. Loading of curcumin onto nanoparticles is a strategy to increase the stability and to increase the amount reaching the tumor cells. Conjugating folat to the nanoparticles will attract the nanoparticles to cancer cells overexpressing the receptor and thereby active target the vaccines to the cancer cells. These novel folat-conjugated particles were loaded with curcumin and showed a pH-sensitive release of drug. This suggests the drug to be released within the tumor, often associated with low pH. We also found that the particles containing curcumin reduced the growth of tumor cell lines and inhibited their migration. The particles also showed in vivo anti-tumor effect in mice. Subunit vaccines are compared to normal protein vaccines attractive as vaccine due to their ability to focus the immune response towards the antigen of interest. But the subunit vaccines often suffer from low immunogenicity. Targeted vaccines are shown to be more efficient than conventional antigen-vaccines since the targeting is directing the antigen to the antigen-presenting cells, like the dendritic cells, the cells involved in the induction of antigen-specific immunoresponses. The targeting involves specific binding of unique receptors found on these dendritic cells. Upon binding to the receptor, the cells are activated and further activate humoral and cytotoxic immune responses against the antigen. We compared nine various targeting units in BALB/c mice. We found that the targeting affected the magnitude and IgG subclass of antibodies elicited, suggesting the targeting to direct the immunoresponse into a Th1 or Th2 response. When targeting the vaccine to cross presenting dendritic cells, the vaccine will induce tumor-specific Th1 responses and cytotoxic CD8+ T cells important to protect against tumor. Targeted tumor DNA vaccines followed by electroporation, needed for an efficient translation of the DNA vaccine into protein vaccine, are tested in a myeloma and a B-cell lymphoma mouse experimental model. These vaccines showed protection against tumor. The vaccinated mice had higher levels of antigen-specific IFN-gamma T cells and deletion of CD8+ T cells prevented the vaccine-induced protection. Closer analysis of the delivery site suggested intra muscular to be superior to intra dermal DNA vaccination, in induction of cytotoxic T cells and thereby protection against cancer. The aim is to combined nanoparticles with these DNA vaccines to increase the protection against tumor.

Cancer remains a challenge of modern mortality as the treatment regimens are still not sufficient to overcome it. Folic acid-nanoconjugates Nanocapsule have the capacity to replace currently used toxic anticancerous agents which thus provides an innovative direction for research in novel non-conventional agent`s highly applicable in the field of biomedicine. The nanoconjugate increased the anticancer effect of natural compound curcumin. Similarly, the use of DNA vaccine against tumor is likely to have few side-effects compared to current cancer treatments (surgery, chemotherapy, and irradiation). The project may therefore result in new and better treatment of human multiple myeloma. The social benefit of establishing efficient cancer vaccines is obvious.

Nanotechnology plays an important role in delivering drugs or DNA vaccines in various disease models. In this project, using multivalent nano-platform, we will engineer nanoparticles that can selective deploy tumoricidal drugs and DNA vaccines. The UIO partner of the project will develop targeted DNA vaccines that encode B-cell cancer antigens. When targeting the vaccine to crosspresenting dendritic cells via specific receptors, cytotoxic CD8+ Tcells against the tumor will be induced. These targeted tumor vaccines will be tested in the MOPC315 myloma and the A20 B lymphoma mouse experimental models. These vaccines will be evaluated in the cancer models for in vivo efficiacy as DNA vaccination with electroporation, targeted protein vaccine combined with laser poration of skin (PLEASE apparatus). Finally, nanoparticles developed by the other partners of the project, containing DNA or mRNA as well as protein with adjuvants will be evaluated as a vaccine delivery platform.