CAREER: Colloidal Micelles as Multifunctional Vaccines

Massachusetts Institute Of Technology, Cambridge MA

Investigators

Abstract

0348259 Irvine Vaccination has produced some of the most spectacular successes in modern medicine, including the elimination of smallpox and the control of diseases such as polio and tuberculosis. However, traditional vaccines have failed to initiate primary immune responses that provide protection against persistent viral infections (e.g. HIV, hepatitis C, malaria) and also have not succeeded in a therapeutic setting, as might be desirable for treatment of cancer patients. During the primary immune response, dendritic cells (DCs) are key 'sentinel' cells responsible for the collection of foreign antigen, which is broken down into peptides and presented on Major Histocompatibility Complex (MHC) molecules to activate naive T cells. The investigators hypothesize that improved vaccines can be obtained by addressing 3 limitations of current vaccination strategies: failure to ensure co-delivery of antigen and DC activation signals, lack of antigen loading on class I MHC, and limited numbers of DCs 'vaccinated'. The approach taken is to deliver DC-specific molecular cues using engineered synthetic polymers that sequentially attract dendritic cells, provide activation signals, and deliver large quantities of antigen to intracellular MHC loading pathways. Delivery will be achieved by the synthesis of two components: hydrogel nanoparticles that deliver encapsulated antigen and trigger DC activation through surface-immobilized ligands, and degradable microspheres that release chemokines at a controlled rate to create an in situ DC-specific attractant gradient at the vaccination site. These two components will be assembled into colloidal micelles formed by linking the antigen delivery/DC activation gel particles to the surface of the chemoattractant-releasing microspheres, promoting physical co-localization of the gel particle signaling component of the vaccine with the source of the chemoattractant gradient. The platform technology developed will allow specific antigen and DC activation signals to be readily tailored to program dendritic cells to respond in the most effective manner in a given clinical setting. The specific aims are: 1) synthesize antigen delivery/DC activation nanoparticle gels and characterize their function in vitro, to determine how coupling particle-based antigen to activation signal delivery affects the function of dendritic cell; 2) synthesize chemoattraction microspheres and characterize dendritic cell attraction to the microspheres in vitro, to determine how DC accumulation by a chemoattracting vaccine varies with the identity of the chemoattractant and quantitative temporal/spatial characteristics of the chemoattractant concentration profile and 3) combine the components from Aims 1 and 2 by fabricating nanoparticle-microsphere colloidal micelles, and characterize in vitro dendritic cell attraction and antigen loading by the complete vaccine, to determine whether physical co-localization of vaccine components can increase the number of activated, antigen-loaded DCs. The educational goals focused on exposing undergraduate students and school-aged students to the excitement and growing possibilities in research at the interface of materials and biology. Specific activities include the development of a summer program recruiting undergraduates to design laboratory experiment modules that will be used 1) as teaching tools in the MIT undergraduate materials science curriculum and 2) as outreach demonstrations to teach elementary and high school-aged students about the content of materials science and its application to biotechnology and bioengineering.