Currently, the standard of care for cancer therapy has limited specificity to only tumor tissue, and can cause devastating side effects. Cancer vaccines utilize the immune system to generate a sustainable and specific anti-tumor response, providing a promising means to improve cancer therapy. However, delivery of vaccine antigen/peptide to dendritic cells (DCs) remains a limiting factor for persistent anti-tumor immune response. Thus, there is a profound need for designing delivery vehicles for vaccine peptides. Current nanocarriers mainly consist of liposomes and polymers, which are larger in size (>100nm in diameter) and tend to stay at injection sites while smaller nanoparticles drain into lymph nodes with subcutaneous injections. They also have known toxicities post degradation. Gold nanoparticles (AuNPs), on the other hand, have three advantages: potential lymph drainage due to their small size, simplistic synthesis/conjugation process and passively collection in antigen presenting cells. Although peptide conjugations on to AuNPs are not new, this proposal aim to be the first to utilize layering techniques onto AuNPs to deliver large does of vaccine peptides for enhanced anti-tumor effect. Thus, the goal of this proposal is to design an effective, simple, versatile gold-based nanovaccine (AuNV) platform for improved anti-tumor immune response.
Three specific aims will be carried out to achieve this goal.
In aim 1, class I peptides, which stimulate tumor-killing cytotoxic T cells, are conjugated onto polyethylene glycol (PEG) coated AuNPs. Peptides used in this proposal are from a model antigen (ovalbumin) and common melanoma antigens (gp100 and Trp-2). From preliminary characterizations of AuNVs, conjugation yield is very high (~90%) and the overall particle size remained sub-100nm. This will allow potential lymphatic drainage post subcutaneous injection. In vitro Immune response from AuNVs will be measured by interferon-? release, a marker for vaccine anti-tumor efficacy. In vivo efficacy of AuNVs will be assessed by splenocyte sensitization, tumor rejection and treatment assays. As part of aim 1, biodistribution of AuNPs from subcutaneous injections will be explored and be the first to look at distribution at the cellular level.
In aim 2, class II peptdes, which stimulate helper T cells, will be incorporated in the AuNV design. In vivo enhancement of antitumor efficacies will be assessed with known class II peptides. However for unknown class II peptides situations, peptide pools will be used to incorporate both class I and class II epitopes.
In aim 3, CpG, a known inflammatory stimulant used for cancer immunotherapy, on AuNPs will be combined with AuNVs for a complete vaccine regimen. Future applications of AuNVs are substantial. This design would dramatically lower the cost of immunotherapy compared cellular vaccines. They are easily synthesized, versatile and can potentially target later stage cancers by using inducing anti-tumor immunity over the whole body.
The American Cancer Society estimated over 1.5 million new cancer cases and over half a million deaths in 2010 with national cancer care expenditures estimated to be 104.1 billion dollars since 2006. Cancer vaccines are effective but are limited by vaccine delivery methods and enormous cost for cellular based methods. Gold-based nanovaccines (AuNV) designs are cost-effective, versatile, and can improve the delivery and efficacy of cutting edge cancer immunotherapies and hopefully improve the survival and quality of life for cancer patients.
|Figueroa, Elizabeth R; Lin, Adam Y; Yan, Jiaxi et al. (2014) Optimization of PAMAM-gold nanoparticle conjugation for gene therapy. Biomaterials 35:1725-34|
|Lin, Adam Yuh; Lunsford, Jessica; Bear, Adham Sean et al. (2013) High-density sub-100-nm peptide-gold nanoparticle complexes improve vaccine presentation by dendritic cells in vitro. Nanoscale Res Lett 8:72|
|Lin, Adam Yuh; Almeida, Joao Paulo Mattos; Bear, Adham et al. (2013) Gold nanoparticle delivery of modified CpG stimulates macrophages and inhibits tumor growth for enhanced immunotherapy. PLoS One 8:e63550|