5 research outputs found
In vivo Gold Nanoparticle Delivery of Peptide Vaccine Induces Anti-Tumor Immune Response in Prophylactic and Therapeutic Tumor Models
Gold nanoparticles (AuNPs) are promising vehicles for cancer immunotherapy, with demonstrated efficacy in immune delivery and innate cell stimulation. Nevertheless, their potential has yet to be assessed in the in vivo application of peptide cancer vaccines. In this study, it is hypothesized that the immune distribution and adjuvant qualities of AuNPs could be leveraged to facilitate delivery of the ovalbumin (OVA) peptide antigen and the CpG adjuvant and enhance their therapeutic effect in a B16-OVA tumor model. AuNP delivery of OVA (AuNP-OVA) and of CpG (AuNP-CpG) enhanced the efficacy of both agents and induced strong antigen-specific responses. In addition, it is found that AuNP-OVA delivery alone, without CpG, is sufficient to promote significant antigen-specific responses, leading to subsequent anti-tumor activity and prolonged survival in both prophylactic and therapeutic in vivo tumor models. This enhanced therapeutic efficacy is likely due to the adjuvant effect of peptide coated AuNPs, as they induce inflammatory cytokine release when cultured with bone marrow dendritic cells. Overall, AuNP-mediated OVA peptide delivery can produce significant therapeutic benefits without the need of adjuvant, indicating that AuNPs are effective peptide vaccine carriers with the potential to permit the use of lower and safer adjuvant doses during vaccination
High-density sub-100-nm peptide-gold nanoparticle complexes improve vaccine presentation by dendritic cells in vitro
Nanocarriers have been explored to improve the delivery of tumor antigens to dendritic cells (DCs). Gold nanoparticles are attractive nanocarriers because they are inert, non-toxic, and can be readily endocytosed by DCs. Here, we designed novel gold-based nanovaccines (AuNVs) using a simple self-assembling bottom-up conjugation method to generate high-peptide density delivery and effective immune responses with limited toxicity. AuNVs were synthesized using a self-assembling conjugation method and optimized using DC-to-splenocyte interferon-γ enzyme-linked immunosorbent spot assays. The AuNV design has shown successful peptide conjugation with approximately 90% yield while remaining smaller than 80 nm in diameter. DCs uptake AuNVs with minimal toxicity and are able to process the vaccine peptides on the particles to stimulate cytotoxic T lymphocytes (CTLs). These high-peptide density AuNVs can stimulate CTLs better than free peptides and have great potential as carriers for various vaccine types
Gold Nanoparticle Delivery of Modified CpG Stimulates Macrophages and Inhibits Tumor Growth for Enhanced Immunotherapy
Gold nanoparticle accumulation in immune cells has commonly been viewed as a side effect for cancer therapeutic delivery;
however, this phenomenon can be utilized for developing gold nanoparticle mediated immunotherapy. Here, we
conjugated a modified CpG oligodeoxynucleotide immune stimulant to gold nanoparticles using a simple and scalable selfassembled
monolayer scheme that enhanced the functionality of CpG in vitro and in vivo. Nanoparticles can attenuate
systemic side effects by enhancing CpG delivery passively to innate effector cells. The use of a triethylene glycol (TEG) spacer
on top of the traditional poly-thymidine spacer increased CpG macrophage stimulatory effects without sacrificing DNA
content on the nanoparticle, which directly correlates to particle uptake. In addition, the immune effects of modified CpGAuNPs
were altered by the core particle size, with smaller 15 nm AuNPs generating maximum immune response. These TEG
modified CpG-AuNP complexes induced macrophage and dendritic cell tumor infiltration, significantly inhibited tumor
growth, and promoted survival in mice when compared to treatments with free CpG
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The biophysical origins of cervical tissue fluorescence and reflectance spectra : modeling, measurements, and clinical implications
textThis dissertation presents research designed to develop a more complete
and quantitative understanding of the propagation of light through cervical tissue,
in particular investigating the connections between optical spectra and underlying
tissue biochemistry, morphology, and architecture. Understanding these
relationships is a key factor in optimizing the diagnostic potential of optical
spectroscopy. A stepwise approach was used to develop forward models of light
propagation, moving from basic experimental and computational investigations of
cellular light scattering properties to macroscopic tissue level models of light
transport.
Six studies are presented. The first two studies used the finite-difference
time-domain (FDTD) method to examine light scattering at a cellular level. The
studies demonstrated that the scattering patterns of cells are strongly dependent on
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cellular biochemical and morphological structure, including features such as DNA
content, nuclear size, and chromatin texture. Next, to examine optical properties
at the tissue level, a clinical study was conducted to investigate the
autofluorescence of fresh normal and dysplastic cervical tissue sections. At 380
nm excitation, dysplastic tissue exhibited increased epithelial fluorescence and
decreased stromal fluorescence relative to paired normal tissue. Using the
fluorescence data from this study as model input, a Monte Carlo model was
developed in order to quantitatively examine how intrinsic NADH and collagen
fluorescence, in combination with tissue scattering and absorption properties,
yield measured spectra. Modeled spectra were consistent with clinical
measurements, and the results of the study provided a viable explanation of the
biophysical origins of differences in normal and dysplastic cervical tissue
fluorescence spectra. To facilitate future research, a hybrid FDTD and Monte
Carlo model was developed, which incorporates detailed descriptions of the
microscopic scattering properties of cells and realistic fiber-optic light delivery
and collection geometries. Finally, a preliminary study was completed to assess
the potential of acetic acid as a contrast agent for optical imaging.
In summary, the work described in this dissertation promotes the
development of more sensitive and specific strategies for the detection of
epithelial precancers using optical spectroscopy. Furthermore, the completed
studies provide valuable insight into the biophysical changes responsible for
measured differences in the optical spectra of normal and neoplastic cervix.Electrical and Computer Engineerin
In Vivo Immune Cell Distribution of Gold Nanoparticles in Naïve and Tumor Bearing Mice
Gold nanoparticles (AuNP) have been widely used for drug delivery and have recently been explored for applications in cancer immunotherapy. Although AuNPs are known to accumulate heavily in the spleen, the particle distribution within immune cells has not been thoroughly studied. Here, cellular distribution of Cy5 labeled 50 nm AuNPs is characterized within the immune populations of the spleen from naïve and tumor bearing mice using flow cytometry. Surprisingly, approximately 30% of the detected AuNPs are taken up by B cells at 24 h, with about 10% in granulocytes, 18% in dendritic cells, and 8% in T cells. In addition, 3% of the particles are detected within myeloid derived suppressor cells, an immune suppressive population that could be targeted for cancer immunotherapy. Furthermore, it is observed that, over time, the particles traveled from the red pulp and marginal zone to the follicles of the spleen. Taking into consideration that the particle cellular distribution does not change at 1, 6 and 24 h, it is highly suggestive that the immune populations carry the particles and migrate through the spleen instead of the particles migrating through the tissue by cell-cell transfer. Finally, no difference is observed in particle distribution between naïve and tumor bearing mice in the spleen, and nanoparticles are detected within 0.7% of dendritic cells of the tumor microenvironment. Overall, these results can help inform and influence future AuNP delivery design criteria including future applications for nanoparticle-mediated immunotherapy