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Technical Program TRACK 6 TRACK 6

by the force balance between the non-specific attractive force and the spe- To further substantiate the effectiveness of gold nanovaccines, studies eval-
cific repulsive force modeled as the elastic spring that supports the particle uating the anti-tumor properties of these AuNP-Trp2 particles are underway.
is considered. With the stiff ligand-receptor pair, the equilibrium distance In addition, because these gold nanovaccines improve antigen delivery,
is lengthened so that the hydrodynamic force on the particle increases. their mechanism of action is complementary to those of checkpoint inhibi-
Secondly, the number of the receptors on the cell could be an important tors such as PD-1, making them good candidates for combination therapies
factor on the probability of adhesion. When the number of the receptors as their effects are predicted to be synergistic. Our aim is to continue to
expressed on the cell increases, the receptors could easily interact with demonstrate the ability of the gold nanovaccine platform to result in specific
the ligands conjugated on the particle so that the probability of adhesion is and clinically relevant immune responses for use in cancer vaccine therapies.
expected to increase. Third, the kinetic binding affinity between the ligands
and the receptors is one of the important parameters on the probability of References:
adhesion. The higher kinetic affinity, the higher probability of adhesion is ex- [1] Almeida, J. P. M. et al. Small. 2015, 11(12): 1453-1459
pected. Lastly, the different length of each ligand-receptor pair is an import-
ant factor. In this presentation, considering the biophysical conditions of dual
ligand-receptor pairs that influence on the particle-cell adhesion probability, Co-delivery of siRNA and anti-cancer drug using polymeric
the several design parameters for multiple ligand conjugated micro/nano nanoparticles
particle based delivery system are suggested.
Poster Presentation. NEMB2016-6120

Gold Nanovaccine Platform for Delivery of Tumor-Associated
Antigens Xiaoyang Xu, New Jersey Institute of Technology, Newark, NJ,
United States

Poster Presentation. NEMB2016-6020 The development of acquired chemoresistance is a persistent clinical
problem limiting the successful treatment of malignancies and considerable
Emily Reiser Evans, Joao Paulo Mattos Almeida, Adam Y. Lin, work has been done to identify the molecular mechanisms involved. Many
Rice University, Houston, TX, United States, Aaron E. Foster, Bel- possible mechanisms have been suggested for anti-cancer drug resistance
licum Pharmaceuticals, Houston, TX, United States, Rebekah A. emergence, such as drug efflux, apoptosis inhibition among others. Due to
Drezek, Rice University, Houston, TX, United States the lack of effective inhibitors and the undruggable feature of some targets,
it is not easy to screen and validate the target combinations, especially in
The goal of cancer vaccines is to stimulate the immune system such that vivo. Since synthetic siRNA has emerged as a class of attractive therapeutics
tumor cells expressing a particular tumor-associated antigen are recognized for treatment of various cancers by silencing genes that cause diseases.
and destroyed. However, vaccinations with peptide antigens have failed to Given the ability to target and silence nearly any gene of interest, specific
elicit sufficiently strong anti-tumor immunity due to poor delivery to antigen siRNA can be constructed to target genes encoding proteins involved in
presenting cells. Gold nanoparticles (AuNPs) are ideal carriers to address DNA repair and the acquisition of multidrug resistance. Although a powerful
this delivery hurdle because AuNPs can be easily functionalized with pep- means to silence the expression of target genes, the safe and effective
tide antigens and naturally distribute to the spleen and relevant immune cell systemic delivery of siRNA therapeutics remains an important challenge.
populations therein. Herein we have developed an innovative chemo-RNAi nanotherapeutic
strategy that can simultaneously deliver platinum drugs and multiple siRNAs.
Previously, our group used gold nanoparticles to improve delivery of the We hypothesize that the NP-mediated delivery of multiple siRNAs against
exogenous peptide antigen ovalbumin (OVA) in vivo. The AuNP-mediated different platinum resistance mechanisms will allow the validation of key
delivery of the OVA peptide resulted in significantly stronger antigen-spe- targets. We aim to improve the efficacy of chemotherapy through additive or
cific immunity and anti-tumor activity compared to OVA alone. AuNP-OVA synergistic effects coupled by platinum drug and siRNAs targeting different
treatment prevented tumor formation and extended survival in prophylactic drug resistance mechanisms. As proof-of-concept, we have used poly(lac-
and therapeutic B16-OVA tumor models [1]. We have since expanded upon tide-co-glycolide)-b-poly(ethylene glycol)-lipid hybrid nanocarriers as a deliv-
this initial success of our gold nanovaccine platform by demonstrating im- ery platform, translesion DNA polymerases Rev1/3L as model target proteins
proved antigen-specific immunity when delivering the melanoma-associated responsible for platinum resistance, and prostate cancer as a model dis-
antigen, Trp2. ease. We have successfully created polymer-lipid NPs that exhibited simulta-
neous entrapment of siRNA (up to 99%) and cisplatin (around 10%). The size
Trp2 peptides were conjugated to 30 nm gold nanoparticles via an inter- of the NPs ranges from 180 to 220 nm and he drug release profile shows a
mediate polyethylene glycol (PEG) layer and EDC/Sulfo-NHS chemistry. To controlled release of cisplatin and siRNA over 10 days. We demonstrated the
evaluate the immune response in vivo, C56BL/7 mice were primed on day 0, potency of the siRNA-containing NPs to efficiently knockdown target genes
boosted on day 7, and their spleens were harvested on day 17. An Enzyme both in vitro and in vivo.
Linked ImmunoSpot (ELISpot) assay illustrated the amount of IFN-y produc-
ing splenocytes following incubation with Trp2 peptides, which corresponds
to the antigen-specific immune response. AuNP-Trp2 demonstrated signifi- Predicting Therapy Response of Pancreatic Cancer Patients by
cantly improved antigen-specific immunity compared to administration of Evaluating Tumor Hypoxic Status with Circulating Hydroxylated
Trp2 alone (p<0.01). Bradykinin in the Blood
Our results indicate that the improvement of antigen-specific immunity Poster Presentation. NEMB2016-6083
imparted by gold nanoparticle delivery is sustained when incorporating an
endogenous tumor-associated antigen, Trp2. This result is important in two
ways. First, the hydrophobic Trp2 peptides are more difficult to incorporate Yajun Gu, Zhiyi Liu, Zaian Deng, Methodist Hospital Research In-
on AuNPs because the hydrophobic surface interactions can lead to particle stitute, Houston, TX, United States, Tony Y. Hu, Houston Methodist
instability under certain synthesis conditions. Thus, our successful synthesis Research Insititute, Houston, TX, United States
and administration indicate that we can incorporate a range of peptides with
our established synthesis approach. Second, it is more difficult to elicit anti- Background: Using hypoxic status to predict outcomes in patients undergo-
gen-specific immunity of endogenous tumor-associated antigens due to im- ing chemotherapy and radiotherapy meets impediments in clinic due to the
mune tolerance mechanisms. Thus, the ability of AuNP-Trp2 to induce strong lack of a reliable, accurate, prompt, and noninvasive detection methodology.
76 immunity toward a melanoma-associated antigen demonstrates the potential In the blood, the circulating peptide bradykinin (BK) and its hydroxylated de-
for clinical translation of gold nanovaccines. rivative hyp-BK can directly reflect the activity of prolyl 4-hydroxylase subunit
alpha-1(P4HA1), which is tightly regulated by hypoxia. In the current study we