University of Southern California


Featured Research


Immunomodulatory and Cytotoxic Micelles for Prostate Cancer
Eun Ji Chung,  Biomedical Engineering, Viterbi School of Engineering
Mitchell Gross, Provost – Ellison Institute, Provost
Kian Kani, Provost – Ellison Institute, Provost
Keyue Shen, Biomedical Engineering, Viterbi School of Engineering

Chimeric Antigen Receptor Engineered Natural Killer Cells as a Carrier of Drug-Encapsulated Nanoparticles Targeting Adenosine Receptors in Ovarian Cancer
Pin Wang, Chemical Engineering, Viterbi School of Engineering
James Hu, Medicine – Onco – Clin Fac, Keck School of Medicine

Characterizing the immune microenvironment of lymphoma and myeloma using multiplexed imaging mass cytometry
Akil Merchant, Medicine, Keck School of Medicine of USC
Kevin Kelly, Medicine – Hemat – Clin Fac, Keck School of Medicine
Wendy Cozen, Center for Genetic Epidemiology, Keck School of Medicine
James Hicks, The Bridge@USC, Dornsife College of Letters, Arts and Sciences
Peter Kuhn, The Bridge@USC, Dornsife College of Letters, Arts and Sciences
Imran Siddiqi, Pathology – Clin Fac, Keck School of Medicine

Next Generation CD19 CAR-T for the treatment of lymphoid malignancies
Preet Chaudhary, Medicine, Keck School of Medicine of USC
Jianming Xie,  Pharmacology and Pharmaceutical Sciences/Faculty, School of Pharmacy


Large-scale Isolation of Cytotoxic Extracellular Vesicles from Activated Natural Killer Cells for Immunotherapy of Cancer
Noah Malmstadt, MFD – Chemical Engineering, Viterbi School of Engineering
Robert Seeger, Pediatrics/Childrens Hospital, Keck School of Medicine of USC
Muller Fabbri, Pediatrics/Childrens Hospital, Keck School of Medicine of USC
Ambrose Jong, Pediatrics/Childrens Hospital, Keck School of Medicine of USC
Alan Wayne, Pediatrics/Childrens Hospital, Keck School of Medicine of USC

Developing Novel Immuno-nanoparticles for Colorectal Cancer
Yong Zhang, Pharmacology and Pharmaceutical Sciences, School of Pharmacy
Heinz-Josef Lenz, Medicine – Onco – Clin Fac, Keck School of Medicine of USC

Development of a nano-encapsulated small molecule immunotherapeutic for colon cancer
Nicos Petasis, Loker Hydrocarbon Research Institute, Dornsife College of Letters, Arts & Sciences
Stan Louie, Clinical Pharmacy & Pharmaceutic Econ&Poli, School of Pharmacy
Heinz-Josef Lenz, Medicine – Onco – Clin Fac, Keck School of Medicine of USC

Imaging Mass Cytometry to Profile Tumor Immune Microenvironment
Akil Merchant, Medicine – Hemat – Clin Fac, Keck School of Medicine of USC
Parkash Gill, Medicine – Hemat – Clin Fac, Keck School of Medicine of USC
Peter Kuhn, The Bridge@USC, Viterbi School of Engineering
Imran Siddiqi, Pathology – Clin Fac, Keck School of Medicine of USC

2017 – Special Solicitation

Machine Learning Applications to the Immunology of Melanoma
Stephen Gruber,, Professor of Medicine and Preventive Medicine; Jane & Kris Popovich Chair in Cancer Research, Keck School of Medicine
Fei Sha,, Computer Science, Viterbi School of Engineering

Integrating Spatiotemporal Single Cell Proteogenomics Data from Liquid Biopsies in Patients with Head and Neck Cancer
Yan Liu,, Computer Science, Viterbi School of Engineering
Peter Kuhn,, The Bridge@USC, Dornsife College of Letters, Arts and Sciences
James Hicks,, The Bridge@USC, Dornsife College of Letters, Arts and Sciences
Jorge Nieva,, Medicine – Onco – Clin Fac, Keck School of Medicine


Optimizing PEOX Formulated C125 for TNBCs
Stan Louie, Clinical Pharmacy and Pharmaceutical Economics and Policies, USC School of Pharmacy
Kathleen Rodgers, Clinical Pharmacy and Pharmaceutical Economics and Policies, USC School of Pharmacy
Nicos Petasis, Chemistry, Dornsife College of Letters, Arts and Sciences
Louis Dubeau, Pathology, Keck School of Medicine

C125 is a specific SERCA2b inhibitor that activates components found in the ERS pathway(s) which ultimately triggers pro-apoptotic activity in tumors. Studies have affirmed its target of
antitumor activity, where 25 mg/kg/day was established as the minimum effective dosage. C125 has poor water solubility (10 μg/mL), thus present a challenge to the development of a parenteral
formulation. We have developed a parenteral C125 using poly(2-ethyl-2-oxazoline) (PEOX) that is stable for >30 days. In this proposal, we will evaluate the impact of C125-PEOX given as a
continuous infusion to determine whether metronomic dosing is an effective approach (SA1). Additionally, we will optimize the oral C125-PEOX formulation and evaluate it in a dosage escalation study (SA2). Finally, the strategy leading to the best antitumor activity will be combined with cytotoxic chemotherapy used for triple negative breast cancers (TNBCs) (SA3).

Bispecific hybrid nanoworms for immunotherapy of B-cell lymphoma
Andrew Mackay,  Pharmacology and Pharmaceutical Sciences, USC School of Pharmacy
Alan Epstein, Pathology, Keck School of Medicine
Peter Conti, Radiology, Keck School of Medicine

Nanoworms may have significant applications as cancer nanomedicines because they: i) specifically modulate receptor-mediated cellular signaling8; ii) potently engage multiple receptors; iii); are biocompatible and biodegradable; iv) can be expressed in bacteria without the need for antibody bioconjugation; and v) phase separate in response to temperature, which may
hyperpotentiate apoptosis. During our first year of funding, we expanded our nanoworm repertoire to recognize four receptors (CD3, CD19, CD20, HLA-DR). In addition, we developed the first monoclonal antibody to recognize unmodified ELPs, which we will use to characterize nanoworm fate in cells and the body. This study innovates where there are few reports of thermally mediated antibodies or bispecific nanoparticles designed to engage cytotoxic T-cells with malignant B-cells. In year two, we plan to test the hypothesis that thermally-mediated assembly on the cell
membrane enhances apoptotic signaling in B-cell lines (Aim1). With these materials, we are now able to co-assemble bispecific nanoworms that link cytotoxic (CD3+) T-cells to (CD19+, CD20+, HLA-DR+) B-cells (Aim2). If successful, this novel platform will be converted into a federally-funded and multidisciplinary (MacKay, Epstein, Conti) project for targeted immunotherapies, with applications from cancer to infectious disease.

Developing new Diagnostics and Therapeutics for an Immune Checkpoint
Richard Roberts,, Chemical Engineering, Viterbi School of Engineering
Mitchell Gross,, Oncology, Keck School of Medicine
Terry Takahashi,, Chemistry, Dornsife College of Letters, Arts & Sciences

The use of antibodies as immune checkpoint inhibitors has shown outstanding results in the clinic. However, the antibodies are large molecules and are slow to diffuse into tumors, resulting in poor tumor uptake and penetration. We have developed small, protease resistant peptides called SUPR Peptides that bind with antibody-like affinities and specificities. Because they are >50-fold smaller than antibodies, SUPR peptides have pharmacokinetic properties that are similar to small molecules, and thus will have better tumor penetration. Here, we propose to
develop SUPR peptides against Programmed Death Ligand 1 (PD-L1) that is often expressed on tumor cells to avoid immune destruction. We will engineer high affinity, highly specific PD-L1-
binding SUPR peptides. These peptides will then be tested to validate that they can recognize PD-L1 on cells. Lastly, we will test if these peptides are capable of detecting PD-L1 in patient derived lung cancer tissue and compare the detection of PD-L1 to a commercially-available antibody.


Nanoscale parenteral formulations of a small molecule therapeutic for the treatment of resistant breast cancer
Stan Louie, Clinical Pharmacy and Pharmaceutical Economics and Policies, USC School of Pharmacy
Nicos Petasis, Chemistry, Dornsife College of Letters, Arts and Sciences
Kathleen Rodgers, Clinical Pharmacy and Pharmaceutical Economics and Policies, USC School of Pharmacy

While most forms of breast cancer (BC) are responsive towards chemotherapy, there is still a large unmet need for the treatment of resistant BCs, such as triple negative breast cancer (TNBC), which has undetectable estrogen receptor (ER), progesterone receptor (PR) as well as low amplification of human epidermal growth factor receptor 2 (HER2) levels. TNBC patients have low overall survival due to tumor recurrence, which is often accompanied by drug resistance.

We have recently developed a novel therapeutic approach targeting cellular adaptive survival mechanisms, which enable tumor cells to survive and proliferate in acidic, as well as nutrient and oxygen-deprived milieu. Although normal cells cannot proliferate under such conditions, cancer cells are able to thrive through these cellular adaptive survival mechanisms, such as autophagy, sustained unfolded protein response (UPR) or persistent endoplasmic reticulum stress (ERS). Our approach for treating resistant cancers is based on disrupting the ERS microenvironment using a small molecule that is able to modestly increase ERS and thus selectively trigger cancer cell apoptosis, without affecting normal cells. By systematically evaluating a prototype compound, we established the desired profile and potential uses for these therapeutics, which we termed ER stress aggravating agents (ERSA).

Multifunctional Gold Nanostars for CD13-Targeted Tumor Imaging and Photothermal Therapy
Kai Chen, Radiology, Keck School of Medicine
Peter Conti, Radiology, Keck School of Medicine
Kirk Shung, Biomedical Engineering, Viterbi School of Engineering

Cancer is the second leading cause of death in the United States and accounts for approximately one in every
four deaths. Employing theranostic nanoprobes, which combine both diagnostic and therapeutic capabilities, has promise to propel the biomedical field toward personalized cancer medicine. CD13 receptor is an important regulator of endothelial morphogenesis during tumor angiogenesis − a vital biomarker in tumor growth and metastatic spread. Herein, we propose a new strategy for individualized diagnosis and treatment of cancer by developing novel multifunctional gold nanostars (GNS), which combine features for CD13-targeted multimodality [positron emission tomography (PET), computed tomography (CT), ultrasound (US), photoacoustic (PA)] imaging and photothermal therapy. Combinations of imaging techniques, as socalled “multimodality imaging”, such as PET/CT/US/PA imaging, are being designed with the purpose of taking advantage of the strengths while overcoming the weaknesses of each modality, which as a result may accurately and simultaneously provide anatomical and functional information. For instance, sensitive PET imaging can be used to quantify the CD13 expression level, while the US/PA imaging is able to combine optical and acoustic information to decipher tumor microenvironment. Based on our promising preliminary results, we hypothesize that our new chelator system and strain-promoted catalyst-free click chemistry approach could provide a reliable kit-like method for the fast construction of biocompatible, multimodal, and theranostic GNS probes. The Specific Aims of this project address important questions regarding the preclinical evaluations of multifunctional GNS.

Engineering Exosome Nanoparticles for Targeted Cancer Therapies
Yong Zhang, Pharmacology and Pharmaceutical Sciences, USC School of Pharmacy
Parkash Gill, Hematology and Pathology, Keck School of Medicine

Exosomes are endogenous nanoparticles secreted by many types of cells and exhibit excellent host biodistribution and biocompatibility. They play important roles in intercellular communication through transfer of mRNA, miRNA, receptors, enzymes, and cytokines. Compared with synthetic virus, lipid, and polymeric nanomedicines which are immunogenic due to their foreign antigen nature and require escape from endosomal-lysosomal pathway for drug delivery, exosomes exhibit significantly reduced immunogenicity and enhanced efficiency for anti-cancer drug delivery attributed to their direct membrane fusion with target cancer cells. By conjugating with targeting ligands, drug carriers can precisely deliver therapeutic agents to cancer cells without harming normal cells. We propose to generate a series of antibody-directed exosome nanomedicines for targeted cancer therapies with enhanced efficiency, safety, and efficacy by engineering natural exosomes with monoclonal antibodies targeting tumor-associated antigens. This will be achieved through three specific aims: (1) development of anti-EphB4 antibodydirected exosome nanomedicines for treatment of head and neck cancer; (2) generation of targeted exosome-based drug delivery system using anti-EGFR antibodies for the therapy of colorectal cancer; (3) design of engineered exosome nanoparticles targeting refractory metastatic breast cancer by bi-specific antibodies binding HER2 and HER3 receptors. The generated antibodydirected exosomes encapsulated with RNAs, chemotherapies, and proteins can allow selective delivery of therapeutic agents to the cytosol of target tumor cells with high efficiency and provide innovative and highly potent nanomedicines for targeted cancer therapies. Translating these novel targeted cancer therapies to exploratory clinical studies in humans will lead to practical applications, benefitting patients with head and neck, colorectal, and metastatic refractory breast cancer, as well as patients with other epithelial cancers.

Nanoparticle Formulations of Mas Agonists for Adjuvant to Cancer Chemotherapy
Kathleen Rodgers, Pharmaceutical Economics and Policy, USC School of Pharmacy
Stan Louie, Clinical Pharmacy and Pharmaceutical Economics and Policies, USC School of Pharmacy
Gere diZerega, Obstetrics and Gynecology, Keck School of Medicine

Cytotoxic chemotherapy has been a primary modality for both solid and hematologic cancers. Despite improving clinical outcomes, chemotherapy-induced toxicities, in particular, myelosuppression continues to be a major clinical challenge. Drug-induce myelosuppression can affect neutrophils, lymphocytes and platelets individually or a combination of these hematopoietic lineages. The reduction in these cells increases the risk for bacterial, fungal or viral infections that may require immediate and aggressive management. The advent of Neupogen and Epogen with their capability to ameliorate chemotherapy-induced neutropenia and anemia has transformed how chemotherapy-induced myelosuppression is managed. In a Phase I/IIa clinical trial, we have found an active peptide in the renin angiotensin system (RAS), angiotensin (1-7) (A(1-7)), reduced grade 2-4 anemia, thrombocytopenia, and lymphopenia as well as mucositis when compare to controlled patients receiving rhG-CSF alone. In a Phase IIb study, Mas receptor agonist A(1-7) reduced the incidence and severity of thrombocytopenia in subjects receiving a combination of gemcitabine and platinum for ovarian carcinoma and allowed maintenance of chemotherapy dose density.

Development of a nano-encapsulated biomimetic small molecule therapeutic for the treatment of colon cancer
Nicos Petasis, Chemistry, Dornsife College of Letters, Arts and Sciences
Stan Louie, Clinical Pharmacy and Pharmaceutical Economics and Policies, USC School of Pharmacy
Heinz-Josef Lenz, Clinical Oncology, Keck School of Medicine

Current therapies for colon cancer rely primarily on drug combinations of cytotoxic chemotherapy, and are often unable to prevent tumor resistance and recurrence. While several biologic agents targeting growth factors have been approved in combination with chemotherapy, there is still a great number of patients that typically do not respond to these standard-of-care treatments.

This proposal will pursue the development of a novel class of non-cytotoxic small molecules for the treatment of colon cancer. These new agents have been designed to mimic the actions of endogenous anti-inflammatory molecules that are able to suppress the chronic inflammatory microenvironment found in the tumor milieu. Chronic inflammation is required for maintaining tumor growth, angiogenesis, and metastasis. The suppression of inflammation ultimately deprives the tumor of essential growth elements, resulting in cellular apoptosis and tumor death. Preliminary studies on this innovative concept show great translational potential for the treatment of colon cancer.


Bispecific hybrid nanoworms for immunotherapy of B-cell lymphoma
John Mackay,  Pharmacology and Pharmaceutical Sciences, USC School of Pharmacy
Alan Epstein,, Pathology, Keck School of Medicine
Zibo Li ,, Radiology, Keck School of Medicine
Peter Conti,, Radiology, Pharmacy and Biomedical Engineering, Keck School of Medicine

About 66,000 US patients were diagnosed with lymphomas in 2011, out of which 65,000 had Non-Hodgkin’s lymphoma (NHL)11. NHL is characterized by increased production of malignant B-cells, which can be targeted through cell-surface CD19 or CD2012, 13. Antibodies against CD20 have been developed for NHL and are clinically successful. The most prominent example is rituximab, a chimeric antibody that targets malignant as well as normal Bcells2. Crosslinking of rituximab using a secondary antibody against the Fc region promotes cell apoptosis, which led to the observation that CD20-mediated apoptosis can be potentiated through strategies that induce multivalency4, 14. In combination with chemotherapy, immunotherapeutics overcome resistance in half of NHL patients3. More recently, bispecific antibodies, such as blinatumomab, that link targets on B-cell lymphomas (CD19, CD20) with effectors on cytotoxic T-cells (CD3) have entered a phase III clinical trial5. Phase II trials suggest that the bispecific antibody outperforms chimeric rituximab because it facilitates killing by T cells that interact with cancer of B cell lineage.

Nanoparticle Mediated Delivery Targeting TAK1 as a Metastatic Breast Cancer Therapy
Min Yu,, Stem Cell Biology and Regenerative Medicine, Keck School of Medicine
Pin Wang,, Chemical Engineering and Materials Science, Viterbi School of Engineering
Julie Lang,, Surgery, Keck School of Medicine

In this multidisciplinary application among the Yu and Lang laboratories from the Norris Cancer Center and the Wang laboratory from Viterbi School of Engineering, we aim to test the hypothesis that the nanoparticle-packaged inhibitor to TAK1 can suppress metastatic breast cancer (MBC) formation in distant organs in a xenografted mouse model and such approach can improve our ability to treat MBC.

Optimization of pH-sensitive peptide nanoconstructs for use in targeting the mildly acidic tumor microenvironment
Jennica Zaro,, Pharmaceutical Sciences, USC School of Pharmacy
Peter Conti,, Radiology, Pharmacy and Biomedical Engineering, Keck School of Medicine

In this renewal application, we plan to investigate the toxicity, particularly in the kidney and liver, of these novel pH-sensitive nanoconstructs in order to evaluate their potential applicability in cancer diagnosis and therapy. Furthermore, several strategies to reduce the nonspecific accumulation of the constructs in the kidney and liver will also be tested. The pH-sensititve nanoconstructs consist of two different types of cell penetrating peptides (CPPs): an amphipathic peptide, Model Amphipathic Peptide, and a cationic ligoarginine peptide. A highly pHsensitive histidine-glutamic acid (HE) copolymer sequence is linked to the CPPs to prevent non-specific internalization of the construct in non-target cells, and to target internalization at the surface of the acidic (pH 6 – 7) tumor microenvironment. According to our recent studies, these constructs show high accumulation and retention near the tumor site in a xenograft breast cancer mouse model.

Nanoparticle enhanced Ultrasound Therapy
Andrea Armani,, MFD – Chemical Engineering
David Agus,, Medicine
Charles Gomer, Pediatrics and Radiation Oncology
Qifa Zhou, Biomedical Engineering Department

The efficacy of the nanoparticle-enhanced ultrasound therapy will be thoroughly studied. Specifically, the dependence on the ultrasound frequency and energy as well as nanoparticle size, concentration and geometry will be measured. Experiments will be performed both in C3H mouse mammary carcinoma cells and in xenographic C3H tumor tissue and liver tissue obtained from mice. Multiple approaches will be used to qualitatively and to quantitatively measure the response of the cells and tissue.

Focused Microwave Cancer Therapy Using Lithographically Defined Nanoparticles
Wei Wu,, Electrical Engineering-Electrophysics
John Stang,, Electrical Engineering-Electrophysics
Mahta Moghaddam,, Electrical Engineering-Electrophysics
Eugene Chung, Radiation Oncology

Project to test the feasibility of a new technology, which combines lithographically defined nanoparticles and focused microwaves to achieve selective thermal ablation and/or hyperthermia treatment of primary tumors where surgical options are not feasible or local control remains an issue. This technology is intended to address the current limitations of existing thermal therapy treatments while also paving the way for the development of entirely new methods for the targeted treatment of cancers. In order to conduct this research, an interdisciplinary team with expertise in nanofabrication, focused microwave therapy, and radiation oncology. The team will use its prior experience with nanofabrication to develop a process of fabricating a new class of custom-engineered nanoparticles designed to enhance absorption at microwave frequencies. The team will characterize the microwave properties of these newly developed nanoparticles. The enhanced heating effects and heating selectivity will be tested on gelatin phantoms designed to mimic human tissue using the team’s prototype focused microwave thermal therapy system.

Metal Oxide Nanoribbon Biosensor Chips for Point of Care Diagnosis
Mark Thompson,, Chemistry
Chongwu Zhou,, Electrical Engineering

The specific aims of this proposal are as follows. (1) We will determine a panel of relevant diseases that can benefit the most from Point of Care (PoC) diagnosis applications. From there, we will research the optimal biomarkers for each disease. We will begin our investigation by conferring with clinicians and literature review. (2) We will investigate and develop straightforward and reliable surface functionalization techniques for bioconjugating capture probes on metal oxide nanoribbons to achieve high sensitivity and signal consistency. (3) We will design and develop microfluidic-compatible metal oxide nanoribbon biosensor chips which will facilitate the translation from a research laboratory model to a clinically compatible PoC device. (4) We will demonstrate electrical detection of a panel of relevant biomarkers using the proposed nanoribbon sensors and investigate the statistical correlation between the electrical signals and concentration of relevant biomarkers.


Therapeutic Nanoplatform Targeted to Bone Metastatic Cancers
Fabien Pinaud,, Biological Science, Dornsife College of Letters, Arts and Sciences
Charles McKenna,, Chemistry, USC Dornsife College of Letters, Arts and Sciences
Mitchell Gross,, Medicine and Urology, Keck School of Medicine

The novel therapeutic nanoplatform developed in this project will allow a highly specific treatment of cancer cells that have spread to the bone, while, at the same time, provide means to block further cell invasion at treated metastatic niches by slowing down bone resorption. In this respect, it will significantly improve and simplify the treatment of bone metastatic cancers by providing a single therapeutic agent with increased specificity compared to current chemotherapeutics without compromise on the palliative and preventive benefits of BPs for improved pain management and quality of life in cancer patients living with bone metastases.

Developing SUPR Peptide Diagnostics and Therapeutics for Oral Cavity Carcinomas
Richard Roberts,, Chemistry, Chemical Engineering, Biology, USC Dornsife College of Letters, Arts and Sciences
Uttam Sinha,, Department of Otolaryngology, Head and Neck Surgery, Keck School of Medicine of USC

The purpose of this project is to develop new molecular agents (SUPR Peptides) that will assist in diagnosis and treatment of head and neck cancers—squamous cell carcinoma of the of the head and neck (SCCHN). Risk factors for developing SCCHN include drinking, smoking/tobacco use, and Human papillomavirus (HPV). Early detection is essential for improving outcomes, especially for high-risk groups. This project will aim at three critical targets—the IL-6 and IL-8 proteins and the human papillomavirus (HPV).


Targeting the Mildly Acidic Tumor Microenvironment using pH-sensitive Recombinant Peptide Nanoconstructs
Jennica Zaro, Pharmacy
Peter Conti, Radiology

This project focuses on the recombinant production and characterization of highly pH sensitive oligopeptidyl nano constructs designed for the selective and efficient targeting toward the acidic microenvironment of tumor cells. Although the acidic tumor microenvironment (pH 6.5 – 7) is well-established (1), it has not been fully exploited in either diagnosis or therapeutic targeting mainly due to the difficulty of achieving (i) chemical activation in this weakly acidic range and (ii) a sufficient depth of tumor penetration. We are testing the feasibility of using our newly designed pH-sensitive nano constructs as a novel diagnostic tool in cancer therapy. We anticipate that the critical experiments will lead to the identification of an optimal nanoconstruct for tumor imaging and/or targeted delivery.

Targeted Nanoparticle Therapy for Ewing’s Sarcoma
Timothy Triche, Pediatrics
Richard Roberts, Chemistry

This project is synthesizing and validating nanoparticles suitable for delivery of small molecules.
We aim to synthesize hybrid polymerized liposomal nanoparticle (PLNs) of uniform size with surface modifications that render them extremely biocompatible, non-immunogenic, and amenable to cellular binding and uptake, suitable for drug delivery.

In addition, we are targeting nanoparticles to tumor cells with CD99 specific peptides. We seek to target these HPLNs to tumor cells while sparing normal tissue, using a novel surface affinity reagent developed at USC by Prof. Roberts. We propose to develop a unique targeting technology based on a human peptides that bind CD99. This technology uses rapid generation of peptides with randomly altered sequence variation that mimics antigen-antibody binding. With each generation, derivatized peptides are chosen with increasing affinity for the target of interest, until those with the greatest affinity are selected.

Scintillating Nanoparticles for Radiosensitization of Cancer Cells
Stephen Bradforth, Chemistry
Colin Hill, Radiation Oncology
Jay Nadeau, Chemistry
Jonathon Ha, Radiation Oncology
Eric Chang, Radiation Oncology

Nearly 11 million people are diagnosed with cancer each year, and approximately half of these
will undergo radiation therapy with photons, fast electrons, X-rays, gamma rays, protons or
neutrons. Although there have been many advances in the accuracy of delivery of radiation to a tumor, this remains a challenge, as malignant tumors do not have well-defined borders and are often surrounded by radiosensitive structures or cells. This project will synthesize ultrasmall, water-soluble LaF3:Ce nanoparticles and conjugate to a cancertargeting molecule and a photosensitizer. In addition, the project will quantify reactive oxygen species (ROS) from each conjugate upon visible and Xirradiation, quantify the cytotoxicity of the conjugates to selected cancer cells in culture using an Xray therapeutic protocol, and determine the enhancement of the X-ray dose in the presence of the particles. Confirming these findings would lead to new clinical avenues for this treatment of refractory cancers.

Multiplexed Polysilicon Nanoribbon Sensors for Therapeutic Monitoring and Detection of Brain Cancer
Chongwu Zhou Electrical Engineering
Mark Thompson, Chemistry
Thomas Chen, Neurosurgery

The specific aims of this project are as follows: (1) We will develop the design and fabrication
of the polysi nanoribbon as a fully functional FET sensor. We will study the correlation between
the device’s electronic characteristics and several design parameters in order to optimize device
performance. (2) We will demonstrate nanoribbon detection of the cancer serum biomarker
Vascular Endothalial Growth Factor (VEGF), which has been demonstrated to be increased in
brain cancer. We will investigate the best antibody-to-surface binding chemistry to achieve the
clinically relevant sensitivity. Conventional antibodies will be used as capture probes in
phosphate buffered (PBS). (3) We will also investigate nanoribbon detection of 2 urinary
biomarkers MMP-2 and MMP-9, their effectiveness in brain cancer monitoring, and correlation
with brain cancer invasiveness. (4) And lastly, we will demonstrate the detection of the above 3
biomarkers in physiological solutions and calibrate our electrical signal with a those obtained
from conventional detection methods such as ELISA.


Diagnostic Imaging of Smart Genetically Engineered Nanomedicines (renewed in 2013)

John MacKay, Pharmacy
Zibo Li, Radiology
Peter Conti, Radiology

Despite four decades of national engagement in the war-on-cancer, cancer caused 569 thousand deaths in the United States last year. Solid tumors are treated using surgery, radiation, chemotherapy, and more recently immunotherapy. Substantial effort has been expended to explore these modalities; however, more innovative ideas are needed to gain ground against cancer. To develop a new modality based on cancer nanomedicine, the MacKay laboratory combines the power of cellular protein expression, bioresponsive peptides, and self-assembly.

Our group studies polypeptides that are biologically inspired from a five amino acid motif identified in tropoelastin, a human extracellular matrix protein. These Elastin-Like Polypeptides (ELPs) are ideal for cancer nanomedicine because they can: (i) be tuned to self-assemble into multivalent polypeptide nanoparticles to modulate cellular uptake2; (ii) be seamlessly fused to proteins (enzymes, targeting ligands, therapeutics) without the need for bioconjugate chemistry; (iii) undergo slow proteolytic biodegradation3; and (iv) be non-immunogenic4. As a platform technology, ELPs provide a powerful approach to co-assemble multivalent core-shell nanoparticles decorated with functional peptides.

The immediate objective is to combine peptide-mediated nanoparticle assembly with Positron Emission Tomography (PET) to visualize the interaction of targeted nanoparticles within the tumor. Diagnostic imaging (optical, MRI, PET, CT, SPECT, ultrasound) is among the most powerful approaches available to improve the effectiveness of cancer therapies by: (i) enabling earlier detection; (ii) providing molecular information about the status of a cancer, which can guide therapy; (iii) following accumulation of drugs in cancer tissue; and (iv) enabling post-therapy monitoring of response. As the most sensitive imaging modality, PET is well-suited for tracking and quantification of nanoparticulate drug carriers in both research and clinical settings. To target cancer, the following strategy is proposed:

Innovation and Significance
• The development of a simple, biosynthetic approach to generate targeted polypeptide nanomedicines, which ultimately may be a platform for displaying a wide variety of protein/peptide ligands.

• Direct labeling of these peptides with novel PET imaging agents (sarcophagine-Cu-64) that permit non-invasive imaging over a period of several days.

• ELP-mediated assembly protects the PET label, encapsulates drugs, and presents targeting peptides.

Engineering Nanoparticles for Enhanced Cancer Therapeutics
Pin Wang, Chemical Engineering and Materials Science
Michael Wong, Medicine

This project is developing tumor-targeted delivery of multifunctional nanoparticles packaged with therapeutic agents in order to maximize the antitumor effect and lower toxicity to the prostate cancer patient. The Wang lab from the Viterbi School of Engineering will team up with the Wong lab from the Keck School of Medicine to test a hypothesis that crosslinked multilamellar lipsomes (CMLs) displaying a tumor vasculature-specific peptide RRL can achieve targeted delivery of the anticancer reagent doxorubicin (Dox) to prostate tumors, and that such a form of nanomedicine can improve our ability to treat cancer. Three specific aims are devised to test this hypothesis.

• Synthesize and characterize the RRL-lipDox nanoparticle. In this aim, we plan to use a 4-step protocol to synthesize the nanoparticle RRL-lipDox, which is a Dox- encapsulating crosslinked multilamellar liposome with the surface-displayed tumor vasculature- specific peptide RRL. Parameters such as size, stability, encapsulation efficiency, in vitro release kinetics and cytotoxicity of the synthesized particle will be extensively characterized.

• Assess the selective binding of RRL-lipDox to tumor tissues in vitro. Prostate tumor-associated cell lines and human prostate cancer cryosections will be used to test the capability of RRL-lipDox to selectively bind to tumor tissues. Assays will also be conducted to determine the spatial relationship between nanoparticles and prostate tumor microenvironment.

• Examine the pharmacokinetics and in vivo potency of RRL-lipDox in preclinical mouse models. Pharmacokinetics, biodistribution, and toxicity of RRL-lipDox will be determined in mice. The human prostate xenograft model and the murine prostate transplantation model will be used to assess the ability of RRL-lipDox to target tumors and mount antitumor responses.

Innovation and Significance
The crosslinked multilamellar lipsome is a newly designed nanoparticle. RRL is an entirely new peptide capable of targeting tumor vasculature. From a scientific perspective, our proposed nanoparticle can become versatile platform technology for targeted delivery of various therapeutic reagents to different tumors. The success of this project has the potential to foster a paradigm shift in treating prostate and other malignant tumors. Successful implementation of our strategy will cure more individuals suffering from advanced cancer since it will now become possible to dose-escalate and dose- intensify cancer therapy resulting in a higher response rate against the targeted tumor with minimal toxicity to the patient. Targeted delivery will also allow for direct manipulation of the tumor and its microenvironment and open the possibility of synergistic combination therapies such as radiation, chemo-, immuno-, and cytotoxic therapy, thus vastly expanding the therapeutic repertoire.

An Ultrasound-Activated Nanoparticle Vehicle for Selective Imaging and Drug Delivery
Travis Williams, Chemistry
Andy Chang, Urology

This project will develop a dual imaging and drug delivery system. Our technology involves a nanoparticle in which a small molecule MRI contrast agent is anchored in the core and the periphery is coated with a selectively removable shell that masks the particle’s MRI contrast properties until it is removed. Additionally, our particle can encapsulate a small molecule drug and limit its ability to escape from its carrier until the desired time and place. The particle’s shell is designed to be removed by clinical ultrasound, which is applied externally. Thus, we are inventing a combined imaging and therapy system that is activated on command deep within the tissue, which will allow simultaneous activation of imaging contrast and delivery of a therapeutic agent.

We will construct phosphate-covered nanoparticles of variable size that contain an MRI contrast agent, load them (non-covalently) with lipophilic drugs, then apply a shell that will simultaneously keep the drug in and hold water out, so that the MRI contrast agent is masked. In principle, once IV injected into patients, this construct should aggregate in tumors because of size-exclusion effects of Enhanced Permeability and Retention (EPR). The particles can then be activated by ultrasound with simultaneous drug release and MRI contrast enhancement.

Innovation and Significance
This project will develop a “smart theragnostic” system that is simultaneously an externally activated imaging agent and an externally activated drug delivery system. As regards the former, several “smart” MRI contrast agents have been reported; these are agents that are responsive to their environment. Our strategy is fundamentally different because it is activated by external ultrasound, rather than environment. This has huge value because ultrasound is a rare form of radiation that can penetrate deep within tissue while causing minimal tissue damage.

Development of dual imaging and therapeutic systems is an emerging topic in medicine; “A main challenge in nanobiomedicine is the design of monodisperse and uniform nanomaterials with a size less than 100 nm that can efficiently encapsulate anti-cancer drugs at a high load and sustain-release their cargo at target sites.” Moreover, “Nanoplatforms that integrate imaging and therapeutic functions have received considerable attention as the next generation of medicine.”

The therapeutic component of this system is based on its ability to house, mask, and release selectively a drug cargo. There are numerous examples of polymeric or porous nanostructures that can non-covalently carry a drug cargo, and then release it slowly, like a “leaky bucket” or molecular sponge. Ours is different because the carrier is encased within a protective shell.

Telomerase Reprogramming Nanoparticles
(TeRN): Design and Validation of a Universal Cancer Therapeutic
(renewed in 2012)
Amir Goldkorn, Internal Medicine
Nicos Petasis, Chemistry

Cancer is a major health concern worldwide, accounting for millions of deaths and untold pain and suffering each year. There is an urgent need for new therapeutic strategies with greater efficacy, fewer toxicities, and – ideally – activity against many types of cancer. Although the development of such a universal cancer therapeutic is highly challenging due to the enormous phenotypic heterogeneity of cancer, one emerging possibility involves the enzyme telomerase. Whereas benign, terminally differentiated tissues have extremely low telomerase levels, over 90% of all human cancers have high levels of telomerase and rely on its activity for continuing proliferation. Indeed, telomerase is virtually unmatched as a therapeutic target that is both universal in malignant cells and unique to them, a profile which contributed to the recent awarding of the 2009 Nobel Prize to Blackburn, Greider and Szostak, the discoverers of this enzyme. However, despite early hopes, most efforts to inhibit telomerase have not been successful.

We have recently been pursuing a novel therapeutic strategy based on “telomerase reprogramming” which – rather than inhibiting the enzymatic function of telomerase – harnesses and reprograms its activity to induce rapid cell death in cancer cells. This approach has been highly effective across a broad spectrum of cancer types, but its development has been limited to in vitro models, because the plasmids used to reprogram telomerase are not suited for systemic delivery. Here, for the first time, we propose to surmount this challenge by rationally designing, synthesizing, and testing a Telomerase Reprogramming Nanoparticle (TeRN) capable of efficiently entering cancer cells and reprogramming their telomerase to induce cell death.

Innovation and Significance
• Telomerase reprogramming is a novel therapeutic strategy which exploits the telomerase activity present in >90% of all malignancies yet absent from normal tissues. Hence, it holds tremendous potential as a highly efficacious, non-toxic universal cancer treatment.

• Telomerase Reprogramming Nanoparticles (TeRN) offer a highly innovative implementation of this approach, transitioning telomerase reprogramming from its current in vitro stage to a potentially viable therapeutic agent capable of systemic delivery against cancer cells.

• The project is a highly collaborative, inter-departmental endeavor leveraging the strengths of a translational oncologist from the USC Keck School of Medicine (Goldkorn) and a synthetic/medicinal chemist from the USC Dornsife College (Petasis).

• The proposal constitutes a stepwise translational progression from nanoparticle design through chemical and biological validation, culminating in a novel therapeutic with major clinical impact that will be highly competitive for subsequent peer reviewed funding.