Center for Cancer Nanotechnology Excellence
for Translational Diagnostics (CCNE-TD)
Nanoparticles offer great promise for imaging cancer and improving patient outcomes, with applications ranging from early diagnosis to early monitoring of tumor response to therapy. However, there are a number of challenges in translating nanoparticle-based contrast agents to clinical cancer imaging that do not apply to small molecule agents, most notably non-target effects and resultant tissue toxicity. We have redesigned the strategy of utilizing nanoparticles for cancer imaging from the bottom-up, avoiding the limitations of nanoparticles while harnessing their great promise: we can build nanoparticles on-demand in tumor tissue with specially engineered self-assembling small molecules. These small molecules are masked by capping groups that prevent their self-assembly until acted upon by a target endogenous enzyme, so that upon specific unmasking they form nanoparticles in the immediate enzyme vicinity. By tagging the small molecules with a radionuclide like 18F, the location and amounts of these aggregates can be detected through PET imaging. In this way, masked probe will be rapidly cleared from the body, where self-assembled nanoparticles will be retained for longer periods of time to signal target enzyme activity. By targeting caspase-3, an enzyme activated by effective cancer chemotherapy that results in the death of the tumor cell and eradication of the tumor, we can effectively detect non-invasively where the tumor is dying and early after treatment. In this project, we will be utilizing this novel strategy of controlled in situ self-assembly to monitor the response of lung cancer to chemotherapy, however with two key modifications to the performance of the probe. Firstly, we will endeavor to enhance the amount of masked small molecule probe that reaches the tumor cells through the attachment of tumor homing groups. We will explore receptor-mediated endocytosis through folate targeting, active transport through glucose targeting, and translocation through a tumor-specific cell penetration peptide independent of receptors or transporters. We hypothesize that the more small molecules reach the tumor, the higher our sensitivity will be for detecting therapy-induced tumor death. Secondly, we will limit the length of time the self-assembled nanoparticles reside in dying tumor tissue by building controlled-degradation chemistry into the small molecule. By inducing the nanoparticles to disassemble into small molecule units in a controlled fashion after imaging has been performed, tissue toxicity associated with extended nanoparticle retention that could otherwise limit clinical translation will be avoided. In building on our controlled self-assembly strategy to improve sensitivity and limit any toxic potential, we endeavor to move our imaging technology to the clinic, providing a means for personalized therapy selection and early monitoring to ultimately improve human health outcomes.
Lung cancer is the most deadly cancer in the United States. Research Project 2 (P2) will accelerate advances toward the accurate diagnosis of the most common type of lung cancer, non-small cell lung cancer (NSCLC), via development of multi-scale nanotechnologies to interrogate bloodborne circulating proteins, autoantibodies, circulating tumor cells (CTCs), circulating tumor microemboli (CTM), and CTC-derived nucleic acid signatures. The proposed nanotechnology platforms strategically bring experts from diverse fields of materials science and electrical engineering (Project Leader Dr. Shan Wang), microfluidics (Co-Investigator Dr. Utkan Demirci), clinical oncology (Project Clinicians Drs. Heather Wakelee and Viswam Nair), business (Significant Contributor, Mr. Luis Carbonell, MBA), and bioinformatics and statistics (Collaborator and Consultant Drs. Olivier Gevaert and Jarrett Rosenberg) together to create rapid, accurate, and robust diagnostic tools for NSCLC patients. We endeavor to create or develop nanotechnologies ranging from magneto-nanosensors for blood-based proteomics of cancer and tumor cell enrichment with magnetic separation using magnetic sifting and magnetic levitation cell sorting, to molecular characterization using targeted multiplexed gene expression and next-generation sequencing for CTCs and CTM at the single-cell level. Our platforms focus not only on diagnosing cancer, but also on pinpointing the course and pace of cancer progression and evolution under treatment. Within the first two years, we will develop the proposed nanotechnologies – magneto-nanosensors, magnetic separation devices, single-cell gene expression assays and gene sequencing to incorporate putative cancer biomarkers – and then test them on two cohorts of NSCLC patients: those in early stage for diagnosis, and those in advanced stages for therapy selection and monitoring. We have access to large cohorts of clinical samples from patients provided by Stanford Hospital and MD Anderson Cancer Center. These devices will not be tested in isolation, but rather integrated with patients’ clinical and imaging data from CT (computed tomography) and PET (Positron Emission Tomography)–CT, which are a crucial part of the current standard of care for diagnosis and surveillance of lung cancer. We anticipate that the development of novel nanotechnologies and pertinent methods as applied to selected bloodborne nucleic acid, proteomic, and cellular biomarkers will enable the detection of early-stage NSCLC. Unprecedented insights into targeted therapy selection and monitoring for late-stage NSCLC patients will be documented to more effectively manage patients than today’s standard of care. These nanotechnologies will enable blood biomarker analyses to be widely adopted in clinics.
Our long-term goals are to clinically translate in vivo imaging tools for the improved management of cancer patients. Our primary focus in this project is developing and using nanotechnology imaging for prostate cancer biopsy and management. In particular, we focus on ultrasound and photoacoustic imaging. There is already an advanced landscape of ultrasound imaging including transrectal ultrasound imaging used to manage prostate cancer. Our work will expand this to photoacoustic imaging. This allows imaging of not only the disturbed vasculature associated with cancer, but adding nanoparticle contrast agents will transform this approach from anatomic imaging to molecular imaging. Although we focus on prostate cancer here, we expect that our strategies will eventually apply to many other cancers studied with ultrasound including liver, ovarian, pancreatic, etc. We have made significant progress over the last cycle of this CCNE competing renewal grant including the development of photoacoustic molecular imaging hardware that has already been evaluated in humans. We will continue to study how our in vivo imaging strategies can be improved even further through use with in vitro diagnostics. Indeed, both in vitro nanosensors and in vivo nano-molecular imaging will be utilized to accomplish our long-term goals. The combination of both in vitro and in vivo diagnostic strategies is expected to lead to a much greater accuracy and cost-effectiveness than either strategy alone. To translate our in vitro and in vivo diagnostic strategies we will utilize mouse models of human cancer that help us to test our approaches prior to clinical translation. The clinical translation will be accomplished through the help of the clinical translation core (Core 2) which links to various clinical trials and leverages on other funding mechanisms already in place in our CCNE.