This proposal aims to develop a novel platform for imaging taxane nano formulation delivery and pharmacodynamic response at the single-cell level in breast cancer, and apply it to understand the impact of passive and active molecular targeting of therapeutic nanoparticles (TNPs). TNPs have been developed to deliver cytotoxic chemotherapies to tumors more safely and effectively; however, clinical trial results often show equivocal ef?cacy, largely owing to heterogeneous TNP tumoral accumulation across patients. Thus, a clear need exists to better understand why many TNP strategies fail in vivo and not result in signi?cantly improved tumoral uptake or therapeutic response. Advanced in vivo imaging allows unique insight into TNP behavior at the single-cell level within tumors: in preliminary work, the candidate Dr. Miles Miller has developed in vivo imaging techniques to uncover a new paradigm for TNP-mediated drug delivery, whereby tumor- associated macrophage (TAM) serve as drug reservoirs that accumulate nanoparticle vehicle and gradually release the drug payload to neighboring tumor cells. TAM imaging using companion magnetic nanoparticles and MRI predicts TNP delivery and ef?cacy across heterogeneous cohorts, thus showing promise as tool for patient selection into TNP clinical trials. This proposal hypothesizes that nano-formulation will dramatically alter how taxanes accumulate at the single-cell level, and that TAM will drive distribution of even so-called ?tumor-targeted? TNPs that have been coated with ligands binding over-expressed proteins on tumor cells. The proposal addresses questions including i) what are the rate-limiting barriers to TNP delivery and action at the single-cell level in breast cancer?, ii) to what degree does molecular targeting improve delivery and action of taxanes?, and iii) can this be combined with other strategies, particularly those related to TAM? In aim 1, a breast cancer imaging platform will be developed and applied to test passively accumulating TNPs (with no molecular targeting).
In aim 2, multi-channel in vivo imaging will be used to study the impact of TNP molecular-targeting, for instance using anti-HER2 antibody-labeled TNP in HER2+ breast cancer models. Dr. Miller has extensive engineering experience in computational analysis of biological variables, new intravital imaging strategies and in multivariate statistics. With this proposal, he aims to undergo structured training in cancer biology, molecular biology, immunology, responsible research conduct, and laboratory management as he transitions to an independent career at the interface of cancer nanotechnology and systems pharmacology. Work will be conducted in the Center for Systems Biology at Massachusetts General Hospital and Harvard Medical School under the primary mentorship of Dr. Ralph Weissleder MD, PhD. Dr. Miller has also brought in co-mentor Prof. Tim Mitchison, expert in taxane pharmacology; Advisory Committee member Dr. Keith Flaherty, clinical oncologist; and Prof. Mikael Pittet, expert in immunology. These mentors will allow him to develop a successful research strategy and career as an independent biomedical cancer investigator.
This project aims to expand on novel in vivo imaging strategies for analyzing the combined distribution and action of taxane-encapsulated nano formulations in breast cancer at the single-cell level. The platform will reveal quantitative principles underlying heterogeneous drug response and emergent drug resistance, including factors related to tumoral microenvironmental context, immune and stromal populations, and vascularization, and will guide the development of new strategies for overcoming barriers to efficacy.
