Ultrasmall particle-based solutions for inducing ferroptosis and improving anti-tumor immune responses in cancer

Project Summary: Enormous strides continue to be made in the design of nanoparticles as highly specialized
therapeutics for achieving superior outcomes over standard pharmacological agents, the latter often associated
with significant toxicity that limits treatment efficacy. While cancer immunotherapies have revolutionized the
treatment of disease and shown therapeutic benefits in hard-to-treat cancers, these agents are limited, for
example, by immune-related adverse events and off-target effects in immunosuppressive microenvironments.
Novel, emerging anti-cancer strategies are therefore critically needed to overcome these limitations and improve
durable response rates in combination with immune therapies. One promising strategy exploits the unique “self-
therapeutic” capabilities of the nanomaterials themselves – the treatment of tumors without the need for cytotoxic
drugs. These capabilities are governed by the intrinsic physico-chemical properties of these materials, which can
lead to disruption of signal transduction pathways, cell cross-talk or invasion, and/or induced cell death programs
within the tumor microenvironment (TME) – providing unprecedented opportunities for combating disease. We
have developed specialized ultrasmall fluorescent core-shell silica nanoparticles, Cornell prime dots (C' dots),
with intrinsic therapeutic capabilities enabling a distinct combination of activities that (1) selectively and directly
induce cancer cell death through the iron-dependent mechanism of ferroptosis and (2) modulate immune cells
directly by priming T cells and polarizing macrophages toward a pro-inflammatory phenotype. As CD8+ T cells
are known to also regulate ferroptosis during immunotherapy, such effects are expected to synergize with those
induced by C' dots. A long-term goal of this proposal is to determine critical C' dot physico-chemical parameters
responsible for maximizing responses to these intrinsic therapeutic activities. In Aim I, we will examine the extent
to which changes in the structural properties of PEG-coated C' dots, plain or modified to specifically bind to
melanocortin-1 receptor (MC1-R; a well-established target overexpressed by our syngeneic murine models and
human melanomas), influence therapeutic efficacy in syngeneic melanoma models by modulating ferroptosis
and the tumor microenvironment, in the presence and absence of checkpoint blockade. In Aim II, we will probe
underlying mechanisms driving regulation of immune cell phenotype and/or induction of ferroptosis in vitro. The
successful completion of the project will provide critical insights into (i) key structural parameters modulating the
combined self-therapeutic activities of these particles related to their induction of ferroptosis and priming the
tumor immune microenvironment; (ii) whether critical differences exist in particle characteristics needed to
optimize these distinct activities; (iii) mechanisms underpinning these activities; and (iv) therapeutic strategies
that maximize potent anti-tumor effects in syngeneic melanoma models by administering therapeutic doses of
particles in tandem with checkpoint inhibitors (anti-PD-1 and anti-CTLA-4).

Grant Number: 5R01CA253658-06
NIH Institute/Center: NIH
Principal Investigator: Michelle Bradbury