Customized nanofibers with preferential lung-targeting properties for treating metastatic pulmonary tumors

Project Summary
Currently, most nanotechnology cancer therapies focus on the treatment of primary tumors, but it is important
to leverage the potential of nanomedicine to combat cancer spread at each stage of the metastatic process.
Lung metastasis is a highly aggressive, complex, and heterogeneous disease. There is no effective treatment
for metastatic lung tumors and chemotherapy is the only option to prolong patients’ clinical prognosis. Alternative
strategies, including targeted therapy and immunotherapy have been proposed, but they failed to successfully
treat metastatic lesions.
There is an urgent need to accelerate progress toward curing lung metastases and
reduce patients’ mortality. Our goal is to develop a new therapeutic approach that carries more drugs to the
metastatic lung tumors and retains on-site to release a broad-spectrum antitumor medication. In this project, we
propose to use peptide-based nanofiber (pNFP6) with preferential lung-targeting properties to overcome the
barrier of selective drug delivery to metastases. The pNFP6 is innovative as multiple nanofibers can rearrange
into a large interfibril network to prolong the local retention and offer a long-term treatment. The nanofiber
technology will be combined with ionizing radiation therapy to enhance the drug post-delivery antitumor efficacy.
Our central hypothesis is that the combinatorial therapy will cooperatively and synergistically inhibit the disease
progression leading to an effective treatment of lung metastases. For proof-of-principle studies, we will use
pNFP6 to carry and deliver doxorobucin (Dox), a standard cytotoxic agent and radiosensitizer. The nanofibers
will favor the drug accumulation and retention on-site while radiotherapy will promote the overall anticancer effect
through direct tumor cell killing and radiation-mediated immunogenicity. The spatiotemporal-controlled drug
release will be essential to ensure the therapeutic success. To establish the potential of this antimetastatic
multiplexed approach, two specific aims will be pursued: (1) evaluate the local drug release and its impact on
the therapeutic efficacy; and (2) define the therapeutic and survival benefit of Dox-pNFP6 when combined with
radiation therapy. To achieve Aim 1, we will synthesize a panel of Dox-loaded pNFP6 analogues using different
cleavable linkers sensitive to tumor microenvironment stimuli to release the drug. We will study the in vivo drug
delivery, release, and tumoral uptake using Light Sheet Fluorescence Microscopy and MALDI-imaging. and
identify the optimal release mechanisms in response to metastatic lung tumors. To complete Aim 2, we will
assess the therapeutic efficacy (tumor inhibition and survival benefit) and toxicity profile of Dox-pNFP6 combined
with radiation therapy in several animal models bearing metastatic lung tumors. The treatment outcomes will be
compared to free Dox and Doxil, the FDA-approved liposomal formulation of Dox. We will also investigate the
molecular and immune pathways activated by this new therapeutic strategy to better understand the mechanisms
responsible for the enhanced anticancer activity. Successful completion of this project will provide an effective
therapeutic solution with clinical impacts on the treatment and management of lung metastases.

Grant Number: 5R37CA278671-03
NIH Institute/Center: NIH
Principal Investigator: Vanessa Bellat