ABSTRACT
In the United States, cancer is the second leading cause of death, and it is projected that 39.5% of all US
adults will be diagnosed with cancer in their lifetimes. Carcinomas comprise up to 90% of all US cancer cases.
Chemotherapeutics and antibody immune checkpoint inhibitors (ICIs) are promising treatments for these
cancers but are not effective in all cases and exact a large toll on the quality of life of patients due to off-target
toxicity. The goal of this proposal is to develop a peptide-based hydrogel therapeutic platform for the local
delivery of chemotherapeutics and ICIs to maximize treatment efficacy and mitigate systemic toxicity.
Boronic acid-containing small molecule drugs (BACSMs) are a growing class of chemotherapeutics for the
treatment of cancer. Bortezomib is an FDA-approved BACSM for the treatment of multiple myeloma and
causes immunogenic cancer cell death to help the body develop an anti-cancer immune response. There is
interest to expand the use of bortezomib to solid tumors but these efforts face challenges due to the inability to
maintain high local concentrations in the tumor without systemic toxicity. Multidomain peptide (MDP) hydrogels
are self-adjuvanting materials that have been investigated for cancer immunotherapy and drug delivery. The
limitations of bortezomib may be ameliorated by using MDPs hydrogels as a local drug delivery platform by
allowing for local intratumoral drug delivery to maximize treatment efficacy while minimizing off-target toxicity.
Boronic acids are known to form dynamic covalent bonds with diols, catechols, and salicylhydroxamic acids
(SHAs), which I plan to use to control the delivery of anti-cancer BACSMs from hydrogels. In the F99 phase of
this proposal, I aim to develop catechol- and SHA-functionalized MDP hydrogels for local bortezomib delivery
to improve the efficacy, safety, and accessibility of this chemotherapeutic treatment. I hypothesize that MDP
adjuvancy will synergize with bortezomib-induced immunogenic cell death to generate protective anti-cancer
immunity in a murine model of head and neck squamous cell carcinoma (HNSCC). These boronic acid-binding
MDPs can be used to control the release of any payload that has a boronic acid moiety. Thus, in the K00
phase of this proposal, I aim to modify ICI antibodies with noncanonical boronic acid motifs to fine-tune their
release from the designed MDPs. I will use this platform to intratumorally co-deliver bortezomib with immune
checkpoint inhibitors to facilitate an anti-cancer immune response in murine models of HNSCC, melanoma,
and breast cancer to demonstrate the broad utility of this platform. These materials could help treat patients
with malignant tumors and protect them from cancer recurrence after treatment while mitigating side effects
associated with chemotherapy and ICIs.