Regulating cancer associated fibroblasts with losartan-loaded injectable peptide hydrogel to potentiate chemotherapy in inhibiting growth and lung metastasis of triple negative breast cancer
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Abstract
Preoperative chemotherapy is effective in improving the prognosis of patients, but
its efficacy is impeded by cancer associated fibroblasts (CAFs) that enhance the survival,
growth, and metastasis of cancer cells. To inhibit the activity of CAFs, prolonged
and localized drug exposure is necessary. Here, we report on the rational design,
screening, and evaluation of an injectable peptide hydrogel as a local losartan depot
aiming to inhibit CAFs and potentiate chemotherapy. We synthesized a set of peptide
derivatives and found that C16-GNNQQNYKD-OH (C16-N) surpassed the others in hydrogel
formation and drug encapsulation, due to its flexible hydrocarbon tail and interpeptide
hydrogen bonding that allowed supramolecular self-assembly into long filaments with
hydrophobic cores. C16-N co-assembled with losartan to form hydrogel from which losartan
was sustainably released over 9 days. After intratumoral injection, the hydrogel could
be retained in the tumor for more than 9 days, significantly inhibited the CAFs and
collagen synthesis in orthotopic 4T1 tumors, and enhanced the efficacy of PEGylated
doxorubicin-loaded liposomes (Dox-L) in inhibiting the tumor growth (64% vs. Dox-L
alone) and lung metastasis (80% vs. Dox-L alone). These results provide important
guiding principles for the rational design of injectable peptide hydrogels aiming
to regulate CAFs and improve chemotherapy.