Cancer
is among the leading causes of death globally. Previous studies have
demonstrated that cancer mortality rate is often greatly reduced by the early
diagnosis and therapy of these diseases. Natural and monoclonal antibodies have
been widely used in cancer diagnosis and therapy as they have the potential to
offer the desired selectivity. However, they are subject to the limitations of
high cost of production, low operational stability, and immunogenicity. As a
promising alternative to natural or monoclonal antibodies, antibody-mimicking
nanoparticles that provide the targeting and inhibition of cancer-related
signaling pathways can pave a new path for the diagnosis and anti-cancer
therapy. In our work, we have designed and synthesized a series of hydrogel
polymer nanoparticles engineered with high affinity and selectivity towards
different cancer biomarkers using chemical directed evolution and imprinting
technology. Combined with surface-enhanced Raman scattering (SERS), the plasmonic
nanoprobes exhibited high specificity and selectivity for the target cancer
biomarkers, with an extracellular Raman detection limit of 10-14 mol/L. Stimuli-responsive behaviour was also achieved by modulating the
external temperature or pH value. The plasmonic properties enabled in situ live cell intracellular Raman
detection and imaging of endogenous cancer biomarkers. We also synthesized a
synthetic artificial antibody as inhibitor for matrix metalloproteinase-9
(MMP-9). The resulting polymer nanoparticle could selectively capture MMP-9 via
the boronate interaction and inhibit its activity by providing steric hindrance
to the active O-glycosylated domains of MMP-9. In vitro cell experiments and in
vivo studies in mice demonstrate that the artificial antibody specifically
binds MMP-9, inhibits the enzymatic activity of MMP-9, and as a result
suppresses the migration and growth of metastatic tumors. The tumor growth
inhibition rate reaches up to 54 ± 15%. By combining with the photothermal
therapy induced by gold nanorods, the inhibition rate of tumor growth further
increases to 94 ± 5%.
Key words: artificial antibody; chemical directed evolution; imprinting;
surface-enhanced Raman scattering; early diagnosis and therapy; cancer diseases
Fund project：National Natural Science Foundation of
China (21576017, 21436002)