To overcome the resistance of nonsmall
cell lung cancer (NSCLC)
cells to cisplatin and inhibit their metastasis, we proposed to develop
a Cu(II) agent based on the specific residue(s) of HSA nanoparticles
(NPs) for multitargeting the tumor microenvironment (TME). To this
end, we not only synthesized four Cu(II) 2-hydroxy-3-methoxybenzaldehyde
thiosemicarbazone compounds (C1–C4), obtaining a Cu compound
(C4) with significant cytotoxicity by studying their structure–activity
relationships, but also revealed the binding mechanism of C4 to HSA
through X-ray crystallography and confirmed the successful construction
of a new HSA-C4 NPs delivery system. C4 and HSA-C4 NPs inhibited the
A549cisR tumor growth and metastasis, and HSA NPs optimized the anticancer
behavior of C4. We further confirmed the anticancer mechanism of the
C4/HSA-C4 NP multitargeting TME to overcome cisplatin resistance:
killing tumor cells by acting on the mtDNA and inducing apoptosis,
polarizing M2-type macrophages to the M1-type, and inhibiting angiogenesis.
To integrate targeted diagnosis and treatment of cancer, we proposed to develop a gadolinium (Gd) agent based on the properties of apoferritin (AFt). To this end, we not only optimized a series of Gd(III) 8-hydroxyquinoline-2-carboxaldehyde-thiosemicarbazone compounds to obtain a Gd(III) compound (C4) with remarkable T 1 -weighted magnetic resonance imaging (MRI) performance and cytotoxicity to cancer cells in vitro but also constructed an AFt−C4 nanoparticle (NP) delivery system. Importantly, AFt−C4 NPs improved the targeting ability of C4 in vivo and showed enhanced MRI performance and tumor growth inhibition ratio relative to C4 alone. Furthermore, we confirmed that C4 and AFt−C4 NPs inhibited tumor growth through apoptosis, ferroptosis, and ferroptosis-induced immune response.
To obtain next-generation metal drugs that can overcome the deficiencies of platinum (Pt) drugs and treat cancer more effectively, we proposed to develop a multitargeted palladium (Pd) agent to the tumor microenvironment (TME) based on the specific residue(s) of human serum albumin (HSA). To this end, we optimized a series of Pd(II) 2-benzoylpyridine thiosemicarbazone compounds to obtain a Pd agent (5b) with significant cytotoxicity. The HSA-5b complex structure revealed that 5b bound to the hydrophobic cavity in the HSA IIA subdomain and then His-242 replaced a leaving group (Cl) of 5b, coordinating with the Pd center. The in vivo results showed that the 5b/HSA-5b complex had significant capacity of inhibiting tumor growth, and HSA optimized the therapeutic behavior of 5b. In addition, we confirmed that the 5b/HSA-5b complex inhibited tumor growth through multiple actions on different components of TME: killing cancer cells, inhibiting tumor angiogenesis, and activating T cells.
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