Novel Brain-Tumor-Inhibiting Copper(II) Compound Based on a Human Serum Albumin (HSA)-Cell Penetrating Peptide Conjugate

It is a great challenge to design drugs that penetrate the blood–brain barrier
to inhibit brain tumor growth by acting against multiple targets and
also improve their delivery efficacy and targeting ability to cancer
cells. To overcome the above problems, we designed a multitarget metal
agent for treating brain tumors based on an human serum albumin (HSA)-cell
penetrating peptide conjugate. Thus, we rationally screened copper
(Cu) and 2-acetyl-3-ethylpyrazine thiosemicarbazones to synthesize
six compounds, and we investigated their structure–activity
relationships and confirmed multiple mechanisms for brain glioma cells.
The HSA–6b complex structure indicated that 6b binds to the IIA
subdomain of HSA and His242 replaces the Br ligand in 6b in coordination with Cu2+. In vivo data suggested that
both 6b and the HSA–6b–peptide
conjugate penetrate the blood–brain barrier and inhibit brain
tumor growth with few side effects. Furthermore, the HSA–peptide
conjugate also improved the delivery efficacy and targeting ability
of 6b in vivo.