A novel brain-tumor-inhibiting copper(II) compound based on a human serum albumin (HSA)-cell penetrating peptide conjugate.

It is great challenge to design drugs that penetrate the blood-brain barrier to inhibit brain tumor growth by acting against multiply target, and also improve their delivery efficacy and targeting ability for cancer cells. To integrate to overcome the above problems, we designed a multi-target metal agent for treating brain tumors based on a HSA-cell penetrating peptide conjugate. Thus, we rational 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. HSA-6b complex structure indicated 6b binds to the IIA sub-domain of HSA and His242 replaced 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.