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

Abstract

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.

Autophagy-Dependent Apoptosis Induced by Apoferritin–Cu(II) Nanoparticles in Multidrug-Resistant Colon Cancer Cells

“…31,32 In addition, as copper ions have been involved in cell signaling pathways, the corresponding metal complexes could be able to influence different cell death mechanisms. 30,33 To date, copper complexes were reported inducing various types of nonapoptotic cell death, such as paraptosis, 34 autophagy, 35 or necrosis. 36 Until now, no examples of copper complexes that induce autophagy-dependent apoptosis have been reported.…”

“…As a trace element, copper plays a critical role in cancer development and tumorigenesis. Interestingly, tumor tissue was found with an increased amount of copper in comparison to healthy tissue, providing potentially a naturally occurring cancer tumor-targeting effect. , In addition, as copper ions have been involved in cell signaling pathways, the corresponding metal complexes could be able to influence different cell death mechanisms. , To date, copper complexes were reported inducing various types of nonapoptotic cell death, such as paraptosis, autophagy, or necrosis . Until now, no examples of copper complexes that induce autophagy-dependent apoptosis have been reported.…”

Design of a novel Pt(ii) complex to reverse cisplatin-induced resistance in lung cancer via a multi-mechanism

“…Previous studies suggested that the terminal H at N-4 of thiosemicarbazone modified with alkyl groups can improve its lipophilicity along with its anticancer activity. [23][24][25][26][27] We thus synthesised a series of novel Pt(II) complexes with 2-thiazolecarboxaldehyde thiosemicarbazones as ligands and investigated crucial structural-activity relationships that enable thiosemicarbazones of this category to be effective against cisplatin-resistant cancer cells. For the purpose of this study, we conducted the following experiments: (1) we synthesised a series of Pt(II) 2-thiazolecarboxaldehyde thiosemicarbazone complexes and explored their structure-activity relationships in cisplatin-resistant cancer cells; (2) we identified the therapeutic efficacy of Pt complexes in cisplatin-resistant A549cisR tumour xenografts; (3) we investigated the effectiveness of Pt complexes in targeting cisplatinresistant cancer cells and their potential mechanism of action; and (4) we confirmed and illuminated in detail the mechanism of Pt complexes in overcoming cisplatin resistance.…”

Developing a Novel Anticancer Gold(III) Agent to Integrate Chemotherapy and Immunotherapy

“…Excitingly, albumin has become one of the most promising carriers for overcoming the challenges mentioned above . Recently, albumin NPs have been designed to enhance the therapeutic efficiency and targeting ability in vivo . − Albumin conjugates have been designed to enhance the targeting ability of metal agents for photodynamic therapy. − HSA–metal agent complex delivery systems have been constructed to improve their targeting ability and decrease their side effects in vivo . − …”