Developing a Copper(II) Agent Based on His-146 and His-242 Residues of Human Serum Albumin Nanoparticles: Integration To Overcome Cisplatin Resistance and Inhibit the Metastasis of Nonsmall Cell Lung Cancer

Abstract

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.

Developing a Gallium(III) Agent Based on the Properties of the Tumor Microenvironment and Lactoferrin: Achieving Two-Agent Co-delivery and Multi-targeted Combination Therapy of Cancer

“…One of the most promising strategies for designing novel metal agents is through rational screening of metals and active ligands. Interestingly, thiosemicarbazone compounds are promising anticancer agents, and the sulfur atoms and two nitrogen atoms of thiosemicarbazones prefer to coordinate with the metal center. , Thus, to obtain a new metal thiosemicarbazone compound with remarkable anticancer activity, we designed and synthesized a series of Ga­(III) isopropyl-2-pyridyl-ketone thiosemicarbazone compounds (C1–C4) by modifying the N4-position of isopropyl-2-pyridyl-ketone thiosemicarbazones (L1–L4) (Figure ).…”

Developing an Anticancer Platinum(II) Compound Based on the Uniqueness of Human Serum Albumin

“…First, 250 μL of defatted HSA (40 mg/mL) was mixed with 360 μL of PA (2.5 mM) and incubated at room temperature for 2 h. Then, 18 μL of the Pt agent (20 mM) was added and incubated overnight. The unbound Pt agent was removed by dialysis and concentrated to 100 mg/mL with a Millipore spin filter (10,000 Da cutoff), and then crystallization was conducted,as previously described . The protein data of the HSA–Pt agent complex were collected by the BL17U beam of the Shanghai Synchrotron Radiation Facility at a low temperature of 100 K, and then processed by HKL2000 .…”

“…The unbound Pt agent was removed by dialysis and concentrated to 100 mg/mL with a Millipore spin filter (10,000 Da cutoff), and then crystallization was conducted,as previously described. 55 The protein data of the HSA−Pt agent complex were collected by the BL17U beam of the Shanghai Synchrotron Radiation Facility at a low temperature of 100 K, and then processed by HKL2000. 87 The crystal structure of the HSA−Pt agent complex was obtained by molecular replacement using the HSA-MyR structure (PDB: 1BJ5) as a model by CCP4 software.…”

“…In the past several decades, human serum albumin (HSA)one of the most promising drug carrierswas extensively studied to solve problems with drug delivery and improve its targeting ability in vivo due to the following unique properties: − (1) HSA is the most abundant endogenous protein in plasma that is nontoxic, nonantigenic, biodegradable, and patient-tolerant; (2) There are larger gaps (approx. ≥200 nm) between the endothelial cells of tumor blood vessels compared to normal blood vessels, while HSA has an effective diameter of approximately 7.2 nm and can accumulate in tumor tissues through an enhanced permeability and retention (EPR) effect; (3) HSA can bind to the gp60 receptor, which is highly expressed on the surface of tumor vascular endothelial cells, further activates caveolin-1 to form a vesicle and effectively penetrates tumor vascular endothelial cells to reach the tumor cell space; (4) HSA can specifically bind to the secreted protein acidic and rich in cysteine (SPARC), which is highly expressed and secreted on the surface of many cancer cells and then absorbed by tumor cells through the endocytosis mechanism; (5) HSA not only has many active residues that can bind to drugs through chemical linkers but also has several binding sites in its three subdomains, so drugs can directly bind to HSA to form an HSA–drug complex delivery system. − Thus, we can rationally design HSA to deliver the Pt­(II) compound to overcome the aforementioned challenges.…”

Development of a zinc(ii) 2-pyridinecarboxaldehyde thiosemicarbazone complex with remarkable antitumor and antiangiogenic activities

“…[16][17][18] In fact, metal thiosemicarbazone complexes are promising anticancer metal agents because they can efficiently inhibit the growth of cancer cells through multiple pathways. [19][20][21][22][23] Therefore, the development of a novel Zn(II) thiosemicarbazone complex is expected to be effective in the treatment of tumors.…”