Transfer of ANS-Like Drugs from Micellar Drug Delivery Systems to Albumin Is Highly Favorable and Protected from Competition with Surfactant by “Reserved” Binding Sites DOI
Iulia Carabadjac,

Leonie C. Vormittag,

Thomas Muszer

et al.

Molecular Pharmaceutics, Journal Year: 2024, Volume and Issue: 21(5), P. 2198 - 2211

Published: April 16, 2024

Micellar drug delivery systems (MDDS) for the intravenous administration of poorly soluble drugs have great advantages over alternative formulations in terms safety their excipients, storage stability, and straightforward production. A classic example is mixed micelles glycocholate (GC) lecithin, both endogenous substances human blood. What limits use MDDS complexity transitions after injection. In particular, as disintegrate partially or completely injection, has to be transferred safely carriers blood, such serum albumin (HSA). If this transfer compromised, might precipitate─a process that needs excluded under all circumstances. The key question paper whether high local concentration GC at moment site dissolution transiently saturate HSA binding sites and, hence, endanger quick transfer. To address question, we used a new approach, which time-resolved fluorescence spectroscopy single tryptophan HSA, Trp-214, characterize competitive substitute anilinonaphthalenesulfonate (ANS) HSA. Time-resolved Trp-214 showed important established methods tackling problem. ANS been standard "model drug" study decades, given its structural similarity class naphthalene-containing acidic fact it displaced from by numerous (which presumably bind same sites). Our complex global fit uses critical approximation average lifetimes behave similarly lifetime, but resulting errors are found moderate results provide convincing explanation the, first glance, counterintuitive behavior. Accordingly, largely line with literature, observed two types HSA: 3 type A, rather peripheral, 2 B, likely more central sites. latter quench Förster Resonance Energy Transfer (FRET) rate constant ≈0.4 ns–1 per ANS. Adding millimolar concentrations displaces not B At incomplete saturation, causes GC-induced translocation FRET-active This leads apparent paradox partial displacement increases quenching effect on Trp-214. most conclusion (ANS-like) cannot type-B sites, consequently, these impaired vicinity dissolving micelle. second unbound above CMC (9 mM), equilibrates between strong preference free That means even persisting would lose cargo readily once exposed For sharing property, targeted approaches involving them nanocarrier pointless.

Language: Английский

Designing a Mitochondria-Targeted Theranostic Cyclometalated Iridium(III) Complex: Overcoming Cisplatin Resistance and Inhibiting Tumor Metastasis through Necroptosis and Immune Response DOI
Wenjuan Li, Ting Li, Ying Pan

et al.

Journal of Medicinal Chemistry, Journal Year: 2024, Volume and Issue: 67(5), P. 3843 - 3859

Published: March 5, 2024

To develop a potential theranostic metal agent to reverse the resistance of cancer cells cisplatin and effectively inhibit tumor growth metastasis, we proposed design cyclometalated iridium (Ir) complex based on properties environment (TME). end, designed synthesized series Ir(III) 2-hydroxy-1-naphthaldehyde thiosemicarbazone complexes by modifying hydrogen atom(s) N-3 position compounds structure dimers then investigated their structure–activity structure–fluorescence relationships obtain an (Ir5) with remarkable fluorescence cytotoxicity cells. Ir5 not only possesses mitochondria-targeted but also overcomes inhibits metastasis in vivo. Besides, confirmed anticancer mechanisms acting different components TME: directly killing liver inducing necroptosis activating necroptosis-related immune response.

Language: Английский

Citations

22
Designing an anticancer Pd(II) complex as poly(ADP-ribose) polymerase 1 inhibitor DOI

Shuangshuang Gai,

Peng Cao,

Xuwei Zhong

et al.

International Journal of Biological Macromolecules, Journal Year: 2025, Volume and Issue: 297, P. 139885 - 139885

Published: Jan. 14, 2025

Language: Английский

Citations

2
Developing a Copper(II) Isopropyl 2-Pyridyl Ketone Thiosemicarbazone Compound Based on the IB Subdomain of Human Serum Albumin–Indomethacin Complex: Inhibiting Tumor Growth by Remodeling the Tumor Microenvironment DOI
Xueyu Man, Shanhe Li, Gang Xu

et al.

Journal of Medicinal Chemistry, Journal Year: 2024, Volume and Issue: 67(7), P. 5744 - 5757

Published: March 29, 2024

To develop a next-generation metal agent and dual-agent multitargeted combination therapy, we developed copper (Cu) compound based on the properties of human serum albumin (HSA)–indomethacin (IND) complex to remodel tumor microenvironment (TME). We optimized series Cu(II) isopropyl 2-pyridyl ketone thiosemicarbazone compounds obtain (C4) with significant cytotoxicity then constructed an HSA–IND–C4 (HSA–IND–C4) delivery system. IND C4 bind hydrophobic cavities IB IIA domains HSA, respectively. In vivo, not only showed enhanced antitumor efficacy relative + but also improved their targeting ability decreased side effects. The mechanism involved acting different components TME. inhibited tumor-related inflammation, while induced apoptosis autophagy cancer cells angiogenesis.

Language: Английский

Citations

16
Development of Cu(II) 4-hydroxybenzoylhydrazone complexes that induce mitochondrial DNA damage and mitochondria-mediated apoptosis in liver cancer DOI
Ming Jiang,

Qiwei Yan,

Yuanping Fu

et al.

Journal of Inorganic Biochemistry, Journal Year: 2024, Volume and Issue: 256, P. 112550 - 112550

Published: April 5, 2024

Language: Английский

Citations

10
Photoactivation of cGAS-STING Pathway and Pyroptosis by Endoplasmic Reticulum-Targeting Ruthenium(II) Complex for Cancer Immunotherapy DOI

Bin-Fa Liang,

Shan Jiang,

Yun-Shi Zhi

et al.

Inorganic Chemistry Frontiers, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 1, 2025

A cholic acid-modified ruthenium( ii ) (Ru1) photosensitizer was synthesized. Ru1 induced pyroptosis and sequentially engaged the downstream proteins p-TBK1 p-IRF3 within STING pathway, thus promoting elicitation of tumor immune responses.

Language: Английский

Citations

1
Developing a Ruthenium(III) Complex to Trigger Gasdermin E-Mediated Pyroptosis and an Immune Response Based on Decitabine and Liposomes: Targeting Inhibition of Gastric Tumor Growth and Metastasis DOI
Wenjuan Li, Shanhe Li, Gang Xu

et al.

Journal of Medicinal Chemistry, Journal Year: 2023, Volume and Issue: 66(18), P. 13072 - 13085

Published: Sept. 13, 2023

To develop next-generation metal drugs with high efficiency and low toxicity for targeting inhibition of gastric tumor growth metastasis, we not only optimized a series ruthenium (Ru, III) 2-hydroxy-1-naphthaldehyde thiosemicarbazone complexes to obtain Ru(III) complex (4b) remarkable cytotoxicity in vitro but also constructed 4b-decitabine (DCT)/liposome (Lip) delivery system (4b-DCT-Lip). The vivo results showed that 4b-DCT-Lip had stronger capacity inhibit metastasis than 4b-DCT addressed the co-delivery problems improved their ability. Furthermore, confirmed mechanism 4b-DCT/4b-DCT-Lip inhibiting tumor. DCT-upregulated gasdermin E (GSDME) was cleaved by 4b-activated caspase-3 afford GSDME-N terminal then aggregated form nonselective pores on cell membrane tumor, thereby inducing pyroptosis pyroptosis-induced immune response.

Language: Английский

Citations

23
Investigating the interaction between sertraline hydrochloride and human serum albumin using equilibrium dialysis and spectroscopic methods DOI

Elaheh Jalali,

Javad Sargolzaei,

Parisa Rajabi

et al.

Inorganic Chemistry Communications, Journal Year: 2024, Volume and Issue: 166, P. 112586 - 112586

Published: May 22, 2024

Language: Английский

Citations

8
Isosteric Replacement of Sulfur to Selenium in a Thiosemicarbazone: Promotion of Zn(II) Complex Dissociation and Transmetalation to Augment Anticancer Efficacy DOI
Büşra Kaya,

Mahan Gholam Azad,

Mediha Süleymanoğlu

et al.

Journal of Medicinal Chemistry, Journal Year: 2024, Volume and Issue: 67(14), P. 12155 - 12183

Published: July 5, 2024

We implemented isosteric replacement of sulfur to selenium in a novel thiosemicarbazone (PPTP4c4mT) create selenosemicarbazone (PPTP4c4mSe) that demonstrates potentiated anticancer efficacy and selectivity. Their design specifically incorporated cyclohexyl styryl moieties sterically inhibit the approach their Fe(III) complexes oxy-myoglobin heme plane. Importantly, contrast clinically trialed thiosemicarbazones Triapine, COTI-2, DpC, PPTP4c4mT PPTP4c4mSe did not induce detrimental oxidation. Furthermore, demonstrated more potent antiproliferative activity than homologous thiosemicarbazone, PPTP4c4mT, with selectivity being superior or similar, respectively, COTI-2. An advantageous property Zn(II) relative analogues was greater transmetalation Cu(II) lysosomes. This latter effect probably promoted activity. Both ligands down-regulated multiple key receptors display inter-receptor cooperation leads aggressive resistant breast cancer.

Language: Английский

Citations

8
A novel Au(III) agent designed to inhibit tumor growth and metastasis through inducing immunogenic cell death DOI
Wenjuan Li, Shanhe Li, Xueyu Man

et al.

Rare Metals, Journal Year: 2024, Volume and Issue: unknown

Published: July 22, 2024

Language: Английский

Citations

5
Recent progress in stimuli‐activable metallo‐prodrugs for cancer therapy DOI Creative Commons
Jinzhe Liang,

Fangmian Wei,

Hui Chao

et al.

Smart Molecules, Journal Year: 2024, Volume and Issue: unknown

Published: Aug. 29, 2024

Abstract The clinical approval of platinum‐based drugs has prompted the development novel metallo‐complexes during last several decades, while severe problems, especially for poor water solubility, drug resistance and toxicity in patients, greatly hindered trials curative efficacy. To address these issues, concept metallo‐prodrugs been proposed oncology. Some stimuli‐activable provide new insights designing preparing site‐specific prodrugs with maximized therapeutic efficacy negligible unfavorable by‐effects. In this review, recent progress past 20 years overviewed, where endogenous exogenous stimuli have involved. Typical examples smart are discussed regarding to their molecular structure, activation mechanism, promising biomedical applications. end, challenges future perspectives discussed.

Language: Английский

Citations

5