Synthesis, characterization, cytotoxic activity, and cellular accumulation of dinuclear platinum complexes derived from N,N′-di-(2-aminoethyl)-1,3-diamino-2-propanol, aryl substituted N-benzyl-1,4-butanediamines, and N-benzyl-1,6-hexanediamines

César, Eloi Teixeira; Almeida, Mauro Vieira de; Fontes, Ana Paula Soares; Pereira-Maia, Elene C.; Garnier‐Suillerot, Arlette; Couri, Mara R.C.; Felício, Emanoel de Castro Antunes

doi:10.1016/s0162-0134(03)00129-6

Cited by 17 publications

(4 citation statements)

References 16 publications

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“…Four main events accompany it in most cases: i) decreased accumulation of drug concentration (to below that necessary for cytotoxic activity), ii) increased levels of sulfur-containing molecules such as glutathione or metallothionein (which could play a role in metal detoxification), iii) enhanced repair of DNA damage caused by CDDP-DNA adducts by nucleotide excision repair proteins such as ERCC1, XPA, and XPB which can remove DNA adducts produced by CDDP, and iv) increased tolerance to CDDP-DNA adducts as a consequence of deficiencies in the mismatch repair system and enhanced replication bypass (15)(16)(17)(18). Among the various resistance mechanisms involved, decreased cellular accumulation of CDDP has been demonstrated in most cases (19)(20)(21)(22)(23)(24). Reduced intracellular CDDP concentration results in decreased DNA platination, which leads to CDDP resistance.…”

Section: Introductionmentioning

confidence: 99%

Preparation and cytotoxicity of cisplatin-containing liposomes

Júnior

Vieira

Melo

et al. 2007

Braz J Med Biol Res

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We encapsulated cisplatin into stealth pH-sensitive liposomes and studied their stability, cytotoxicity and accumulation in a human small-cell lung carcinoma cell line (GLC4) and its resistant subline (GLC4/CDDP). Since reduced cellular drug accumulation has been shown to be the main mechanism responsible for resistance in the GLC4/CDDP subline, we evaluated the ability of this new delivery system to improve cellular uptake. The liposomes were composed of dioleoylphosphatidylethanolamine (DOPE), cholesteryl hemisuccinate (CHEMS), and distearoylphosphatidylethanolamine-polyethyleneglycol 2000 (DSPE-PEG 2000 ) and were characterized by determining the encapsulation percentage as a function of lipid concentration. Among the different formulations, DOPE/CHEMS/DSPE-PEG liposomes (lipid concentration equal to 40 mM) encapsulated cisplatin more efficiently than other concentrations of liposomes (about 20.0%, mean diameter of 174 nm). These liposomes presented good stability in mouse plasma which was obtained using a 0.24-M EDTA solution (70% cisplatin was retained inside the liposomes after 30 min of incubation). Concerning cytotoxic effects, they are more effective (1.34-fold) than free cisplatin for growth inhibition of the human lung cancer cell line A549. The study of cytotoxicity to GLC4 and GLC4/ CDDP cell lines showed similar IC 50 values (approximately 1.4 µM), i.e., cisplatin-resistant cells were sensitive to this cisplatin formulation. Platinum accumulation in both sensitive and resistant cell lines followed the same pattern, i.e., approximately the same intracellular platinum concentration (4.0 x 10 -17 mol/cell) yielded the same cytotoxic effect. These results indicate that long-circulating pH-sensitive liposomes, also termed as stealth pH-sensitive liposomes, may present a promising delivery system for cisplatin-based cancer treatment. This liposome system proved to be able to circumvent the cisplatin resistance, whereas it was not observed when using non-long-circulating liposomes composed of phosphatidylcholine, phosphatidylserine, and cholesterol.

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Section: Introductionmentioning

confidence: 99%

Preparation and cytotoxicity of cisplatin-containing liposomes

Júnior

Vieira

Melo

et al. 2007

Braz J Med Biol Res

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“…It can be interpreted as dinuclear platinum compounds, which were preferentially accumulated in tumor cells by endocytosis taken up to a high extent in the nucleus and bound to DNA . For compounds of similar molecular weights, an inhibitory effect on cell proliferation was observed − . C(PtCl 2 ) 3 caused a significantly lower platinum concentration in the tumor cells/nuclei compared to A(PtCl 2 ) 2 but showed comparable cytotoxicity.…”

Section: Resultsmentioning

confidence: 99%

Platinum(II)−Dendrimer Conjugates: Synthesis and Investigations on Cytotoxicity, Cellular Distribution, Platinum Release, DNA, and Protein Binding

2010

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A set of polyamidoamine dendrimers were modified in such a way that they are able to act as carrier and drug delivery systems for cytostatics. The terminal binding of the non-proteinogenic D,L-2,3-diaminopropionic acid allowed the attachment of the cytotoxic PtX(2) moiety (X = Cl, I: A(PtI(2))(2), A(PtCl(2))(2), B(PtI(2))(2), B(PtCl(2))(2)), while the 2-carboxypentanedioic acid acted as leaving group for [meso-1,2-bis(4-fluorophenyl)ethylenediamine]platinum(II) ((m-4F-Pt)(3)C, (m-4F-Pt)(3)D). Poly(ethylene glycol) chains at C(PtI(2))(3) and C(PtCl(2))(3) as well as (m-4F-Pt)(3)C and (m-4F-Pt)(3)D mediated sufficient water solubility. Additional dansyl residues (B(PtI(2))(2) and (m-4F-Pt)(3)D) made a simultaneous determination of platinum (graphite furnace atomic absorption spectroscopy (GF-AAS)) and dendrimer (fluorimetry) possible. The ethylenediamine-terminated dendrimers were typically accumulated into MCF-7 cells in clathrin-dependent pathways and targeted the platinum moieties to the nuclear compartment. The highest intracellular platinum concentration and DNA binding caused the dendrimers A(PtX(2))(2) and B(PtX(2))(2). A coordinative DNA binding, however, is very unlikely because of low cytotoxic effects. (m-4F-Pt)(3)C and (m-4F-Pt)(3)D are labile conjugates and liberated the m-4F-Pt moiety in biological systems. The effects of these dendrimers were similar to that of the reference compounds m-4F-PtCl(2) and m-4F-Pt(H(2)O)(2).

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“…On the other hand, no antitumor activity was observed vs L1210 leukemia in DBA2 mice. Cesar et al described the synthesis and characterization of six new dinuclear platinum complexes having N,N'-di-(2-aminoethyl)-1,3-diamino-2-propanol, aryl substituted N-benzyl-1,4-butanediamines and N-benzyl-1,6-hexanedia-mines as ligands [164]. They reported the cytotoxic activity and cellular accumulation of these complexes in a human small-cell lung carcinoma cell line and its resistant subline.…”

Section: Multinuclear Platinum Complexesmentioning

confidence: 99%

Platinum Complexes as Anticancer Agents

Kostova

2006

PRA

444

206

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The application of inorganic chemistry to medicine is a rapidly developing field, and novel therapeutic and diagnostic metal complexes are now having an impact on medical practice. Advances in biocoordination chemistry are crucial for improving the design of compounds to reduce toxic side effects and understand their mechanisms of action. Cisplatin, as one of the leading metal-based drugs, is widely used in the treatment of cancer. Significant side effects and drug resistance, however, have limited its clinical applications. Biological carriers conjugated to cisplatin analogs have improved specificity for tumor tissue, thereby reducing side effects and drug resistance. Platinum complexes with distinctively different DNA binding modes from that of cisplatin also exhibit promising pharmacological properties. This review focuses on recent advances in developing platinum anticancer agents with an emphasis on platinum coordination complexes.

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Synthesis, characterization, cytotoxic activity, and cellular accumulation of dinuclear platinum complexes derived from N,N′-di-(2-aminoethyl)-1,3-diamino-2-propanol, aryl substituted N-benzyl-1,4-butanediamines, and N-benzyl-1,6-hexanediamines

Cited by 17 publications

References 16 publications

Preparation and cytotoxicity of cisplatin-containing liposomes

Preparation and cytotoxicity of cisplatin-containing liposomes

Platinum(II)−Dendrimer Conjugates: Synthesis and Investigations on Cytotoxicity, Cellular Distribution, Platinum Release, DNA, and Protein Binding

Platinum Complexes as Anticancer Agents

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