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Amide Coupling Reaction for the Synthesis of Bispyridine-based Ligands and Their Complexation to Platinum as Dinuclear Anticancer Agents

Amide coupling reactions can be used to synthesize bispyridine-based ligands for use as bridging linkers in multinuclear platinum anticancer drugs. ...

Nature Publishing Group

The platinum-based anticancer drugs cisplatin, carboplatin, and oxaliplatin are an important component of chemotherapy but are limited by severe dose-limiting side effects and the ability of tumors to develop resistance rapidly. These drugs can be improved through the use of drug-delivery vehicles that are able to target cancers passively or actively. In this study, we have tethered the active component of the anticancer drug oxaliplatin to a gold nanoparticle for improved drug delivery. Naked gold nanoparticles were functionalized with a thiolated poly(ethylene glycol) (PEG) monolayer capped with a carboxylate group. [Pt(1R,2R-diaminocyclohexane)(H(2)O)(2)]2NO(3) was added to the PEG surface to yield a supramolecular complex with 280 (+/-20) drug molecules per nanoparticle. The platinum-tethered nanoparticles were examined for cytotoxicity, drug uptake, and localization in the A549 lung epithelial cancer cell line and the colon cancer cell lines HCT116, HCT15, HT29, and RKO. The platinum-tethered nanoparticles demonstrated as good as, or significantly better, cytotoxicity than oxaliplatin alone in all of the cell lines and an unusual ability to penetrate the nucleus in the lung cancer cells.

Gold nanoparticles for the improved anticancer drug delivery of the active component of oxaliplatin.

Gold nanoparticles (AuNPs) can be used as delivery vehicles for platinum anticancer drugs, improving their targeting and uptake into cells. Here, we examine the appropriateness of different-sized AuNPs as components of platinum-based drug-delivery systems, investigating their controlled synthesis, reproducibility, consistency of drug loading, and stability. The active component of cisplatin was tethered to 25, 55, and 90 nm AuNPs, with the nanoparticles being almost spherical in nature and demonstrating good batch-to-batch reproducibility (24.37 ± 0.62, 55.2 ± 1.75, and 89.1 ± 2.32 nm). The size distribution of 25 nm AuNPs has been significantly improved, compared with a previous method that produces polydispersed nanoparticles. Attachment of platinum to the AuNP surface through a poly(ethylene glycol) (PEG) linker exhibits an increase in the drug loading with increasing particle size: 25 nm (815 ± 106 drug molecules per AuNP), 55 nm (14216 ± 880), and 90 nm (54487 ± 15996). The stability of the naked, PEGylated, and platinum-conjugated nanoparticles has been examined over time under various conditions. When stored at 4 °C, there is minimal variation in the diameter for all three AuNP sizes; variation after 28 days for the 25 nm AuNPs was 2.4%; 55 nm, 3.3%; and 90 nm, 3.6%. The 25 nm AuNPs also demonstrate minimal changes in UV-visible absorbance over the same time period.

Cisplatin-tethered gold nanoparticles that exhibit enhanced reproducibility, drug loading, and stability: a step closer to pharmaceutical approval?

Picoplatin is a sterically hindered mononuclear platinum drug undergoing clinical trials. The 2-methylpyridine ring provides steric hindrance to the drug, preventing attack from biological nucleophiles. BBR3464 is a trinuclear platinum drug which was recently in Phase II clinical trials, and is highly cytotoxic both in vitro and in vivo; it derives this activity through the flexible adducts it forms with DNA. In this work we sought to combine the properties of both drugs to synthesise a family of sterically hindered, dinuclear platinum complexes as potential anticancer agents. The bis-pyridyl-based ligands were synthesised through a peptide coupling reaction using diaminoalkanes of differing lengths (n = 2, 4 or 8) and 4-carboxypyridine or 2-methyl-4-carboxypyridine. The resultant dinuclear platinum complexes were synthesised by reacting two equivalents of transplatin or mono-aquated transplatin to each ligand, followed by purification by precipitation with acetone. The unprotected complexes react faster with 5'-guanosine monophosphate (drug to nucleotide ratio 1:2; t(1/2) = 2 h), glutathione (1:10, t(1/2) = 55 min) and human serum albumin (HSA) (1:1, t(1/2) = 24 h) compared to their hindered, protected equivalents (5'-guanosine monophosphate, t(1/2) = 3.5 h; glutathione = 1.7 h; HSA, t(1/2) = 110 h). The complexes were tested for in vitro cytotoxicity in the A2780 and A2780/cp70 ovarian cancer cell line. The unprotected platinum complexes were more cytotoxic than their protected derivatives, but none of the complexes were able to overcome resistance. The results provide important proof-of-concept for the development of a larger family of sterically hindered multinuclear-based platinum complexes.

Combining aspects of the platinum anticancer drugs picoplatin and BBR3464 to synthesize a new family of sterically hindered dinuclear complexes; their synthesis, binding kinetics and cytotoxicity.

Sarah D. Brown

Nature Publishing Group

Amide Coupling Reaction for the Synthesis of Bispyridine-based Ligands and Their Complexation to Platinum as Dinuclear Anticancer Agents