The platinum drugs, cisplatin, carboplatin, and oxaliplatin, prevail in the treatment of cancer, but new platinum agents have been very slow to enter the clinic. Recently, however, there has been a surge of activity, based on a great deal of mechanistic information, aimed at developing nonclassical platinum complexes that operate via mechanisms of action distinct from those of the approved drugs. The use of nanodelivery devices has also grown, and many different strategies have been explored to incorporate platinum warheads into nanomedicine constructs. In this Review, we discuss these efforts to create the next generation of platinum anticancer drugs. The introduction provides the reader with a brief overview of the use, development, and mechanism of action of the approved platinum drugs to provide the context in which more recent research has flourished. We then describe approaches that explore nonclassical platinum(II) complexes with trans geometry or with a monofunctional coordination mode, polynuclea...

The Next Generation of Platinum Drugs: Targeted Pt(II) Agents, Nanoparticle Delivery, and Pt(IV) Prodrugs

Advances in copper complexes as anticancer agents.

Anti-cancer drugs

Cisplatin: The first metal based anticancer drug.

Colorectal cancer (CRC) is the third most common cancer and the fourth most common cause of cancer-related death. Most cases of CRC are detected in Western countries, with its incidence increasing year by year. The probability of suffering from colorectal cancer is about 4%–5% and the risk for developing CRC is associated with personal features or habits such as age, chronic disease history and lifestyle. In this context, the gut microbiota has a relevant role, and dysbiosis situations can induce colonic carcinogenesis through a chronic inflammation mechanism. Some of the bacteria responsible for this multiphase process include Fusobacterium spp, Bacteroides fragilis and enteropathogenic Escherichia coli. CRC is caused by mutations that target oncogenes, tumour suppressor genes and genes related to DNA repair mechanisms. Depending on the origin of the mutation, colorectal carcinomas can be classified as sporadic (70%); inherited (5%) and familial (25%). The pathogenic mechanisms leading to this situation can be included in three types, namely chromosomal instability (CIN), microsatellite instability (MSI) and CpG island methylator phenotype (CIMP). Within these types of CRC, common mutations, chromosomal changes and translocations have been reported to affect important pathways (WNT, MAPK/PI3K, TGF-β, TP53), and mutations; in particular, genes such as c-MYC, KRAS, BRAF, PIK3CA, PTEN, SMAD2 and SMAD4 can be used as predictive markers for patient outcome. In addition to gene mutations, alterations in ncRNAs, such as lncRNA or miRNA, can also contribute to different steps of the carcinogenesis process and have a predictive value when used as biomarkers. In consequence, different panels of genes and mRNA are being developed to improve prognosis and treatment selection. The choice of first-line treatment in CRC follows a multimodal approach based on tumour-related characteristics and usually comprises surgical resection followed by chemotherapy combined with monoclonal antibodies or proteins against vascular endothelial growth factor (VEGF) and epidermal growth receptor (EGFR). Besides traditional chemotherapy, alternative therapies (such as agarose tumour macrobeads, anti-inflammatory drugs, probiotics, and gold-based drugs) are currently being studied to increase treatment effectiveness and reduce side effects.

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Colorectal Carcinoma: A General Overview and Future Perspectives in Colorectal Cancer

Since its approval in 1979 cisplatin has become an important component in chemotherapy regimes for the treatment of ovarian, testicular, lung and bladder cancers, as well as lymphomas, myelomas and melanoma. Unfortunately its continued use is greatly limited by severe dose limiting side effects and intrinsic or acquired drug resistance. Over the last 30 years, 23 other platinum-based drugs have entered clinical trials with only two (carboplatin and oxaliplatin) of these gaining international marketing approval, and another three (nedaplatin, lobaplatin and heptaplatin) gaining approval in individual nations. During this time there have been more failures than successes with the development of 14 drugs being halted during clinical trials. Currently there are four drugs in the various phases of clinical trial (satraplatin, picoplatin, Lipoplatin™ and ProLindac™). No new small molecule platinum drug has entered clinical trials since 1999 which is representative of a shift in focus away from drug design and towards drug delivery in the last decade. In this perspective article we update the status of platinum anticancer drugs currently approved for use, those undergoing clinical trials and those discontinued during clinical trials, and discuss the results in the context of where we believe the field will develop over the next decade.

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The status of platinum anticancer drugs in the clinic and in clinical trials.

Cisplatin drug delivery using gold-coated iron oxide nanoparticles for enhanced tumour targeting with external magnetic fields

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, PE...

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Cisplatin-Tethered Gold Nanoparticles That Exhibit Enhanced Reproducibility, Drug Loading, and Stability: a Step Closer to Pharmaceutical Approval?

A nanoparticle comprises a metal nanoparticle, e.g. gold, functionalised with at least one linker, the at least one linker comprising at least one first moiety capable of interacting with the metal nanoparticle, and at least one second moiety capable of interacting with at least one platinum group metal-based biologically active compound, e.g. a drug, wherein the molar ratio or capacity of platinum group metal-based biologically active compounds per nanoparticle is greater than (150). The present invention also relates to a method of preparing a nanoparticle according to the present invention. The present invention also relates to a biologically active nanoparticle comprising a nanoparticle according to the present invention, and at least one platinum group metal-based biologically active compound. The biologically active nanoparticle is more efficiently targeted to specific parts of the body, e.g. cancer cells, while reducing the side effects of the biomolecules being delivered.

Nanoparticle for biomolecule delivery

La presente invention concerne une nanoparticule comprenant une nanoparticule de metal, par exemple de l'or, fonctionnalisee avec au moins un element de liaison, le ou les element(s) de liaison comprenant au moins une premiere fraction pouvant interagir avec la nanoparticule de metal, et au moins une seconde fraction pouvant interagir avec au moins un compose biologiquement actif a base de metal du groupe platine, par exemple, un medicament, le rapport molaire ou la capacite des composes biologiquement actifs a base de metal du groupe platine par nanoparticule etant superieur a 150. La presente invention concerne egalement un procede de preparation d'une nanoparticule selon la presente invention. La presente invention concerne egalement une nanoparticule biologiquement active comprenant une nanoparticule selon la presente invention, et au moins un compose biologiquement actif a base de metal du groupe platine. La nanoparticule biologiquement active est plus efficacement dirigee vers des parties specifiques du corps, par exemple des cellules cancereuses, tout en reduisant les effets secondaires des biomolecules administrees.

Gemma E. Craig

Papers

The status of platinum anticancer drugs in the clinic and in clinical trials.

Cisplatin drug delivery using gold-coated iron oxide nanoparticles for enhanced tumour targeting with external magnetic fields

Cisplatin-Tethered Gold Nanoparticles That Exhibit Enhanced Reproducibility, Drug Loading, and Stability: a Step Closer to Pharmaceutical Approval?

Nanoparticle for biomolecule delivery

Nanoparticule pour administration de biomolécules