Lipoplatin Formulation Review Article

Patented platform technologies have been used for the liposomal encapsulation of cisplatin (Lipoplatin) into tumor-targeted 110 nm (in diameter) nanoparticles. The molecular mechanisms, preclinical and clinical data concerning lipoplatin, are reviewed here. Lipoplatin has been successfully administered in three randomized Phase II and III clinical trials. The clinical data mainly include non-small-cell lung cancer but also pancreatic, breast, and head and neck cancers. It is anticipated that lipoplatin will replace cisplatin as well as increase its potential applications. For the first time, a platinum drug has shown superiority to cisplatin, at least in non-squamous non-small-cell lung cancer as reported in a Phase III study which documented a simultaneous lowering of all of the side effects of cisplatin

Antimicrobial activity of an iron triple helicate

The prevalence of antibiotic resistance has resulted in the need for new approaches to be developed to combat previously easily treatable infections. Here we investigated the potential of the synthetic metallomolecules [Fe2L3]4+ and [Cu2(L’)2]2+ as antibacterial agents. Both molecules have been shown to bind DNA; [Fe2L3]4+ binds in the major groove and causes DNA coiling, whilst [Cu2(L’)2]2+ can act as an artificial nuclease. The work described here shows that only [Fe2L3]4+ is bactericidal for Bacillus subtilis and Escherichia coli. We demonstrate that [Fe2L3]4+ binds bacterial DNA in vivo and, strikingly, that it kills B. subtilis cells very rapidly

Synthetic metallomolecules as agents for the control of DNA structure

This tutorial review summarises B-DNA structure and metallomolecule binding modes and illustrates some DNA structures induced by molecules containing metallic cations. The effects of aquated metal ions, cobalt amines, ruthenium octahedral metal complexes, metallohelicates and platinum complexes such as cis-platin are discussed alongside the techniques of NMR, X-ray crystallography, gel electrophoresis, circular dichroism, linear dichroism and molecular dynamics. The review will be of interest to people interested in both DNA structure and roles of metallomolecules in biological systems

Liposomal cisplatin combined with paclitaxel versus cisplatin and paclitaxel in non-small-cell lung cancer: a randomized phase III multicenter trial

Background: Liposomal cisplatin is a new formulation developed to reduce the systemic toxicity of cisplatin while simultaneously improving the targeting of the drug to the primary tumor and to metastases by increasing circulation time in the body fluids and tissues. The primary objectives were to determine nephrotoxicity, gastrointestinal side-effects, peripheral neuropathy and hematological toxicity and secondary objectives were to determine the response rate, time to tumor progression (TTP) and survival

Cucurbit[n]uril binding of platinum anticancer complexes

The encapsulation of cisplatin by cucurbit[7]uril (Q[7]) and multinuclear platinum complexes linked via a 4,4′-dipyrazolylmethane (dpzm) ligand by Q[7] and cucurbit[8]uril (Q[8]) has been studied by NMR spectroscopy and molecular modelling. The NMR studies suggest that some cisplatin binds in the cucurbituril cavity, while cis-[PtCl(NH3)2(H2O)]+ only binds at the portals. Alternatively, the dpzm-linked multinuclear platinum complexes are quantitatively encapsulated within the cavities of both Q[7] and Q[8]. Upon encapsulation, the non-exchangeable proton resonances of the multinuclear platinum complexes show significant upfield shifts in 1H NMR spectra. The H3/H3* resonances shift upfield by 0.08 to 0.55 ppm, the H5/H5* shift by 0.9 to 1.6 ppm, while the methylene resonances shift by 0.74 to 0.88 ppm. The size of the resonance shift is dependent on the cavity size of the encapsulating cucurbituril, with Q[7] encapsulation producing larger shifts than Q[8]. The upfield shifts of the dpzm resonances observed upon cucurbituril encapsulation indicate that the Q[7] or Q[8] is positioned directly over the dpzm linking ligand. The terminal platinum groups of trans-[{PtCl(NH3)2}2μ-dpzm]2+ (di-Pt) and trans-[trans-{PtCl(NH3)2}2-trans-{Pt(dpzm)2(NH3)2}]4+ (tri-Pt) provide a barrier to the on and off movement of cucurbituril, resulting in binding kinetics that are slow on the NMR timescale for the metal complex. Although the dpzm ligand has relatively few rotamers, encapsulation by the larger Q[8] resulted in a more compact di-Pt conformation with each platinum centre retracted further into each Q[8] portal. Encapsulation of the hydrolysed forms of di-Pt and tri-Pt is considerably slower than for the corresponding Cl forms, presumably due to the high-energy cost of passing the +2 platinum centres through the cucurbituril portals. The results of this study suggest that cucurbiturils could be suitable hosts for the pharmacological delivery of multinuclear platinum complexe

Nanoparticle-mediated targeting of MAPK signaling predisposes tumor to chemotherapy

The MAPK signal transduction cascade is dysregulated in a majority of human tumors. Here we report that a nanoparticle-mediated targeting of this pathway can optimize cancer chemotherapy. We engineered nanoparticles from a unique hexadentate-polyD,L-lactic acid-co-glycolic acid polymer chemically conjugated to PD98059, a selective MAPK inhibitor. The nanoparticles are taken up by cancer cells through endocytosis and demonstrate sustained release of the active agent, resulting in the inhibition of phosphorylation of downstream extracellular signal regulated kinase. We demonstrate that nanoparticle-mediated targeting of MAPK inhibits the proliferation of melanoma and lung carcinoma cells and induces apoptosis in vitro. Administration of the PD98059-nanoparticles in melanoma-bearing mice inhibits tumor growth and enhances the antitumor efficacy of cisplatin chemotherapy. Our study shows the nanoparticle-mediated delivery of signal transduction inhibitors can emerge as a unique paradigm in cancer chemotherapy.Department of Defense Breast Cancer Research Program Era of Hope Award (W81XWH-07–1-0482)Mary Kay Ash Charitable Trus

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

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, LipoplatinTM and ProLindacTM). 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

Pharmacological screening using an FXN-EGFP cellular genomic reporter assay for the therapy of Friedreich ataxia

Copyright @ 2013 Li et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.Friedreich ataxia (FRDA) is an autosomal recessive disorder characterized by neurodegeneration and cardiomyopathy. The presence of a GAA trinucleotide repeat expansion in the first intron of the FXN gene results in the inhibition of gene expression and an insufficiency of the mitochondrial protein frataxin. There is a correlation between expansion length, the amount of residual frataxin and the severity of disease. As the coding sequence is unaltered, pharmacological up-regulation of FXN expression may restore frataxin to therapeutic levels. To facilitate screening of compounds that modulate FXN expression in a physiologically relevant manner, we established a cellular genomic reporter assay consisting of a stable human cell line containing an FXN-EGFP fusion construct, in which the EGFP gene is fused in-frame with the entire normal human FXN gene present on a BAC clone. The cell line was used to establish a fluorometric cellular assay for use in high throughput screening (HTS) procedures. A small chemical library containing FDA-approved compounds and natural extracts was screened and analyzed. Compound hits identified by HTS were further evaluated by flow cytometry in the cellular genomic reporter assay. The effects on FXN mRNA and frataxin protein levels were measured in lymphoblast and fibroblast cell lines derived from individuals with FRDA and in a humanized GAA repeat expansion mouse model of FRDA. Compounds that were established to increase FXN gene expression and frataxin levels included several anti-cancer agents, the iron-chelator deferiprone and the phytoalexin resveratrol.Muscular Dystrophy Association (USA), the National Health and Medical Research Council (Australia), the Friedreich’s Ataxia Research Alliance (USA), the Brockhoff Foundation (Australia), the Friedreich Ataxia Research Association (Australasia), Seek A Miracle (USA) and the Victorian Government’s Operational Infrastructure Support Program