The Effect of Ligand Lipophilicity on the Nanoparticle Encapsulation of Pt(IV) Prodrugs

In an effort to expand the therapeutic range of platinum anticancer agents, several new approaches to platinum-based therapy, including nanodelivery, are under active investigation. To better understand the effect of ligand lipophilicity on the encapsulation of Pt­(IV) prodrugs within polymer nanoparticles, the series of compounds <i>cis</i>,<i>cis</i>,<i>trans</i>-[Pt­(NH₃)₂Cl₂L₂] was prepared, where L = acetate, propanoate, butanoate, pentanoate, hexanoate, heptanoate, octanoate, nonanoate, and decanoate. The lipophilicities of these compounds, assessed by reversed-phase HPLC, correlate with the octanol/water partition coefficients of their respective free carboxylic acid ligands, which in turn affect the degree of encapsulation of the Pt­(IV) complex within the hydrophobic core of poly­(lactic-<i>co</i>-glycolic acid)-<i>block</i>-poly­(ethylene glycol) (PLGA-PEG-COOH) nanoparticles. The most lipophilic compound investigated, <i>cis</i>,<i>cis</i>,<i>trans</i>-[Pt­(NH₃)₂Cl₂(O₂C­(CH₂)₈CH₃)₂], displayed the best encapsulation. This compound was therefore selected to evaluate the effect of increased platinum concentration on encapsulation. As the platinum concentration was increased, there was an initial increase in encapsulation followed by a decrease due to macroscopic precipitation. Maximal loading occurred when the platinum complex was present at a 40% w/w ratio with respect to polymer during the nanoprecipitation step. Particles formed under these optimal conditions had diameters of approximately 50 nm, as determined by transmission electron microscopy

The Effect of Ligand Lipophilicity on the Nanoparticle Encapsulation of Pt(IV) Prodrugs

In an effort to expand the therapeutic range of platinum anticancer agents, several new approaches to platinum-based therapy, including nanodelivery, are under active investigation. To better understand the effect of ligand lipophilicity on the encapsulation of Pt­(IV) prodrugs within polymer nanoparticles, the series of compounds <i>cis</i>,<i>cis</i>,<i>trans</i>-[Pt­(NH₃)₂Cl₂L₂] was prepared, where L = acetate, propanoate, butanoate, pentanoate, hexanoate, heptanoate, octanoate, nonanoate, and decanoate. The lipophilicities of these compounds, assessed by reversed-phase HPLC, correlate with the octanol/water partition coefficients of their respective free carboxylic acid ligands, which in turn affect the degree of encapsulation of the Pt­(IV) complex within the hydrophobic core of poly­(lactic-<i>co</i>-glycolic acid)-<i>block</i>-poly­(ethylene glycol) (PLGA-PEG-COOH) nanoparticles. The most lipophilic compound investigated, <i>cis</i>,<i>cis</i>,<i>trans</i>-[Pt­(NH₃)₂Cl₂(O₂C­(CH₂)₈CH₃)₂], displayed the best encapsulation. This compound was therefore selected to evaluate the effect of increased platinum concentration on encapsulation. As the platinum concentration was increased, there was an initial increase in encapsulation followed by a decrease due to macroscopic precipitation. Maximal loading occurred when the platinum complex was present at a 40% w/w ratio with respect to polymer during the nanoprecipitation step. Particles formed under these optimal conditions had diameters of approximately 50 nm, as determined by transmission electron microscopy

Selective Chromium(VI) Trapping by an Acetate-Releasing Coordination Polymer

We report the high-capacity and selective uptake of Cr(VI) from water using the coordination polymer silver bipyridine acetate (SBA, [Ag(4,4′-bipy)][CH3CO2]·3H2O). Cr capture involves the release of acetate, and we have structurally characterized two of the product phases that form: silver bipyridine chromate (SBC, SLUG-56, [Ag(4,4′-bipy)][CrO4]0.5·3.5H2O) and silver bipyridine dichromate (SBDC, SLUG-57, [Ag(4,4′-bipy)][Cr2O7]0.5·H2O). SBA maintains a high Cr uptake capacity over a wide range of pH values (2–10), reaching a maximum of 143 mg Cr/g at pH 4. This Cr uptake capacity is one of the highest among coordination polymers. SBA offers the additional benefits of a one-step, room temperature, aqueous synthesis and its release of a non-toxic anion following Cr(VI) capture, acetate. Furthermore, SBA capture of Cr(VI) remains >97% in the presence of a 50-fold molar excess of sulfate, nitrate, or carbonate. We also investigated the Cr(VI) sequestration abilities of silver 1,2-bis(4-pyridyl)ethane nitrate (SEN, [Ag(4,4′-bpe)][NO3]) and structurally characterized the silver 1,2-bis(4-pyridyl)ethane chromate (SEC, SLUG-58, [Ag(4,4′-bpe)][CrO4]0.5) product. SEN was, however, a less effective Cr(VI) sequestering material than SBA

A Fast and Selective Near-Infrared Fluorescent Sensor for Multicolor Imaging of Biological Nitroxyl (HNO)

The first near-infrared fluorescent turn-on sensor for the detection of nitroxyl (HNO), the one-electron reduced form of nitric oxide (NO), is reported. The new copper-based probe, CuDHX1, contains a dihydroxanthene (DHX) fluorophore and a cyclam derivative as a Cu­(II) binding site. Upon reaction with HNO, CuDHX1 displays a five-fold fluorescence turn-on in cuvettes and is selective for HNO over thiols and reactive nitrogen and oxygen species. CuDHX1 can detect exogenously applied HNO in live mammalian cells and in conjunction with the zinc-specific, green-fluorescent sensor ZP1 can perform multicolor/multianalyte microscopic imaging. These studies reveal that HNO treatment elicits an increase in the concentration of intracellular mobile zinc

Nanoparticle Encapsulation of Mitaplatin and the Effect Thereof on <i>In Vivo</i> Properties

Nanoparticle (NP) therapeutics have the potential to significantly alter the <i>in vivo</i> biological properties of the pharmaceutically active agents that they carry. Here we describe the development of a polymeric NP, termed M-NP, comprising poly(d,l-lactic-<i>co</i>-glycolic acid)-<i>block</i>-poly(ethylene glycol) (PLGA-PEG), stabilized with poly(vinyl alcohol) (PVA), and loaded with a water-soluble platinum(IV) [Pt(IV)] prodrug, mitaplatin. Mitaplatin, <i>c</i>,<i>c</i>,<i>t</i>-[PtCl₂(NH₃)₂(OOCCHCl₂)₂], is a compound designed to release cisplatin, an anticancer drug in widespread clinical use, and the orphan drug dichloroacetate following chemical reduction. An optimized preparation of M-NP by double emulsion and its physical characterization are reported, and the influence of encapsulation on the properties of the platinum agent is evaluated <i>in vivo</i>. Encapsulation increases the circulation time of Pt in the bloodstream of rats. The biodistribution of Pt in mice is also affected by nanoparticle encapsulation, resulting in reduced accumulation in the kidneys. Finally, the efficacy of both free mitaplatin and M-NP, measured by tumor growth inhibition in a mouse xenograft model of triple-negative breast cancer, reveals that controlled release of mitaplatin over time from the nanoparticle treatment produces long-term efficacy comparable to that of free mitaplatin, which might limit toxic side effects

Nanoparticle Encapsulation of Mitaplatin and the Effect Thereof on <i>In Vivo</i> Properties

Nanoparticle (NP) therapeutics have the potential to significantly alter the <i>in vivo</i> biological properties of the pharmaceutically active agents that they carry. Here we describe the development of a polymeric NP, termed M-NP, comprising poly(d,l-lactic-<i>co</i>-glycolic acid)-<i>block</i>-poly(ethylene glycol) (PLGA-PEG), stabilized with poly(vinyl alcohol) (PVA), and loaded with a water-soluble platinum(IV) [Pt(IV)] prodrug, mitaplatin. Mitaplatin, <i>c</i>,<i>c</i>,<i>t</i>-[PtCl₂(NH₃)₂(OOCCHCl₂)₂], is a compound designed to release cisplatin, an anticancer drug in widespread clinical use, and the orphan drug dichloroacetate following chemical reduction. An optimized preparation of M-NP by double emulsion and its physical characterization are reported, and the influence of encapsulation on the properties of the platinum agent is evaluated <i>in vivo</i>. Encapsulation increases the circulation time of Pt in the bloodstream of rats. The biodistribution of Pt in mice is also affected by nanoparticle encapsulation, resulting in reduced accumulation in the kidneys. Finally, the efficacy of both free mitaplatin and M-NP, measured by tumor growth inhibition in a mouse xenograft model of triple-negative breast cancer, reveals that controlled release of mitaplatin over time from the nanoparticle treatment produces long-term efficacy comparable to that of free mitaplatin, which might limit toxic side effects

Bidentate Ligands on Osmium(VI) Nitrido Complexes Control Intracellular Targeting and Cell Death Pathways

The cellular response evoked by antiproliferating osmium­(VI) nitrido compounds of general formula OsN­(N^N)­Cl₃ (N^N = 2,2′-bipyridine <b>1</b>, 1,10-phenanthroline <b>2</b>, 3,4,7,8-tetramethyl-1,10-phenanthroline <b>3</b>, or 4,7-diphenyl-1,10-phenanthroline <b>4</b>) can be tuned by subtle ligand modifications. Complex <b>2</b> induces DNA damage, resulting in activation of the p53 pathway, cell cycle arrest at the G2/M phase, and caspase-dependent apoptotic cell death. In contrast, <b>4</b> evokes endoplasmic reticulum (ER) stress leading to the upregulation of proteins of the unfolded protein response pathway, increase in ER size, and p53-independent apoptotic cell death. To the best of our knowledge, <b>4</b> is the first osmium compound to induce ER stress in cancer cells

Bidentate Ligands on Osmium(VI) Nitrido Complexes Control Intracellular Targeting and Cell Death Pathways

The cellular response evoked by antiproliferating osmium­(VI) nitrido compounds of general formula OsN­(N^N)­Cl₃ (N^N = 2,2′-bipyridine <b>1</b>, 1,10-phenanthroline <b>2</b>, 3,4,7,8-tetramethyl-1,10-phenanthroline <b>3</b>, or 4,7-diphenyl-1,10-phenanthroline <b>4</b>) can be tuned by subtle ligand modifications. Complex <b>2</b> induces DNA damage, resulting in activation of the p53 pathway, cell cycle arrest at the G2/M phase, and caspase-dependent apoptotic cell death. In contrast, <b>4</b> evokes endoplasmic reticulum (ER) stress leading to the upregulation of proteins of the unfolded protein response pathway, increase in ER size, and p53-independent apoptotic cell death. To the best of our knowledge, <b>4</b> is the first osmium compound to induce ER stress in cancer cells

A Breast Cancer Stem Cell-Selective, Mammospheres-Potent Osmium(VI) Nitrido Complex

The effect of a newly developed osmium(VI) nitrido complex, <b>1</b>, on breast cancer stem cells (CSCs) is reported. The complex displays selective toxicity for HMLER breast cancer cells enriched with CD44-positive, CSC-like cells over the same cells having reduced CSC character. Remarkably, <b>1</b> also reduces the proportion of CSCs within a heterogeneous breast cancer cell population and irreversibly inhibits the formation of free-floating mammo­spheres to an extent similar to that of salino­mycin, a natural product that targets CSCs. Detailed mechanistic studies reveal that in breast cancer cells <b>1</b> induces DNA damage and endoplasmic reticulum stress, the latter being responsible for the CSC selectivity. The anti-CSC properties of <b>1</b> provide a strong impetus for the development of new metal-based compounds to target CSCs and to treat chemotherapy-resistant and relapsed tumors