Photoactive monofunctional platinum(II) anticancer complexes of multidentate phenanthridine-containing ligands: photocytotoxicity and evidence for interaction with DNA.

Pt(II) complexes supported by chelating, multidentate ligands containing π-extended, planar phenanthridine (benzo[c]quinoline) donors (RLPtCl) exhibit a promising in vitro therapeutic index compared with phenanthriplatin, a leading preclinical anticancer complex containing a monodentate phenanthridine ligand. Here, we report evidence for non-specific interactions of CF3LPtCl with DNA through intercalation-mediated turn-on luminescence in O2-saturated aqueous buffer. Brief irradiation with visible light (490 nm) was also found to drastically increase the activity of CF3LPtCl, with photocytotoxicity increased up to 87% against a variety of human cancer cell lines. Mechanistic studies highlight significantly improved cellular uptake of CF3LPtCl compared with cisplatin, with localization in the nucleus and mitochondria triggering effective apoptosis. Photosensitization experiments with 1,3-diphenylisobenzofuran demonstrate that CF3LPtCl efficiently mediates the generation of singlet dioxygen (1O2), highlighting the potential of RLPtCl in photodynamic therapy.

Visible light-activatable platinum(IV) prodrugs harnessing CD36 for ovarian cancer therapy.

We hereby engineered photoactivatable Pt(IV) metallodrugs that harness CD36 to target ovarian cancer cells. Pt(IV) compounds mimic the structure of fatty acids and take advantage of CD36 as a "Trojan horse" to gain entry into the cells. We confirmed that CD36-dependent entry occurs using graphite furnace atomic absorption spectroscopy with ovarian cancer cells expressing different levels of CD36 and a CD36 inhibitor, SSO. Once the Pt(IV) metallodrugs enter the cancer cells, they can be activated to form Pt(II) with characteristics of cisplatin under visible light (490 nm) irradiation, promoting photoinduced electron transfer from the attached fluorophore to the metal center. This light-induced activation can increase the cytotoxicity of the Pt(IV) metallodrugs by up to 20 times toward ovarian cancer cells, inducing DNA damage and enabling efficient elimination of drug-resistant cancer cells.

Interactions between mitochondria-damaging platinum(IV) prodrugs and cytochrome c.

In this work, we present the first study about the interactions of mitochondria-damaging Pt(IV) prodrugs with cytochrome c. We synthesized a cisplatin-based Pt(IV) prodrug bearing a lipophilic hydrocarbon tail and anionic dansyl head group. The amphiphilic structure facilitates its accumulation in the mitochondria of cancer cells, which was validated using graphite furnace atomic absorption spectroscopy (GFAAS) and fluorescence imaging. Accordingly, this Pt(IV) prodrug is able to trigger mitochondrial damage and apoptosis. Overall, the Pt(IV) prodrug exhibits superior therapeutic effects against a panel of human cancer cells compared to cisplatin. It also overcomes drug resistance in ovarian cancer. Notably, HPLC analysis indicates that cytochrome c accelerates reduction (or activation) of the Pt(IV) prodrug in the presence of the electron donor nicotinamide adenine dinucleotide (NADH). More interestingly, additional studies indicate that cytochrome c was platinated by the reduced product of Pt(IV) prodrugs, and that empowers the proapoptotic peroxidase activity.

Fatty acid-like Pt(IV) prodrugs overcome cisplatin resistance in ovarian cancer by harnessing CD36.

Resistance to the platinum-based chemotherapy drug, cisplatin, is a significant setback in ovarian cancer. We engineered fatty acid-like Pt(iv) prodrugs that harness the fatty acid transporter CD36 to facilitate their entry to ovarian cancer cells. We show that these novel constructs effectively kill cisplatin-resistant ovarian cancer cells.

Dual-action organoplatinum polymeric nanoparticles overcoming drug resistance in ovarian cancer.

Drug resistance to the conventional platinum chemotherapy remains a major challenge for treating ovarian cancer. Herein, we present a novel approach to overcome the drug resistance by utilizing "dual-action" organometallic polymeric nanoparticles (OPNPs). The OPNPs were formed by the assembly of the organoplatinum payloads and the anionic block copolymer, methoxy polyethylene glycol-block-polyglutamic acid (MPEG5k-PGA50). The OPNPs enhance the solubility and biocompatibility of the hydrophobic organoplatinum payloads. The OPNPs enter the cancer cells via endocytosis, and the payloads loaded in the core of the nanoparticles are slowly released under the acidic conditions of endosomes. Unlike conventional platinum therapeutics, the organoplatinum compound exhibits a "dual-action" attack by triggering nuclear DNA damage and mitochondrial damage. As a result, drug-resistant ovarian cancer cells become vulnerable to the organoplatinum payloads.

A spermine-conjugated lipophilic Pt(iv) prodrug designed to eliminate cancer stem cells in ovarian cancer.

We developed a spermine-conjugated lipophilic Pt(iv) prodrug that is able to reduce the cancer stem cell population in ovarian cancer. The therapeutic effect is attributed to the hydrophobic tail and cationic spermine head group, the combination of which allows the Pt(iv) prodrug to localize in mitochondria and induce corresponding damage.

Nanoparticles of Metal-Organic Cages Overcoming Drug Resistance in Ovarian Cancer.

A long-standing challenge in the treatment of ovarian cancer is drug resistance to standard platinum-based chemotherapy. Recently, increasing attention has been drawn to the use of self-assembled metal-organic complexes as novel therapeutics for cancer treatment. However, high hydrophobicity that is often associated with these structures lowers their solubility and hinders their clinical translation. In this article, we present a proof-of-concept study of using nanoprecipitation to formulate the hydrophobic metal-organic cages and facilitate their use in treating chemoresistant ovarian cancer. The Pt6L4 Cage 1 is an octahedral cage formed by self-assembly of six 1,10-phenanthroline-Pt(II) centers and four 2,4,6-tris(4-pyridyl)-1,3,5-triazine ligands (L). Cage 1 is able to trigger DNA damage and exhibits promising in vitro potency against a panel of human ovarian cancer cell lines. However, due to the large portion of aromatic components, this cage structure has very limited solubility in cell culture media (<20µM). Notably, upon nanoformulation by using fluorescein (2) and a pegylated anionic polymer (3), the concentration of Cage 1 can reach up to 0.4 mM. Production of the nanoparticles of metal-organic cages (nMOC) is driven by the formation of the 1:1 host-guest complex of 1 and 2 in aqueous solution, which then form nanoprecipitation in presence of poly glutamic acid-b-poly ethylene glycol (3). The resulted nMOC are about 100 nm in diameter, and they serve as a delivery platform that slowly releases the therapeutic content. The use of fluorescein facilitates monitoring cell entry of nMOC and drug release using flow cytometry. Finally, comparing to cisplatin, the nMOC exhibit comparable in vitro efficacy against a panel of human cancer cell lines, and notably, it shows a much lower resistance factor against chemoresistant ovarian cancer cell lines.