RESUMEN
Cisplatin is a platinum-based chemotherapeutic agent widely used in the treatment of various solid tumors. However, a major challenge in the use of cisplatin and in the development of cisplatin derivatives, namely Pt(iv) prodrugs, is their premature reduction in the bloodstream before reaching cancer cells. To circumvent this problem, we designed liposomal nanoparticles coupled with a cholesterol-tethered amphiphilic Pt(iv) prodrug. The addition of cholesterol served to stabilize the formation of the liposome, while selectively incorporating cholesterol as the axial ligand also allowed the Pt(iv) prodrug to readily migrate into the liposomal bilayer. Notably, upon embedding into the nanoparticles, the Pt(iv) prodrug showed marked resistance against premature reduction in human plasma in vitro. Pharmacokinetic analysis in a mouse model also showed that the nanoparticles significantly extend the half-life of the Pt(iv) prodrug to 180 min, which represents a >6-fold increase compared to cisplatin. Importantly, such lipid modification did not compromise the genotoxicity of cisplatin, as the Pt(iv) prodrug induced DNA damage and apoptosis in ovarian cancer cell lines efficiently. Taken together, our strategy provides a novel insight as to how to stabilize a platinum-based compound to increase the circulation time in vivo, which is expected to enhance the efficacy of drug treatment.
Asunto(s)
Antineoplásicos/farmacología , Nanopartículas/química , Compuestos Organoplatinos/farmacología , Profármacos/farmacología , Tensoactivos/farmacología , Antineoplásicos/sangre , Antineoplásicos/química , Apoptosis/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Colesterol/sangre , Colesterol/química , Colesterol/farmacología , Cisplatino/sangre , Cisplatino/química , Cisplatino/farmacología , Daño del ADN , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Liposomas/sangre , Liposomas/química , Estructura Molecular , Nanopartículas/metabolismo , Compuestos Organoplatinos/sangre , Compuestos Organoplatinos/química , Profármacos/química , Profármacos/metabolismo , Relación Estructura-Actividad , Tensoactivos/química , Tensoactivos/metabolismo , Factores de Tiempo , Células Tumorales CultivadasRESUMEN
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.
Asunto(s)
Antineoplásicos/farmacología , Resistencia a Antineoplásicos/efectos de los fármacos , Nanopartículas/química , Compuestos Organoplatinos/farmacología , Neoplasias Ováricas/tratamiento farmacológico , Polímeros/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Apoptosis/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Humanos , Estructura Molecular , Compuestos Organoplatinos/síntesis química , Compuestos Organoplatinos/química , Neoplasias Ováricas/patología , Polímeros/síntesis química , Polímeros/química , Relación Estructura-Actividad , Células Tumorales CultivadasRESUMEN
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.
Asunto(s)
Antineoplásicos/farmacología , Células Madre Neoplásicas/efectos de los fármacos , Neoplasias Ováricas/patología , Compuestos de Platino/farmacología , Profármacos/farmacología , Espermina/química , Línea Celular Tumoral , Femenino , Citometría de Flujo , Humanos , Interacciones Hidrofóbicas e Hidrofílicas , Profármacos/química , Espectrofotometría Atómica , Espermina/farmacologíaRESUMEN
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.
RESUMEN
This article presents a new strategy to engage coordination-driven self-assembly for platinum drug delivery. The self-assembled supramolecular hexagon is conjugated with three equivalents of Pt(iv) prodrugs and displays a superior therapeutic index compared to cisplatin against a panel of human cancer cell lines.
Asunto(s)
Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Sustancias Macromoleculares/química , Compuestos Organoplatinos/farmacología , Profármacos/química , Profármacos/farmacología , Antineoplásicos/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Cisplatino/administración & dosificación , Cisplatino/química , Cisplatino/farmacología , Relación Dosis-Respuesta a Droga , Sistemas de Liberación de Medicamentos , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Sustancias Macromoleculares/síntesis química , Sustancias Macromoleculares/farmacología , Modelos Moleculares , Estructura Molecular , Compuestos Organoplatinos/síntesis química , Compuestos Organoplatinos/química , Profármacos/síntesis química , Relación Estructura-ActividadRESUMEN
We present a novel design to use metal-organic cages (MOCs) to encapsulate Pt-based anticancer agents for delivery. A fluorescein-conjugated Pt(iv) prodrug of cisplatin is developed for its encapsulation in a cationic MOC via host-guest interactions, which then forms drug-loaded nanoparticles with an anionic polymer.
Asunto(s)
Antineoplásicos/química , Cisplatino/química , Portadores de Fármacos/química , Nanopartículas/química , Compuestos Organometálicos/química , Antineoplásicos/metabolismo , Apoptosis/efectos de los fármacos , Cápsulas , Cisplatino/metabolismo , Cisplatino/farmacología , Células HeLa , Humanos , Profármacos/metabolismoRESUMEN
Medium-sized cyclic oligomeric phosphazenes [PCl2N]m (where m = 5-9) that were prepared from the reaction of PCl5 and NH4Cl in refluxing chlorobenzene have been isolated by a combination of sublimation/extraction and column chromatography from the predominant products [PCl2N]3 and [PCl2N]4. The medium-sized rings [PCl2N]m have been characterized by electrospray ionization-mass spectroscopy (ESI-MS), their (31)P chemical shifts have been reassigned, and their T1 relaxation times have been obtained. Crystallographic data has been recollected for [PCl2N]5, and the crystal structures of [PCl2N]6, and [PCl2N]8 are reported. Halogen-bonding interactions were observed in all the crystal structures of cyclic [PCl2N]m (m = 3-5, 6, 8). The crystal structures of [P(OPh)2N]7 and [P(OPh)2N]8, which are derivatives of the respective [PCl2N]m, are also reported. Comparisons of the intermolecular forces and torsion angles of [PCl2N]8 and [P(OPh)2N]8 with those of three other octameric rings are described. The comparisons show that chlorophosphazenes should not be considered prototypical, in terms of solid-state structure, because of the strong influence of halogen bonding.
RESUMEN
INTRODUCTION: The purpose of this study was to quantitatively investigate the effect of magnification on fine motor skills used in endodontics. METHODS: This study used a novel manual dexterity test that was performed with and without magnification. An 8x operating microscope and 2.5x dental loupes were used for the magnification tests. Forty subjects, 20 with microscope experience and 20 without, participated in the study. Performance on the test was evaluated by using an accuracy scoring system, and the time needed to complete the test was recorded for each subject. RESULTS: A significant increase in accuracy score with each level of magnification was demonstrated (P Asunto(s)
Lentes
, Microscopía/instrumentación
, Destreza Motora/fisiología
, Tratamiento del Conducto Radicular/métodos
, Adulto
, Competencia Clínica
, Humanos
, Iluminación/instrumentación
, Persona de Mediana Edad
, Factores de Tiempo