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ACS Nano ; 8(11): 11591-602, 2014 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-25333568


Nanomedicines capable of smart operation at the targeted site have the potential to achieve the utmost therapeutic benefits. Providing nanomedicines that respond to endogenous stimuli with an additional external trigger may improve the spatiotemporal control of their functions, while avoiding drawbacks from their inherent tissue distribution. Herein, by exploiting the permeabilization of endosomes induced by photosensitizer agents upon light irradiation, we complemented the intracellular action of polymeric micelles incorporating camptothecin (CPT), which can sharply release the loaded drug in response to the reductive conditions of the cytosol, as an effective strategy for precisely controlling the function of these nanomedicines in vivo, while advancing toward a light-activated chemotherapy. These camptothecin-loaded micelles (CPT/m) were stable in the bloodstream, with minimal drug release in extracellular conditions, leading to prolonged blood circulation and high accumulation in xenografts of rat urothelial carcinoma. With the induction of endosomal permeabilization with the clinically approved photosensitizer, Photofrin, the CPT/m escaped from the endocytic vesicles of cancer cells into the cytosol, as confirmed both in vitro and in vivo by real-time confocal laser microscopies, accelerating the drug release from the micelles only in the irradiated tissues. This spatiotemporal switch significantly enhanced the in vivo antitumor efficacy of CPT/m without eliciting any toxicity, even at a dose 10-fold higher than the maximum tolerated dose of free CPT. Our results indicate the potential of reduction-sensitive drug-loaded polymeric micelles for developing safe chemotherapies after activation by remote triggers, such as light, which are capable of permeabilizing endosomal compartments.

Antineoplásicos Fitogênicos/administração & dosagem , Camptotecina/administração & dosagem , Citosol/metabolismo , Luz , Micelas , Polímeros/química , Animais , Linhagem Celular Tumoral , Oxirredução , Ratos
Chemistry ; 20(23): 6991-7000, 2014 Jun 02.
Artigo em Inglês | MEDLINE | ID: mdl-24753131


The synthesis, structure, and solution-state behavior of clothespin-shaped binuclear trans-bis(ß-iminoaryloxy)palladium(II) complexes doubly linked with pentamethylene spacers are described. Achiral syn and racemic anti isomers of complexes 1-3 were prepared by treating Pd(OAc)2 with the corresponding N,N'-bis(ß-hydroxyarylmethylene)-1,5-pentanediamine and then subjecting the mixture to chromatographic separation. Optically pure (100 % ee) complexes, (+)-anti-1, (+)-anti-2, and (+)-anti-3, were obtained from the racemic mixture by employing a preparative HPLC system with a chiral column. The trans coordination and clothespin-shaped structures with syn and anti conformations of these complexes have been unequivocally established by X-ray diffraction studies. (1)H NMR analysis showed that (±)-anti-1, (±)-anti-2, syn-2, and (±)-anti-3 display a flapping motion by consecutive stacking association/dissociation between cofacial coordination planes in [D8]toluene, whereas syn-1 and syn-3 are static under the same conditions. The activation parameters for the flapping motion (ΔH(≠) and ΔS(≠)) were determined from variable-temperature NMR analyses as 50.4 kJ mol(-1) and 60.1 J mol(-1) K(-1) for (±)-anti-1, 31.0 kJ mol(-1) and -22.7 J mol(-1) K(-1) for (±)-anti-2, 29.6 kJ mol(-1) and -57.7 J mol(-1) K(-1) for syn-2, and 35.0 kJ mol(-1) and 0.5 J mol(-1) K(-1) for (±)-anti-3, respectively. The molecular structure and kinetic parameters demonstrate that all of the anti complexes flap with a twisting motion in [D8]toluene, although (±)-anti-1 bearing dilated Z-shaped blades moves more dynamically than I-shaped (±)-anti-2 or the smaller (±)-anti-3. Highly symmetrical syn-2 displays a much more static flapping motion, that is, in a see-saw-like manner. In CDCl3, (±)-anti-1 exhibits an extraordinary upfield shift of the (1)H NMR signals with increasing concentration, whereas solutions of (+)-anti-1 and the other syn/anti analogues 2 and 3 exhibit negligible or slight changes in the chemical shifts under the same conditions, which indicates that anti-1 undergoes a specific heterochiral association in the solution state. Equilibrium constants for the dimerizations of (±)- and (+)-anti-1 in CDCl3 at 293 K were estimated by curve-fitting analysis of the (1)H NMR chemical shift dependences on concentration as 26 M(-1) [KD(racemic)] and 3.2 M(-1) [KD(homo)], respectively. The heterochiral association constant [KD(hetero)] was estimated as 98 M(-1), based on the relationship KD(racemic) = 1/2 KD(homo) +1/4 KD(hetero). An inward stacking motif of interpenetrative dimer association is postulated as the mechanistic rationale for this rare case of heterochiral association.

J Am Chem Soc ; 127(26): 9324-5, 2005 Jul 06.
Artigo em Inglês | MEDLINE | ID: mdl-15984832


The first molecule that assembles by ultrasound is described. An association-inert dinuclear Pd complex, anti-1a, which is stabilized by intramolecular pi-stacking interactions, gelatinizes a variety of organic solvents instantly upon brief presonication for a few seconds. This is the first quick, positive, and reversible method for the remote switching of stable sol-gel phases. Uniquely, the rate can be precisely controlled over the range between "no gelation" and "instant gelation" simply by tuning the sonication time.