Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 8 de 8
Filtrar
Mais filtros











Base de dados
Intervalo de ano de publicação
1.
Int J Mol Sci ; 24(23)2023 Nov 24.
Artigo em Inglês | MEDLINE | ID: mdl-38069036

RESUMO

The DNA origami method has revolutionized the field of DNA nanotechnology since its introduction. These nanostructures, with their customizable shape and size, addressability, nontoxicity, and capacity to carry bioactive molecules, are promising vehicles for therapeutic delivery. Different approaches have been developed for manipulating and folding DNA origami, resulting in compact lattice-based and wireframe designs. Platinum-based complexes, such as cisplatin and phenanthriplatin, have gained attention for their potential in cancer and antiviral treatments. Phenanthriplatin, in particular, has shown significant antitumor properties by binding to DNA at a single site and inhibiting transcription. The present work aims to study wireframe DNA origami nanostructures as possible carriers for platinum compounds in cancer therapy, employing both cisplatin and phenanthriplatin as model compounds. This research explores the assembly, platinum loading capacity, stability, and modulation of cytotoxicity in cancer cell lines. The findings indicate that nanomolar quantities of the ball-like origami nanostructure, obtained in the presence of phenanthriplatin and therefore loaded with that specific drug, reduced cell viability in MCF-7 (cisplatin-resistant breast adenocarcinoma cell line) to 33%, while being ineffective on the other tested cancer cell lines. The overall results provide valuable insights into using wireframe DNA origami as a highly stable possible carrier of Pt species for very long time-release purposes.


Assuntos
Neoplasias da Mama , Nanoestruturas , Humanos , Feminino , Cisplatino/farmacologia , Platina/farmacologia , Preparações Farmacêuticas , DNA/química , Nanoestruturas/química , Conformação de Ácido Nucleico
2.
J Phys Chem Lett ; 14(20): 4704-4710, 2023 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-37171167

RESUMO

Guanine quadruplexes (G4s) play essential protective and regulatory roles within cells, influencing gene expression. In several gene-promoter regions, multiple G4-forming sequences are in close proximity and may form three-dimensional arrangements. We analyze the interplay among the three neighboring G4s in the c-KIT proto-oncogene promoter (WK1, WSP, and WK2). We highlight that the three G4s are structurally linked and their cross-talk favors the formation of a parallel structure for WSP. Relying on all-atom molecular dynamic simulations exceeding the µs time scale and using enhanced sampling methods, we provide the first computationally resolved structure of a well-organized G4 cluster in the promoter of a crucial gene involved in cancer development. Our results indicate that neighboring G4s influence their mutual three-dimensional arrangement and provide a powerful tool to predict and interpret complex DNA structures that can ultimately be used as a starting point for drug discovery.


Assuntos
Quadruplex G , Regiões Promotoras Genéticas/genética , DNA/química , Proto-Oncogenes
3.
J Am Chem Soc ; 141(26): 10205-10213, 2019 07 03.
Artigo em Inglês | MEDLINE | ID: mdl-31244182

RESUMO

The proto-oncogene KIT encodes for a tyrosine kinase receptor, which is a clinically validated target for treating gastrointestinal stromal tumors. The KIT promoter contains a G-rich domain within a relatively long sequence potentially able to form three adjacent G-quadruplex (G4) units, namely, K2, SP, and K1. These G4 domains have been studied mainly as single quadruplex units derived from short truncated sequences and are currently considered promising targets for anticancer drugs, alternatively to the encoded protein. Nevertheless, the information reported so far does not contemplate the interplay between those neighboring G4s in the context of the whole promoter, possibly thwarting drug-discovery efforts. Here we report the structural and functional study of the KIT promoter core sequence, in both single- and double-stranded forms, which includes all three predicted G4 units. By preventing the formation of alternatively one or two G4 units and by combining biophysical techniques and biological assays, we show for the first time that these quadruplexes cannot be analyzed independently, but they are correlated to each other. Our data suggest that, while K2 and K1 G-rich sequences retain the ability to fold into parallel G4 motifs within a long sequence, the SP G-rich domain contributes to G4 structure only together with K2. Remarkably, we have found that, in the context of a dynamic equilibrium between the three G4 units, the G4 formed by K1 has the most significant influence on the structure stability and on the biological role of the whole promoter.


Assuntos
Quadruplex G , Regiões Promotoras Genéticas/genética , Proteínas Proto-Oncogênicas c-kit/genética , Humanos , Proto-Oncogene Mas
4.
J Mater Chem B ; 3(12): 2472-2486, 2015 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-26257912

RESUMO

Histamine functionalized block copolymers based on poly(allyl glycidyl ether)-b-poly(ethylene oxide) (PAGE-b-PEO) were prepared with different ratios of histamine and octyl or benzyl groups using UV-initiated thiol-ene click chemistry. At neutral pH, the histamine units are uncharged and hydrophobic, while in acidic environments, such as in the endosome, lysosomes, or extracellular sites of tumours, the histamine groups are positively charged and hydrophilic. pH responsible polymer drug delivery systems is a promising route to site specific delivery of drugs and offers the potential to avoid side effects of systemic treatment. Our detailed in vitro experiments of the efficacy of drug delivery and the intracellular localization characteristics of this library of NPs in 2D and 3D cultures of breast cancer revealed that the 50% histamine-modified polymer loaded with DOX exhibited rapid accumulation in the nucleus of free DOX within 2 h. Confocal studies showed enhanced mitochondrial localization and lysosomal escape when compared to controls. From these combined studies, it was shown that by accurately tuning the structure of the initial block copolymers, the resulting self-assembled NPs can be designed to exploit histamine as an endosomal escape trigger and the octyl/benzyl units give rise to a hydrophobic core resulting in highly efficacious drug delivery systems (DDS) with control over intracellular localization. Optimization and rational control of the intracellular localization of both DDS and the parent drug can give nanomedicines a substantial increase in efficacy and should be explored in future studies.

5.
Biomacromolecules ; 15(6): 2235-45, 2014 Jun 09.
Artigo em Inglês | MEDLINE | ID: mdl-24784843

RESUMO

A library of amphiphilic, hyperbranched dendritic-linear polymers (HBDLPs) are successfully synthesized, and evaluated as potential unimolecular micelles. Hyperbranched macroinitiators (HBMI), extended with poly(ethylene glycol) methacrylate (P(OEGMA)), are afforded via a combination of self-condensing vinyl (co)polymerization (SCV(C)P) and atom transfer radical polymerization (ATRP), providing a versatile two-step synthetic route. The HBDLP architecture and chain lengths are varied, and the effect on the nanoparticle (NP) stability and properties are evaluated. The HBDLPs form predominantly stable and spherical NPs, and the NP dimensions could be tailored by the HBDLP characteristics. The NPs formed are of high molecular weight, and their stability varies with the properties of the corresponding HBDLP. Too small dendritic segment, or too low degree of PEGylation, results to some extent in NP aggregation, while higher molecular weight HBDLPs, with a high amount of hydrophilic segments, appears to form discrete unimolecular micelles. The versatility of the platform is further demonstrated by the convenience of forming a HBDLP with a more complex, linear copolymer extension instead of P(OEGMA).


Assuntos
Dendrímeros/química , Portadores de Fármacos/química , Micelas , Animais , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Dendrímeros/farmacologia , Portadores de Fármacos/farmacologia , Humanos , Células MCF-7 , Camundongos
6.
Chemistry ; 18(35): 10983-90, 2012 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-22806942

RESUMO

The interaction with native DNA of a 2,7-diazapyrenium-based ligand 1 and its Pt(II) rectangular metallacycle 2 is explored through circular and linear dichroism and fluorescence spectroscopies. The metal-free ligand 1 binds through intercalation, with a binding constant of approximately 5×10(5) M(-1), whereas the metallacycle 2 binds and bends the DNA with a binding constant of 7×10(6) M(-1). PCR assays show that metallo-supramolecular box 2 interferes with DNA transactions in vitro whereas the intercalator 1 does not. The metallacycle is active against four human cancer cell lines, with IC(50) values ranging between 3.1 and 19.2 µM and shows similar levels of efficacy, but a different spectrum of activity, to cisplatin.


Assuntos
Antineoplásicos/química , DNA de Neoplasias/química , Substâncias Intercalantes/química , Compostos Organoplatínicos/química , Fenantrolinas/química , Platina/química , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Dicroísmo Circular , Cisplatino/química , DNA de Neoplasias/antagonistas & inibidores , Humanos , Concentração Inibidora 50 , Substâncias Intercalantes/farmacologia , Cinética , Ligantes , Conformação Molecular , Desnaturação de Ácido Nucleico/efeitos dos fármacos , Compostos Organoplatínicos/farmacologia , Espectrometria de Fluorescência , Termodinâmica
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA