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1.
Bioconjug Chem ; 25(7): 1261-71, 2014 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-24911830

RESUMO

In this report we describe the synthesis, characterization, and cytotoxic properties of DNA-capped gold nanoparticles having attached folic acid (FA), a thermoresponsive polymer (p), and/or poly(ethylene glycol) (PEG) oligomers that could be used to deliver the anticancer drug doxorubicin (DOX) in chemotherapy. The FA-DNA oligomer used in the construction of the delivery vehicle was synthesized through the reaction of the isolated folic acid N-hydroxysuccinimide ester with the amino-DNA and the conjugated DNA product was purified using high performance liquid chromatography (HPLC). This approach ultimately allowed control of the amount of FA attached to the surface of the delivery vehicle. Cytotoxicity studies using SK-N-SH neuroblastoma cells with drug loaded delivery vehicles were carried out using a variety of exposure times (1-48 h) and recovery times (1-72 h), and in order to access the effects of varying amounts of attached FA, in culture media deficient in FA. DOX loaded delivery vehicles having 50% of the DNA strands with attached FA were more cytotoxic than when all of the strands contained FA. Since FA stimulates cell growth, the reduced cytotoxicity of vehicles fully covered with FA suggests that the stimulatory effects of FA can more than compensate for the cytotoxic effects of the drug on the cell population. While attachment of hexa-ethylene glycol PEG(18) to the surface of the delivery vehicle had no effect on cytotoxicity, 100% FA plus the thermoresponsive polymer resulted in IC50 = 0.48 ± 0.01 for an exposure time of 24 h and a recovery time of 1 h, which is an order of magnitude more cytotoxic than free DOX. Confocal microscopic studies using fluorescence detection showed that SK-N-SH neuroblastoma cells exposed to DOX-loaded vehicles have drug accumulation inside the cell and, in the case of vehicles with attached FA and thermoresponsive polymer, the drug appears more concentrated. Since the biological target of DOX is DNA, the latter observation is consistent with the high cytotoxicity of vehicles having both FA and the thermoresponsive polymer. The study highlights the potential of DNA-capped gold nanoparticles as delivery vehicles for doxorubicin in cancer chemotherapy.


Assuntos
Antibióticos Antineoplásicos/administração & dosagem , Proliferação de Células/efeitos dos fármacos , Doxorrubicina/administração & dosagem , Sistemas de Liberação de Medicamentos , Ouro/química , Nanopartículas Metálicas/química , Neuroblastoma/tratamento farmacológico , Antibióticos Antineoplásicos/farmacologia , Doxorrubicina/farmacologia , Portadores de Fármacos , Ácido Fólico/química , Humanos , Estrutura Molecular , Neuroblastoma/patologia , Polietilenoglicóis/química , Polímeros/química , Espectroscopia de Infravermelho com Transformada de Fourier , Relação Estrutura-Atividade , Succinimidas/química , Células Tumorais Cultivadas
2.
Langmuir ; 29(49): 15217-23, 2013 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-24266340

RESUMO

In this paper, we describe the use of a temperature responsive polymer to reversibly assemble gold nanoparticles of various sizes. Temperature responsive, low critical solution temperature (LCST) pNIPAAm-co-pAAm polymers, with transition temperatures (T(C)) of 51 and 65 °C, were synthesized with a thiol modification, and grafted to the surface of 11 and 51 nm gold nanoparticles (AuNPs). The thermal-responsive behavior of the polymer allowed for the reversible aggregation of the nanoparticles, where at T < T(C) the polymers were hydrophilic and extended between particles. In contrast, at T > T(C), the polymer shell undergoes a hydrophilic to hydrophobic phase transition and collapses, decreasing interparticle distances between particles, allowing aggregation to occur. The AuNP morphology and polymer conjugation were probed by TEM, FTIR, and (1)H NMR. The thermal response was probed by UV-vis and DLS. The structure of the assembled aggregates at T > T(C) was studied via in situ small-angle X-ray scattering, which revealed interparticle distances defined by polymer conformation.


Assuntos
Nanopartículas/química , Ouro/química , Espectroscopia de Ressonância Magnética , Nanopartículas Metálicas/química , Microscopia Eletrônica de Transmissão , Nanopartículas/ultraestrutura , Polímeros/química , Espectroscopia de Infravermelho com Transformada de Fourier , Temperatura
3.
ACS Nano ; 7(8): 7011-20, 2013 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-23899347

RESUMO

In this paper we describe the use of a temperature-responsive polymer to regulate DNA interactions in both a DNA-mediated assembly system and a DNA-encoded drug delivery system. A thermoresponsive pNIPAAm-co-pAAm polymer, with a transition temperature (TC) of 51 °C, was synthesized with thiol modification and grafted onto gold nanoparticles (Au NPs) also containing single-stranded oligonucleotides (ssDNA). The thermoresponsive behavior of the polymer regulated the accessibility of the sequence-specific hybridization between complementary DNA-functionalized Au NPs. At T < TC, the polymer was hydrophilic and extended, blocking interaction between the complementary sequences at the periphery of the hydrodynamic diameter. In contrast, at T > TC, the polymer shell undergoes a hydrophilic to -phobic phase transition and collapses, shrinking below the outer ssDNA, allowing for the sequence-specific hybridization to occur. The potential application of this dynamic interface for drug delivery is shown, in which the chemotherapy drug doxorubicin (DOX) is bound to double-stranded DNA (dsDNA)-functionalized Au NPs whose sequences are known to be high-affinity intercalation points for it. The presence of the polymer capping is shown to decrease drug release kinetics and equilibrium at T < TC, but increase release at T > TC, thus improving the cytotoxicity of the encoded nanocarrier design.


Assuntos
DNA/química , Doxorrubicina/administração & dosagem , Portadores de Fármacos/química , Nanopartículas/química , Polímeros/química , Linhagem Celular Tumoral , DNA de Cadeia Simples/química , Ouro/química , Humanos , Nanopartículas Metálicas/química , Micelas , Hibridização de Ácido Nucleico , Temperatura , Fatores de Tempo , Raios Ultravioleta
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