RESUMO
In this work we hypothesized that the chemokine fractalkine can serve as a cancer molecular target. We engineered aptamer micelles functionalized with an outer poly(ethylene glycol) (PEG) corona, and investigated the extent and efficacy of using them as a targeting tool against fractalkine-expressing colon adenocarcinoma cells. In vitro cell binding results showed that aptamer micelles bound and internalized to fractalkine-expressing cancer cells with the majority of the micelles found free in the cytoplasm. Minimal surface binding was observed by healthy cells. Even though partial PEGylation did not prevent serum adsorption, micelles were highly resistant to endonuclease and exonuclease degradation. In vivo biodistribution studies and confocal studies demonstrated that even though both aptamer and control micelles showed tumor accumulation, only the aptamer micelles internalized into fractalkine-expressing cancer cells, thus demonstrating the potential of the approach and showing that fractalkine may serve as a specific target for nanoparticle delivery to cancer cells.
Assuntos
Adenocarcinoma/tratamento farmacológico , Aptâmeros de Nucleotídeos/administração & dosagem , Quimiocina CX3CL1/metabolismo , Neoplasias do Colo/tratamento farmacológico , Fibroblastos/efeitos dos fármacos , Micelas , Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Animais , Aptâmeros de Nucleotídeos/química , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Portadores de Fármacos/química , Sistemas de Liberação de Medicamentos , Fibroblastos/metabolismo , Fibroblastos/patologia , Humanos , Técnicas In Vitro , Camundongos , Polietilenoglicóis/química , Células Tumorais CultivadasRESUMO
Mesoporous silica nanoparticles (MSN)-polymer hybrid combined with the aliphatic biodegradable polyester caps on the surface were first developed in order to manipulate the smart intracellular release of anticancer drugs. First, poly(ethylene glycol)-b-poly(ε-caprolactone) (PEG-PCL) was successfully grafted on the surface of MSN via disulfide bonds which could cleave under a reduction environment in tumor cells. The anticancer drug doxorubicin (DOX) was encapsulated into the particle pores. The in vitro drug release profile showed that DOX release was significantly restricted by the polymer caps at pH 7.4, while it was greatly accelerated upon the addition of GSH. Cytotoxicity evaluation showed good biocompatibility with the hybrid particles. Fast endocytosis and intracellular DOX release were observed by confocal laser scanning microscopy (CLSM). The DOX-loaded particles exhibited comparable antitumor activity with free DOX towards HeLa cells and showed in a time-dependent manner. This work developed an extensive method of utilizing aliphatic biodegradable polyesters as polymer caps for MSN to control drug delivery. The paper might offer a potential option for cancer therapy.
Assuntos
Nanopartículas/química , Poliésteres/química , Dióxido de Silício/química , Animais , Antibióticos Antineoplásicos/toxicidade , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Doxorrubicina/toxicidade , Portadores de Fármacos/síntese química , Portadores de Fármacos/química , Células HeLa , Humanos , Lactonas/química , Camundongos , Oxirredução , Poliésteres/síntese química , Polietilenoglicóis/química , PorosidadeRESUMO
Biodegradable nucleobase-grafted amphiphilic copolymer, the methoxyl poly (ethylene glycol)-b-poly (L-lactide-co-2-methyl-2(3-(2,3-dihydroxylpropylthio) propyloxycarbonyl)-propylene carbonate/1-carboxymethylthymine) (mPEG-b- P(LA-co-MPT)), was synthesized. (1)H NMR titration and FT-IR spectroscopy indicated that the hydrogen-bonding could be formed between mPEG-b-P(LA-co-MPT) and 9-hexadecyladenine (A-C16). The hydrophobic microenvironment of the amphiphilic copolymer can protect the complementary multiple hydrogen bonds between mPEG-b-P(LA-co-MPT) and A-C16 from water effectively. The addition of A-C16 not only lowered the critical aggregation concentration (CAC) of mPEG-b-P(LA-co-MPT)/A-C16 nanoparticles (NPs) in aqueous solution but also induced different morphologies, which can be observed by transmission electron microscopy (TEM). Meanwhile, dynamic light scattering (DLS) and turbidometry was utilized to evaluate the effect of temperature and pH change on the stability of mPEG-b-P(LA-co-MPT)/A-C16 NPs. Cytotoxicity evaluation showed good biocompatibility of the mPEG-b-P(LA-co-MPT)/A-C16 NPs. The in vitro drug release profile showed that with the increase of A-C16 content, the doxorubiucin (DOX) release at pH 7.4 decreased, while the faster release rate was observed with the addition of A-C16 with a pH of 5.0. Importantly, DOX-loaded NPs exerted comparable cytotoxicity against MDA-MB-231 cells. This work provided a new method to stabilize NP structure using hydrogen-bonds and would have the potential to be applied in controlled drug delivery.
Assuntos
Adenina/análogos & derivados , Antibióticos Antineoplásicos/química , Materiais Biocompatíveis/síntese química , Preparações de Ação Retardada/síntese química , Doxorrubicina/química , Polietilenoglicóis/síntese química , Tensoativos/síntese química , Timina/análogos & derivados , Timina/síntese química , Antibióticos Antineoplásicos/farmacologia , Materiais Biocompatíveis/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Preparações de Ação Retardada/farmacologia , Doxorrubicina/farmacologia , Humanos , Ligação de Hidrogênio , Concentração de Íons de Hidrogênio , Interações Hidrofóbicas e Hidrofílicas , Cinética , Espectroscopia de Ressonância Magnética , Micelas , Microscopia Eletrônica de Transmissão , Estrutura Molecular , Nanopartículas/química , Nanopartículas/ultraestrutura , Polietilenoglicóis/farmacologia , Soluções , Espectroscopia de Infravermelho com Transformada de Fourier , Tensoativos/farmacologia , Temperatura , Timina/farmacologia , ÁguaRESUMO
Liposomal nanomedicine has led to clinically useful cancer therapeutics like Doxil and DaunoXome. In addition, peptide-functionalized liposomes represent an effective drug and gene delivery vehicle with increased cancer cell specificity, enhanced tumor-penetrating ability and high tumor growth inhibition. The goal of this article is to review the recently published literature of the peptide-amphiphiles that were used to functionalize liposomes, to highlight successful designs that improved drug and gene delivery to cancer cells in vitro, and cancer tumors in vivo, and to discuss the current challenges of designing these peptide-decorated liposomes for effective cancer treatment.
Assuntos
Antineoplásicos/administração & dosagem , Sistemas de Liberação de Medicamentos/métodos , Desenho de Fármacos , Técnicas de Transferência de Genes , Neoplasias/tratamento farmacológico , Neoplasias/genética , Peptídeos/química , Animais , Humanos , Ligantes , Lipossomos , Neoplasias/metabolismo , Peptídeos/síntese químicaRESUMO
A photo-cross-linked micelle is synthesized via photodimerization of thymine moieties fabricated from amphiphilic block copolymers (mPEG-b-P(LA-co-MPT). The crosslinking behavior is monitored by UV-Vis spectra and (1) H NMR. Dynamic light scattering (DLS) and transmission electron microscopy (TEM) showed that cross-linked micelles had smaller sizes than their uncross-linked precursors. In vitro studies reveal that cross-linking of the micelle cores results in a slow drug release and faster cellular uptake in comparison with uncross-linked ones in MCF-7 and Hela cells. Moreover, the paclitaxel (PTX)-loaded core-cross-linked micelles exhibit similar anticancer efficacy as free PTX. This work provides a convenient tool for designing a more stable structure in the blood circulation to realize a controlled drug delivery.