RESUMEN
Breast cancer stem cells (CSCs) are believed to be responsible for tumor initiation, invasion, metastasis, and recurrence, which lead to treatment failure. Thus, developing effective CSC-targeted therapeutic strategies is crucial for enhancing therapeutic efficacy. In this work, GNSs-dPG-3BP, TPP, and HA nanocomposite particles are developed by simultaneously conjugating hexokinase 2 (HK2) inhibitor 3-bromopyruvate (3BP), mitochondrial targeting molecule triphenyl phosphonium (TPP), and CSCs targeting agent hyaluronic acid (HA) onto gold nanostars-dendritic polyglycerol (GNSs-dPG) nanoplatforms for efficient eradication of CSCs. The nanocomposite particles possess good biocompatibility and exhibit superior mitochondrial-bound HK2 binding ability via 3BP to inhibit metabolism, and further induce cellular apoptosis by releasing the cytochrome c. Therefore, it enhanced the therapeutic efficacy of CSCs-specific targeted photothermal therapy (PTT), and achieved a synergistic effect for the eradication of breast CSCs. After administration of the synergistic treatment, the self-renewal of breast CSCs and the stemness gene expression are suppressed, CSC-driven mammosphere formation is diminished, the in vivo tumor growth is effectively inhibited, and CSCs are eradicated. Altogether, GNSs-dPG-3BP, TPP, and HA nanocomposite particles have been developed, which will provide a novel strategy for precise and highly efficient targeted eradication of CSCs.
Asunto(s)
Neoplasias de la Mama , Oro , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/metabolismo , Línea Celular Tumoral , Femenino , Glicerol , Oro/farmacología , Humanos , Ácido Hialurónico/química , Células Madre Neoplásicas , Terapia Fototérmica , PolímerosRESUMEN
Porous poly (lactic acid) (PLA)-based scaffolds have been widely used as a promising product in tissue engineering. However, it is still a challenge to prepare the PLA-based scaffolds with high expansion ratio, good hydrophilicity, and excellent cytocompatibility by a green and cost-effective fabrication approach. Herein, we prepared porous PLA-based scaffolds using carbon dioxide (CO2) as the physical foaming agent. To improve the hydrophilicity and foaming behavior of PLA, poly (ethylene glycol) (PEG) was selected as a good additive to blend with PLA. It revealed that the introduction of PEG could improve the foaming behavior of PLA and promote the formation of opening cells via reducing the matrix strength of PLA. The obtained 3D PLA/PEG scaffolds exhibited high expansion ratio (9.1), high open-cell content (95.2%), and super-hydrophilicity (water contact angle 0°). Additionally, the mouse fibroblast NIH/3T3 cells with live/dead cell fluorescence staining assay was utilized to examine the biocompatibility of PLA/PEG scaffolds. The result demonstrated that the proliferation ratio of NIH/3 T3 cells on the surface of PLA/PEG scaffolds was higher than that of PLA scaffolds, indicating that the highly interconnected cell structure was conducive to cell adhesion and attachment. Consequently, such hydrophilic open-cell structure obtained by adding PEG into PLA possesses great potential for use in tissue engineering.
Asunto(s)
Dióxido de Carbono , Andamios del Tejido , Animales , Materiales Biocompatibles/química , Materiales Biocompatibles/farmacología , Interacciones Hidrofóbicas e Hidrofílicas , Ácido Láctico/química , Ratones , Poliésteres/química , Porosidad , Ingeniería de Tejidos , Andamios del Tejido/químicaRESUMEN
The existence of cancer stem cells (CSCs) poses a major obstacle for the success of current cancer therapies, especially the fact that non-CSCs can spontaneously turn into CSCs, which lead to the failure of the treatment and tumor relapse. Therefore, it is very important to develop effective strategies for the eradication of the CSCs. In this work, we have developed a CSCs-specific targeted, retinoic acid (RA)-loaded gold nanostars-dendritic polyglycerol (GNSs-dPG) nanoplatform for the efficient eradication of CSCs. The nanocomposites possess good biocompatibility and exhibit effective CSCs-specific multivalent targeted capability due to hyaluronic acid (HA) decorated on the multiple attachment sites of the bioinert dendritic polyglycerol (dPG). With the help of CSCs differentiation induced by RA, the self-renewal of breast CSCs and tumor growth were suppressed by the high therapeutic efficacy of photothermal therapy (PTT) in a synergistic inhibitory manner. Moreover, the stemness gene expression and CSC-driven tumorsphere formation were significantly diminished. In addition, the in vivo tumor growth and CSCs were also effectively eliminated, which indicated superior anticancer activity, effective CSCs suppression, and prevention of relapse. Taken together, we developed a CSCs-specific targeted, RA-loaded GNSs-dPG nanoplatform for the targeted eradication of CSCs and for preventing the relapse.
Asunto(s)
Oro , Neoplasias , Glicerol , Células Madre Neoplásicas , Terapia Fototérmica , Polímeros , Tretinoina/farmacologíaRESUMEN
Drug-loaded nanoparticles can be specifically uptaken by tumor cells to realize active targeting due to the conjugated ligands or antibodies on their surface. However, some non-cancerous cells express non-specific receptors or antigens on their surface, which can react with the ligands or antibodies conjugated on the nanoparticle surface and then result in non-specific uptake of the nanoparticles by non-cancerous cells. In order to reduce the non-specific uptake of nanoparticles by non-cancerous cells, in this study, we proposed a pH-sensitive polymer based precise tumor targeting strategy and synthesized superparamagnetic iron oxide nanoparticle (SPION) encapsulated albumin nanoparticles (AN) with conjugation of folic acid (FA) and mPEG-DCA (SPION-AN-FA@mPEG), in which mPEG can shield FA, avoiding the non-specific recognition by normal cells under physiological conditions, and can be shed to expose FA in tumor microenvironments. The pH-sensitivity of mPEG-DCA was verified by HPLC characterization and 1H-NMR spectroscopy. The graft density and length of mPEG-DCA were optimized via the cellular uptake of SPION-AN-FA@mPEG measured by flow cytometry analysis. The r2 value and r2/r1 ratio of the optimized SPION-AN-FA@mPEG (i.e., SPION-AN-FA@mPEG4) are 168.6 mM-1 s-1 and 42.8, respectively, which are both much higher than that of the commercial contrast agent Resovist®. The in vitro T2-weighted MR images and in vivo MRI performance demonstrate that our SPION-AN-FA@mPEG4 nanoparticles can be used as an effective T2-weighted MRI contrast agent.
Asunto(s)
Terapia Molecular Dirigida , Nanopartículas/química , Nanopartículas/metabolismo , Polietilenglicoles/química , Polietilenglicoles/metabolismo , Transporte Biológico , Compuestos Férricos/química , Receptor 1 de Folato/metabolismo , Ácido Fólico/química , Humanos , Concentración de Iones de Hidrógeno , Células MCF-7RESUMEN
The recently emerged exceedingly small magnetic iron oxide nanoparticles (ES-MIONs) (<5 nm) are promising T1-weighted contrast agents for magnetic resonance imaging (MRI) due to their good biocompatibility compared with Gd-chelates. However, the best particle size of ES-MIONs for T1 imaging is still unknown because the synthesis of ES-MIONs with precise size control to clarify the relationship between the r1 (or r2/r1) and the particle size remains a challenge. In this study, we synthesized ES-MIONs with seven different sizes below 5 nm and found that 3.6 nm is the best particle size for ES-MIONs to be utilized as T1-weighted MR contrast agent. To enhance tumor targetability of theranostic nanoparticles and reduce the nonspecific uptake of nanoparticles by normal healthy cells, we constructed a drug delivery system based on the 3.6 nm ES-MIONs for T1-weighted tumor imaging and chemotherapy. The laser scanning confocal microscopy (LSCM) and flow cytometry analysis results demonstrate that our strategy of precise targeting via exposure or hiding of the targeting ligand RGD2 on demand is feasible. The MR imaging and chemotherapy results on the cancer cells and tumor-bearing mice reinforce that our DOX@ES-MION3@RGD2@mPEG3 nanoparticles are promising for high-resolution T1-weighted MR imaging and precise chemotherapy of tumors.
Asunto(s)
Sistemas de Liberación de Medicamentos , Nanopartículas de Magnetita/uso terapéutico , Neoplasias/diagnóstico por imagen , Neoplasias/tratamiento farmacológico , Animales , Línea Celular Tumoral , Medios de Contraste/química , Medios de Contraste/uso terapéutico , Imagen de Difusión por Resonancia Magnética , Compuestos Férricos/química , Compuestos Férricos/uso terapéutico , Humanos , Nanopartículas de Magnetita/química , Ratones , Neoplasias/patología , Polietilenglicoles/química , Polietilenglicoles/uso terapéutico , Nanomedicina Teranóstica/métodosRESUMEN
One big challenge with active targeting of nanocarriers is non-specific binding between targeting molecules and non-target moieties expressed on non-cancerous cells, which leads to non-specific uptake of nanocarriers by non-cancerous cells. Here, we propose a novel Trojan-horse targeting strategy to hide or expose the targeting molecules of nanocarriers on-demand. The non-specific uptake by non-cancerous cells can be reduced because the targeting molecules are hidden in hydrophilic polymers. The nanocarriers are still actively targetable to cancer cells because the targeting molecules can be exposed on-demand at tumor regions. Typically, Fe3O4 nanocrystals (FN) as magnetic resonance imaging (MRI) contrast agents were encapsulated into albumin nanoparticles (AN), and then folic acid (FA) and pH-sensitive polymers (PP) were grafted onto the surface of AN-FN to construct PP-FA-AN-FN nanoparticles. Fourier transform infrared spectroscopy (FT-IR), dynamic light scattering (DLS), transmission electron microscope (TEM) and gel permeation chromatography (GPC) results confirm successful construction of PP-FA-AN-FN. According to difference of nanoparticle-cellular uptake between pH 7.4 and 5.5, the weight ratio of conjugated PP to nanoparticle FA-AN-FN (i.e. graft density) and the molecular weight of PP (i.e. graft length) are optimized to be 1.32 and 5.7 kDa, respectively. In vitro studies confirm that the PP can hide ligand FA to prevent it from binding to cells with FRα at pH 7.4 and shrink to expose FA at pH 5.5. In vivo studies demonstrate that our Trojan-horse targeting strategy can reduce the non-specific uptake of the PP-FA-AN-FN by non-cancerous cells. Therefore, our PP-FA-AN-FN might be used as an accurately targeted MRI contrast agent.
Asunto(s)
Portadores de Fármacos/química , Endocitosis , Nanopartículas/química , Neoplasias/metabolismo , Resinas Acrílicas/síntesis química , Resinas Acrílicas/química , Animales , Medios de Contraste/química , Ácidos Grasos/química , Femenino , Compuestos Férricos/química , Ácido Fólico/farmacología , Humanos , Concentración de Iones de Hidrógeno , Células MCF-7 , Imagen por Resonancia Magnética , Metacrilatos/química , Ratones Endogámicos BALB C , Ratones Desnudos , Polimerizacion , Temperatura , Factores de TiempoRESUMEN
The aim of this study is to explore an improved double emulsion technology with in situ reaction of lysine (Lys) and glutaraldehyde (GA) for fabricating autofluorescent Lys-poly(lactic-co-glycolic acid)-GA (Lys-PLGA-GA) microcapsules as novel ultrasonic/fluorescent dual-modality contrast agents. Scanning electron microscope (SEM) and static light scattering (SLS) results show that 80% of the Lys-PLGA-GA microcapsules are larger than 1.0 µm and 90% of them are smaller than 8.9 µm. SEM and laser confocal scanning microscope (LCSM) data demonstrate that the structure of our Lys-PLGA-GA microcapsules is hollow. Compared with the FT-IR spectrum of PLGA microcapsules, a new peak at 1,644 cm(-1) in that of Lys-PLGA-GA microcapsules confirms the formed Schiff base in Lys-PLGA-GA microcapsules. LCSM images and fluorescence spectra show that our Lys-PLGA-GA microcapsules exhibit bright and stable autofluorescence without conjugation to any fluorescent agent, which can be ascribed to the n-π transitions of the CN bonds in the formed Schiff base. Our autofluorescent Lys-PLGA-GA microcapsules might have more wide applications than traditional fluorescent dyes because their excitation and emission spectra are both broad. The fluorescence intensity can also be tuned by the feeding amount of Lys and GA. The MTT assays reveal that the autofluorescent microcapsules are biocompatible. The results of fluorescent imaging in cells and in vitro ultrasonic imaging demonstrate the feasibility of our autofluorescent Lys-PLGA-GA microcapsules as ultrasonic/fluorescent dual-modality contrast agents. This novel ultrasonic/fluorescent dual-modality contrast agent might have potential for a variety of biological and medical applications.