RESUMO
Chemotherapy is a traditional treatment method in clinical cancer treatment. However, it is limited due to the large toxic side effects of chemotherapeutics. Nanomedicines have shown great potential in the application of tumor therapy. The size of nanoparticles as a crucial factor in the enhanced permeability and retention (EPR) effect can be regulated for the enhanced chemotherapy. Therefore, we believe that regulation of nanoparticle size can be used as an effective sensitizer to enhance the therapeutic effect of chemotherapy drugs on tumors. Here, we prepared several nanoparticles of different hydrodynamic diameters commonly found in nanomedical applications by the diblock copolymer of methoxy polyethylene glycol-poly (ϵ-caprolactone) (mPEG-PCL). The blood circulation effect and organ distribution in blood were detected by fluorescence labeled nanoparticles. We found that the small-sized nanoparticles exhibited much longer blood circulation time than the large-sized nanoparticles in vivo, and thus the nanoparticle concentration in the tumor tissue was relatively high. Systematic injection of the doxorubicin (DOX) loaded nanoparticles can effectively inhibit tumor growth. Compared to the free drug, tumor cells were much more sensitive to DOX loaded nanoparticles of small size. Our nano-drug delivery system has been proven to be safe and nontoxic in vivo and was suitable for use as a sensitizer in clinical oncology chemotherapy.
Assuntos
Doxorrubicina/uso terapêutico , Glioma/tratamento farmacológico , Nanopartículas/química , Tamanho da Partícula , Polímeros/química , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Circulação Sanguínea/efeitos dos fármacos , Linhagem Celular Tumoral , Doxorrubicina/farmacologia , Humanos , Camundongos Endogâmicos NOD , Camundongos SCID , Nanopartículas/efeitos adversosRESUMO
Nanoparticles (NP) of 12.7 nm in diameter of the poly(methyl methacrylate (MMA)-co-methacrylic acid (MAA)) copolymer were prepared. 13C-NMR results showed a MMA:MAA molar ratio of 0.64:0.36 in the copolymer, which is similar to the poly(MMA-co-MAA) commercially known as the FDA approved Eudragit S100 (0.67:0.33). The NP prepared in this study were loaded at pH 5 with varying amounts (from 0.54 to 6.91%) of doxorubicin (DOX), an antineoplastic drug. 1H-NMR results indicated the electrostatic interactions between the ionized carboxylic groups of the MAA units in the copolymer and the proton of the glycosidic amine in DOX. Measurements by QLS and TEM indicated that the loading destabilizes the NP, and that for increase stability, they aggregate in a reversible way, forming aggregates with a diameter up to 99.5 nm at a DOX load of 6.91%. The analysis of drug release data at pH 7.4 showed that loaded NP with at least 4.38% DOX release the drug very slowly and follows the Higuchi model; the former suggests that they could remain for long periods in the bloodstream to reach and destroy cancer cells.
Assuntos
Sistemas de Liberação de Medicamentos , Nanopartículas , Doxorrubicina , Portadores de Fármacos , Concentração de Íons de Hidrogênio , Metacrilatos , Polimetil MetacrilatoRESUMO
INTRODUCTION: The overexpression of Human Epidermal Growth Factor Receptor 2 (HER2) is usually associated with aggressive and infiltrating breast cancer (BC) phenotype, and metastases. Functionalized silica-based nanocarriers (SiNPs) can be labeled for in vivo imaging applications and loaded with chemotherapy drugs, making possible the simultaneous noninvasive diagnosis and treatment (theranostic) for HER2-positive BC. METHODS: Firstly, FITC-filled SiNPs, were engineered with two different amounts of Hc-TZ (trastuzumab half-chain) per single nanoparticle (1:2 and 1:8, SiNPs to Hc-TZ ratio), which was 99mTc-radiolabeled at histidine residues for ex vivo and in vivo biodistribution evaluations. Secondly, nanoparticles were loaded with DOX and their in vitro and ex vivo/in vivo delivery was assessed, in comparison with liposomal Doxorubicin (Caelyx). Finally, the treatment efficacy of DOX-SiNPs-TZ (1:8 Hc-TZ) was evaluated in vivo by PET and supported by MS-based proteomics profiling of tumors. RESULTS: SiNPs-TZ (1:8 Hc-TZ) tumor uptake was significantly greater than that of SiNPs-TZ (1:2 Hc-TZ) at 6 hours post-injection (p.i.) in ex vivo biodistribution experiment. At 24 h p.i., radioactivity values remained steady. Fluorescence microscopy, confirmed the presence of radiolabeled SiNPs-TZ (1:8 Hc-TZ) within tumor even at later times. SiNPs-TZ (1:8 Hc-TZ) nanoparticles loaded with Doxorubicin (DOX-SiNPs-TZ) showed a similar DOX delivery capability than Caelyx (at 6 h p.i.), in in vitro and ex vivo assays. Nevertheless, at the end of treatment, tumor volume was significantly reduced by DOX-SiNPs-TZ (1:8 Hc-TZ), compared to Caelyx and DOX-SiNPs treatment. Proteomics study identified 88 high stringent differentially expressed proteins comparing the three treatment groups with controls. CONCLUSION: These findings demonstrated a promising detection specificity and treatment efficacy for our system (SiNPs-TZ, 1:8 Hc-TZ), encouraging its potential use as a new theranostic agent for HER2-positive BC lesions. In addition, proteomic profile confirmed that a set of proteins, related to tumor aggressiveness, were positively affected by targeted nanoparticles.