ABSTRACT
The clinical tumor therapy was greatly challenged due to the complex characteristics of tumor microenvironment, however, which also provide arena for novel therapeutic strategies. In this study, poly(2-ethyl-2-oxazoline)-poly(lactic acid)-SS-poly(β-amino ester (PEOz-PLA-SS-PBAE) triblock copolymers with pH and GSH double response were synthesized, polymer micelles were prepared by thin film hydration method for loading of silybin to improve its antitumor activity. The critical micelle concentration was determined by pyrene fluorescence method as 1.8 μg·mL-1. The particle size was 155.30 ± 1.80 nm as determined by dynamic light scattering, with polydispersity index of 0.168 ± 0.004. The drug loading and entrapment efficiency of the micelles were determined by HPLC as (5.48 ± 0.04)% and (68.52 ± 0.48)%, respectively. The in vitro drug release profiles showed that the micelles have low pH sensitivity and high GSH responsiveness, and exhibited sustained release profiles. The good biocompatibility of the material was proved by measuring the hemolysis rate and cytotoxicity of the blank micelle. The cytotoxicity and apoptosis rate of tumor cells showed that the drug loaded PEOz-PLA-SS-PBAE micelles had significant inhibitory effect and apoptosis-inducing effect on MDA-MB-231 cells. The results of wounding healing assay and Transwell invasion test showed that the drug loaded PEOz-PLA-SS-PBAE micelles could significantly inhibit the metastasis of MDA-MB-231 cells. The PEOz-PLA-SS-PBAE drug-loaded micelles prepared in this study have good inhibitory effect on tumor growth and anti-tumor metastasis in vitro, which lays the foundation for the further application of silybin.
ABSTRACT
Paclitaxel( PTX) is used as a broad spectrum anti-tumor medicine. However,serious drawbacks restrict clinical application of PTX. In this study,we prepared tumor-targeting and pH-sensitive lipoprotein-mimic nanocarrier containing paclitaxel( BSALC/DOPE-PTX) to study the effective antitumor activity. The in vivo targeting ability of the nanocarrier in tumor bearing nude mice was evaluated by using a Kodak in vivo imaging system FX PRO. The in vivo anti-tumor activity was evaluated in MDA-MB-231 tumor bearing mice,and representative sections were stained with hematoxylin and eosin( H&E),and examined by light microscopy. The results showed that DiR-loaded FA-BSA-LC/DOPE selectively targeted tumor,and had a relatively long residence in the tumor tissue. According to the in vivo anti-tumor activity study,FA-BSA-LC/DOPE-PTX exhibited an outstanding tumor inhibition effect with a tumor growth inhibition rate of 79.3%,and tumor tissue sections stained by hematoxylin and eosin( HE) showed severe necrosis areas and many dead cells with condensed nuclei in the FA-BSA-LC/DOPE-PTX group. Therefore,FA-BSA-LC/DOPE-PTX is a biocompatible,tumor-targeting and pH-sensitive lipoprotein-mimic nanocarrier,with a very marked anti-tumor activity in tumor-bearing mice in vivo.
Subject(s)
Animals , Mice , Antineoplastic Agents, Phytogenic , Pharmacology , Cell Line, Tumor , Drug Carriers , Hydrogen-Ion Concentration , Lipoproteins , Mice, Nude , Nanoparticles , Neoplasms, Experimental , Drug Therapy , Paclitaxel , PharmacologyABSTRACT
A multiple-stimuli-responsive drug-conjugated cross-linked micelles was prepared by radical copolymerization. The chemical structure, morphology, and size of the cross-linked micelles were characterized, and the drug loading of the micelle was calculated. The experimental results indicated that the hydrodynamic size of the drug-loaded micelles were about 100 nm, and the as prepared micelles could be degraded and swelled in presence of reducing glutathione (GSH). The low critical solution temperature (LCST) of the micelle was around 39.4℃. According to the experimental results, the micelles will shrink at temperature above the LCST. Subsequently, the accumulative drug release rate was up to 91.78% under acidic (pH 5.0), reductive (GSH 10 mmol/L) and high temperature (42.0℃) conditions mimicking the tumor microenvironment, while a relatively low release rate of 1.12% was observed without stimulation. The drug-conjugated cross-linked micelles showed a strong cell uptake behavior. In the cytotoxicity assay, the micelles exhibited effective anti-cancer activity and excellent biocompatibility. In brief, the experimental results show that the as-prepared drug-conjugated cross-linked micelle exhibits multiple stimuli-responsiveness, which holds great promise for anti-cancer drug delivery.
ABSTRACT
In order to construct a novel multifunctional targeting nano-carrier based on pH-redox characteristics of tumor microenvironment,ketone bonds and disulfide bonds were bonded to the oligomeric hyaluronic acid (oHA) being sensitive to pH and the reduction environment.The chemical structure of oligomeric hyaluronic acid-8-mercaptomenthone 1,2-glycerolketal (oHMST) was characterized by 1H NMR,IR and ESI-MS.Curcuminloaded micelles were prepared by dialysis.The single factor investigation was carried out on the dosage form.Some properties,including particle size zeta potential,the morphology of micelles,and pH-sensitivity were studied.The materials were synthesized successfully.The micelles were spheric with a diameter of about 100 nm.The Zeta potential of the micelles was-(21.97 ± 1.08) mV.The in vitro test showed that oHMST carriers have good pH-sensitivity and redox-sensitivity.
ABSTRACT
OBJECTIVE To explore a novel pH-sensitive fluorescent probe for in vivo tumor imaging. METHODS Zn5 were obtained in 140℃ after mixed with MeOH, water, Zn(NO3)2 · 6H2O, H4L and trimethylamine. The fluorescence spectra of Zn5 with the same concentration in different pH aqueous solutions were detected. And the stability of Zn5 was investigated by time dependent fluorescence emission spectra of Zn5 in BSA aqueous solution and 5.0% serum solution. Then, the cytotoxicity of Zn5 was detected by MTT assays. To clarify whether a similar fluorescence response occurs in biological organisms, HeLa cells were pretreated with probe Zn5 (0.5 μmol·L- 1) and fluorescence imaging were collected for targeting lysosomes in living cells because of lysosomes' acidic microenvironment. The A375 tumor-bearing mice were used to assess the imaging ability of Zn5 in vivo. Mouse tumor xenografts were established by injection of A375 cells with 2×106 cells per flank. Probe (1 μg·g-1) was administered to mice by injection. Images were obtained using IVIS Spectrum CT Imaging System. RESULTS There is a 11-fold intensity increasing as the pH values changing from 8 to 2. The almost unchanged emission intensities suggest Zn5 is stable in both BSA and serum. Zn5 has negligible cytotoxicity for HeLa, 293T and CHO-K1 cells. Zn5 can selectively display lysosomes in living cells. Both the 2D and 3D images in vivo distinguish the tumor from other tissues with good fluorescence contrast. CONCLUSION The high chemical stability, emission in the Vis/NIR range, pH sensitivity, a pKa located in the tumor pH range, and low toxicity make Zn5 is suitable for application as a pH- sensitive fluorescent probe for bio-imaging.
ABSTRACT
OBJECTIVE: To construct a tumor-targeting and pH-sensitive lipoprotein-mimic nanocarrier containing paclitaxel(BSA-LC/DOPE-PTX)for effective antitumor therapy. METHODS: In vitro drug release study was conducted using dialysis method. The stability of BSA-LC/DOPE-PTX was studied by testing the aggregation of BSA-LC/DOPE-PTX in 50% human plasma. The cytotoxicity of drug-loaded nanocarrier against MCF-7 cells was evaluated by standard MTT assay. The subcellular localization and intracellular drug release behavior of BSA-LC/DOPE were evaluated by LSCM. RESULTS: In vitro drug release study demonstrated that paclitaxel(PTX)was released from BSA-LC/DOPE in a pH-dependent manner. The stability study showed that there was no significant change, suggesting that the coupling BSA could increase the stability in plasma. The cellular inhibition of BSA-LC/DOPE-PTX with BSA targeting agents was greater than that of LC/DOPE-PTX. BSA-LC/DOPE facilitated the capacity of endosomal escape, and rapidly released the loaded agents into the cytoplasm under acid conditions in lysosomes. CONCLUSION: BSA-LC/DOPE, as biocompatible, tumor-targeting and pH-sensitive lipoprotein-mimic nanocarrier, is a promising system for effective intracellular delivery of PTX to tumors with optimal anti-tumor efficacy.
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Objective To prepare titanium dioxide (TiO2 ) nanoparticles with good near-infrared light and study the loading and release of doxorubicin. Methods The Sm doped TiO2 nanoparticles (Sm-TiO2 ) were synthesized using a modified solvothermal reaction and then observed with transmission electron microscope. The fluorescence spectrum, doxorubicin loading capacity and release profile were also determined. Results The obtained Sm-TiO2 nanoparticles with the length from 100-200 nm were fusiform and well dispersed. The emission wavelength was 640-670 nm. The drug loading capacity in water was 11. 5% . DOX in vitro was pH sensitive to release. Conclusion Sm-TiO2 nanoparticles have good near-infrared light, high drug loading capacity and controllable drug release are obtained and should be studied further more as a novel carrier.
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OBJECTIVE: To prepare the new drug chitosan-ketoprofen (CTS-KPF), and evaluate its characteristics in vitro release. METHODS: The drug ketoprofen (KPF) molecules was grafted to the molecular chain the linear polymer chitosan (CTS) by homogeneous liquid phase method, preparing the new drug CTS-KPF. The fourier transform infrared spectrum (FT-IR) and the nuclear magnetic resonance spectroscopy (CP/MAS13 C-NMR, 1H-NMR) was used to characterize the structure CTS-KPF; the scanning electron microscopy (SEM) was used to observe the CTS-KPF apparent morphology; the X-ray diffraction (XRD) was used to study the change crystallinity CTS-KPF and the ultraviolet-visible spectrophotometry (UV-Vis) was used to analyze the drug release performance under different pH conditions and establish the model CTS-KPF releasing drug in vitro. RESULTS: The synthetic route is reasonable and the CTS-KPF new pH-sensitive drug was synthezed successfully. The FT-IR, CP/MAS13 C-NMR, 1H-NMR, SEM and XRD verified the chemical reaction mechanism and the molecular structure CTS-KPF. The CTS-KPF drug release performance in simulated body fluid indicates that the CTS-KPF has desired pH-sensitive and it tend to release in low pH simulated gastric fluid. CONCLUSION: CTS-KPF is a pH-sensitive polymer drug, the results can provide a reference for the research pH-sensitive polymer smart drugs based on CTS.
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OBJECTIVE:To prepare nifedipine sustained-release hydrogels and to study their drug release in vitro.METHODS:Nifedipine sustained-release hydrogels were prepared by complex coacervation.An orthogonal experiment was performed with chitosan,concentration of sodium alginate,mixing speed and the volume ratio of chitosan solution to sodium alginate solution as factors.Meanwhile,the dissolution rate of the prepared hydrogels was determined by basket-rotating method,and pH-sensitivity of the released drug in different pH medium was investigated.RESULTS:The optimal technical condition was as follows:the concentration of chitosan was 0.4% and that of sodium alginate was 1.5%;the mixing speed was 160 r?min-1;the volume ratio of chitosan solution to sodium alginate solution was 6:1.The dissolution rate of sustained-release hydrogels containing nifedipine was 13.43% in simulated gastric fluid(pH 1.5) at 4 hours,which stood at 52.30% at 4 hours and 81.72% at 12 hours in simulated intestinal fluid(pH 6.8).CONCLUSION:The sustained-release hydrogels of nifedipine showed remarkable sustained-release properties and strong pH sensibility in vitro.