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1.

Purpose

In this study, the contrasting properties of human serum albumin nanoparticles (HSA-NPs) loaded with gadolinium-diethylenetriamine pentaacetic acid (Gd-DTPA) and coated with transferrin in MRI in mice are evaluated.

Procedures

HSA-NPs were conjugated with Gd-DTPA (Gd-HSA-NPs) and coupled with transferrin (Gd-HSA-NP-Tf). Mice underwent MRI before or after injection of Gd-DTPA, Gd-HSA-NP, or Gd-HSA-NP-Tf.

Results

All the studied contrast agents provided a contrast enhancement (CE) in the blood, heart muscle, and liver. Compared to Gd-DTPA, CE with HSA-NP was achieved at lower Gd doses. Gd-HSA-NP-Tf yielded significantly higher CE than Gd-HSA-NP in the skeletal muscle, blood, cardiac muscle, and liver (p?<?0.05). Gd-HSA-NP-Tf achieved a significantly higher CE than Gd-HSA-NP and Gd-DTPA in the blood, cardiac muscle, and liver (p?<?0.05). In the brain, only Gd-HSA-NP-Tf was found to cause a significant CE (p?<?0.05).

Conclusions

The Gd-HSA nanoparticles have potential as MRI contrast agents. In particular, Gd-HSA-NP-Tf has a potential as a specific contrast agent for the brain, while the blood–brain barrier is still intact, as well as in the heart, liver, and skeletal muscle.  相似文献   
2.
The cytotoxicity of doxorubicin bound to poly(butyl cyanoacrylate) nanoparticles (Dox-PBCA-NP) was investigated in the rat glioma cell lines GS-9L, F-98 and RG-2. MTT and LDH assays were used as cytotoxic assays. In general, the cytotoxicity of nanoparticle-bound doxorubicin (Dox) was enhanced compared to the free drug in solution. However, responses of the cell lines towards the drug effects were different. In the case of free Dox in solution, this difference correlated with different intracellular concentrations of Dox, which in turn, depended on the level of P-glycoprotein (P-gp) expression in these cell lines. Accordingly, the 9L gliosarcoma (GS-9L) cells, which appeared to be most resistant towards Dox, were characterized by the highest P-gp expression.

Additionally, the influence of surfactants on the cytotoxic effect was investigated at different Dox concentrations. It was shown that the presence of polysorbate 80 (Tween® 80) in the nanoparticle formulation significantly enhanced the cytotoxicity, whereas poloxamer 188 (Pluronic® F68) and poloxamine 908 (Tetronic® 908) had a negligible influence.  相似文献   
3.
A comparative toxicological study of doxorubicin bound to poly(butyl cyanoacrylate) nanoparticles coated with polysorbate 80 was performed in male and female Wistar rats. The drug substance was used as a reference formulation. The formulations were injected intravenously at a therapeutic dose of 6 mg/kg administered either as a single injection or in form of four weekly injections. The animals were followed up for 4 and 40 days (single injection) or 25 and 61 days (multiple injections) for assessment of the dynamics of body weight, hematological parameters, blood biochemical parameters, and urinalysis. Pathomorphological evaluation included macroscopic evaluation and weight measurement of the internal organs. The heart, lung, spleen, testes, and liver were also subjected to the histological evaluation. The overall result of this study suggests that the surfactant-coated nanoparticle formulation of doxorubicin has a favorable toxicological profile. Specifically, this formulation displays a considerably reduced cardio- and testicular toxicity, as compared to a free drug.  相似文献   
4.
The cytotoxicity of doxorubicin bound to poly(butyl cyanoacrylate) nanoparticles (Dox-PBCA-NP) was investigated in the rat glioma cell lines GS-9L, F-98 and RG-2. MTT and LDH assays were used as cytotoxic assays. In general, the cytotoxicity of nanoparticle-bound doxorubicin (Dox) was enhanced compared to the free drug in solution. However, responses of the cell lines towards the drug effects were different. In the case of free Dox in solution, this difference correlated with different intracellular concentrations of Dox, which in turn, depended on the level of P-glycoprotein (P-gp) expression in these cell lines. Accordingly, the 9L gliosarcoma (GS-9L) cells, which appeared to be most resistant towards Dox, were characterized by the highest P-gp expression.Additionally, the influence of surfactants on the cytotoxic effect was investigated at different Dox concentrations. It was shown that the presence of polysorbate 80 (Tween 80) in the nanoparticle formulation significantly enhanced the cytotoxicity, whereas poloxamer 188 (Pluronic F68) and poloxamine 908 (Tetronic 908) had a negligible influence.  相似文献   
5.
It was recently shown that doxorubicin (DOX) bound to polysorbate-coated nanoparticles (NP) crossed the intact blood-brain barrier (BBB), and thus reached therapeutic concentrations in the brain. Here, we investigated the biodistribution in the brain and in the body of poly(butyl-2-cyano[3-(14)C]acrylate) NP ([(14)C]-PBCA NP), polysorbate 80 (PS 80)-coated [(14)C]-PBCA NP, DOX-loaded [(14)C]-PBCA NP in glioblastoma 101/8-bearing rats after i.v. injection. The biodistribution profiles and brain concentrations of radiolabeled NP were determined by radioactivity counting after i.v. administration in rats. Changes in BBB permeability after tumour inoculation were assessed by i.v. injection of Evans Blue solution. The accumulation of NP in the tumour site and in the contralateral hemisphere in glioblastoma bearing-rats probably was augmented by the enhanced permeability and retention effect (EPR effect) that may have been becoming instrumental due to the impaired BBB on the NP delivery into the brain.The uptake of the NP by the organs of the reticuloendothelial system (RES) was reduced after PS 80-coating, but the addition of DOX increased again the concentration of NP in the RES.  相似文献   
6.
Purpose. It has recently been suggested that the poly(butylcyanoacrylate) (PBCA) nanoparticle drug delivery system has a generalized toxic effect on the blood-brain barrier (BBB) (8) and that this effect forms the basis of an apparent enhanced drug delivery to the brain. The purpose of this study is to explore more fully the mechanism by which PBCA nanoparticles can deliver drugs to the brain. Methods. Both in vivo and in vitro methods have been applied to examine the possible toxic effects of PBCA nanoparticles and polysorbate-80 on cerebral endothelial cells. Human, bovine, and rat models have been used in this study. Results. In bovine primary cerebral endothelial cells, nontoxic levels of PBCA particles and polysorbate-80 did not increase paracellular transport of sucrose and inulin in the monolayers. Electron microscopic studies confirm cell viability. In vivo studies using the antinociceptive opioid peptide dalargin showed that both empty PBCA nanoparticles and polysorbate-80 did not allow dalargin to enter the brain in quantities sufficient to cause antinociception. Only dalargin preadsorbed to PBCA nanoparticles was able to induce an antinociceptive effect in the animals. Conclusion. At concentrations of PBCA nanoparticles and polysorbate-80 that achieve significant drug delivery to the brain, there is little in vivo or in vitro evidence to suggest that a generalized toxic effect on the BBB is the primary mechanism for drug delivery to the brain. The fact that dalargin has to be preadsorbed onto nanoparticles before it is effective in inducing antinociception suggests specific mechanisms of delivery to the CNS rather than a simple disruption of the BBB allowing a diffusional drug entry.  相似文献   
7.
Glioblastomas belong to the most aggressive human cancers with short survival times. Due to the blood-brain barrier, they are mostly inaccessible to traditional chemotherapy. We have recently shown that doxorubicin bound to polysorbate-coated nanoparticles crossed the intact blood-brain barrier, thus reaching therapeutic concentrations in the brain. Here, we investigated the therapeutic potential of this formulation of doxorubicin in vivo using an animal model created by implantation of 101/8 glioblastoma tumor in rat brains. Groups of 5-8 glioblastoma-bearing rats (total n = 151) were subjected to 3 cycles of 1.5-2.5 mg/kg body weight of doxorubicin in different formulations, including doxorubicin bound to polysorbate-coated nanoparticles. The animals were analyzed for survival (% median increase of survival time, Kaplan-Meier). Preliminary histology including immunocytochemistry (glial fibrillary acidic protein, ezrin, proliferation and apoptosis) was also performed. Rats treated with doxorubicin bound to polysorbate-coated nanoparticles had significantly higher survival times compared with all other groups. Over 20% of the animals in this group showed a long-term remission. Preliminary histology confirmed lower tumor sizes and lower values for proliferation and apoptosis in this group. All groups of animals treated with polysorbate-containing formulations also had a slight inflammatory reaction to the tumor. There was no indication of neurotoxicity. Additionally, binding to nanoparticles may reduce the systemic toxicity of doxorubicin. This study showed that therapy with doxorubicin bound to nanoparticles offers a therapeutic potential for the treatment of human glioblastoma.  相似文献   
8.
Apolipoprotein E3, A-I as well as B-100 were covalently attached to human serum albumin nanoparticles via the NHS-PEG-Mal 3400 linker. Loperamide as a model drug was bound to these nanoparticles, and the antinociceptive reaction of these preparations was recorded after intravenous injection in mice by the tail-flick test. After 15 min, all three nanoparticle preparations with the coupled apolipoproteins E3, A-I, and B-100 yielded considerable antinociceptive effects, which lasted over 1 h. The maximally possible effects [MPE] of these preparations amounted to 95%, 65%, and 50%, respectively, and were statistically different from the controls (p<0.02), whereas the loperamide solution achieved no effect. This result demonstrates that more than one mechanism is involved in the interaction of nanoparticles with the brain endothelial cells and the resulting delivery of drugs to the central nervous system.  相似文献   
9.
Poly(butyl cyanoacrylate) nanoparticles coated with poloxamer 188 (Pluronic) F68) and also, as shown previously, polysorbate 80 (Tween 80) considerably enhance the anti-tumour effect of doxorubicin against an intracranial glioblastoma in rats. The investigation of plasma protein adsorption on the surface of the drug-loaded nanoparticles by two-dimensional electrophoresis (2-D PAGE) revealed that both surfactants, besides other plasma components, induced a considerable adsorption of apolipoprotein A-I (ApoA-I). It is hypothesized that delivery of doxorubicin to the brain by means of nanoparticles may be augmented by the interaction of apolipoprotein A-I that is anchored on the surface of the nanoparticles with the scavenger receptor class B type I (SR-BI) located at the blood-brain barrier. This is the first study that shows a correlation between the adsorption of apolipoprotein A-I on the nanoparticle surface and the delivery of the drug across the blood-brain barrier.  相似文献   
10.
A toxicological study of doxorubicin bound to poly(butyl cyanoacrylate) or human serum albumin nanoparticles coated with polysorbate 80 was performed in healthy rats. The doxorubicin formulations were injected at a therapeutic dose regimen (3 x 1.5 mg/kg with a 72 h interval), and the animals were followed up for 15 or 30 days. The overall result of this study suggests that the surfactant-coated nanoparticle formulations of doxorubicin have favorable toxicological profiles. Specifically, these formulations display a considerably reduced cardio- and testicular toxicity, as compared to a free drug.  相似文献   
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