The cytotoxicity of chemotherapeutic agents to healthy organs and drug resistance of tumor cells are believed to be the main obstacles to the successful cancer chemotherapy in the clinic. To ensure that anticancer drugs could be delivered to the tumor region, are quickly released from carriers in tumor cells and rapidly escape from endo/lysosomes, YPSMA-1-modified pH-sensitive polymeric micelles, which would be advantageous in recognizing the prostate specific membrane antigen (PSMA), were designed and fabricated for targeted delivery of paclitaxel to tumors based on the pH-sensitive diblock copolymer poly(2-ethyl-2-oxazoline)-poly(D,L-lactide) (PEOz-PLA) and YPSMA-1-PEOz-PLA for treating prostate cancer. HOOC-PEOz-PLA with a critical micelle concentration of 5.0 mg L(-1) was synthesized and characterized by (1)H NMR and gel permeation chromatography. The prepared YPSMA-1-modified micelles, about 30 nm in diameter, exhibited a rapid release behavior at endo/lysosome pH and a favorable ability of fast endo/lysosome escape as observed by confocal microscopy. More importantly, we evidenced for the first time that both endosome and lysosome escape existed for pH-sensitive micelles via real time tracing using confocal microscopy, and the real time endo/lysosome escape process was also presented. The YPSMA-1-modified micelles were very effective in enhancing the cytotoxicity of paclitaxel by increasing the cellular uptake in PSMA-positive 22Rv1 cells, which was verified the correlation with PSMA expression in tumor cells by flow cytometric analysis and confocal microscopy. Moreover, the active targeting and pH-sensitivity endowed YPSMA-1-modified micelles with a higher antitumor efficacy and negligible systemic toxicity in 22Rv1 xenograft-bearing nude mice compared with unmodified micelles and Taxol®. These results suggested that the application of combining YPSMA-1 modification with pH-sensitivity to polymeric micelles may be one approach in the efficient delivery of anticancer drugs for treating PSMA-positive prostate cancers.
Nanofluids in recent years have shown great potential as a chemical enhanced oil recovery (EOR) technology, thanks to their excellent performance in altering interfacial properties. However, because of the great challenge in preparing stable systems suitable for an elevated temperature and a high salinity environment, expanding the application of nanofluids has been greatly restrained. In this work, a novel nanofluid was prepared by integrating positively charged amino-terminated silica nanoparticles (SiNP-NH 2 ) with negatively charged anionic surfactant (Soloterra 964) via electrostatic force. The resulted nanofluid could be stored at relatively high salinity (15 wt % NaCl solution) and high temperature (65 °C) for more than 30 days without aggregation. Successful coating of the surfactant on target SiNPs was verified by Fourier transform infrared spectrometry and the surface charge and size distribution. In addition, the potential of the nanofluid in recovering oil was investigated by analyzing the nanofluid/Bakken oil interfacial tension and the variation trend of the oil contact angle when brine was replaced by nanofluids. Experimental results showed that the water−oil interfacial tension of the Bakken crude oil decreased by 99.85% and the contact angle increased by 237.8% compared to the original value of 13.78 mN/m and 43.4°, respectively, indicating strong oil displacement efficiency and obvious wetting transition from oil-wet toward water-wet. Spontaneous imbibition tests conducted on Berea rocks showed that the nanofluid yielded a high oil recovery rate of 46.61%, compared to that of 11.30, 16.58, and 22.89% for brine, pure SiNP-NH 2 , and pure surfactant (Soloterra 964), respectively. In addition, when core flooding was applied, a total of 60.88% of the original oil in place could be recovered and an additional oil recovery of 17.23% was achieved in the chemical flooding stage. Moreover, a possible mechanism of the EOR using the nanofluid was proposed. Overall, the developed nanofluid is a promising new material for EOR.
Most anticancer drugs are poorly soluble and nonspecific, which restricts their clinical application. Drug conjugates, as a prodrug strategy, provide the possibility to overcome these shortcomings, especially combined with nanotechnology. Drug conjugate nanoparticles possess the advantages of high drug loading capacity and passive tumor targeting ability. Here, we prepared doxorubicin drug-drug conjugate nanoparticles (DOX-SS-DOX NPs) based on disulfide-linked doxorubicin drug-drug conjugate (DOX-SS-DOX). Dynamic light scattering (DLS) and transmission electron microscope (TEM) characterization indicated that DOX-SS-DOX NPs were spherical with a uniform size distribution around 89 nm. DLS and in vitro release experiment revealed that DOX-SS-DOX NPs possessed reduction responsive activity. In vitro cellular uptake studies reflected that DOX-SS-DOX NPs could increase the uptake level substantially compared with DOX liposomes. Endocytosis mechanism assay demonstrated that DOX-SS-DOX NPs internalized into cells through a clathrin-mediated endocytosis pathway in an energy-dependent manner. In this manner, the amidase in lysosomes could break the amide bond to release free DOX, which would be helpful to antitumor activity. The in vitro cytotoxicity of DOX-SS-DOX NPs was a bit weaker than that of DOX liposomes, which might be the result of the slow cleavage of the disulfide bridge; but the antitumor efficacy of DOX-SS-DOX NPs evaluated in MCF-7 bearing mice was demonstrated to be higher than that of DOX liposomes. This might be because of the long lasting effect resulting from the slow cleavage of the disulfide bond. In summary, DOX-SS-DOX NPs, prepared nearly totally with drug, provide a good strategy for cancer therapy.
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