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Objective To investigate the efficacy of bio-targeted drug loaded nanoparticles for the diagnosis and treatment of breast cancer based on tumor hypoxia microenvironment. Methods Lipid nanoparticles loaded with perfluorohexane (PFH) and tirazamine (TPZ) were prepared by film hydration. Bifidobacteria were cultured and detected for basic characterizations. Then, the bacteria and nanoparticles were connected by electrostatic adsorption to prepare bio-targeted drug-loaded nanoparticles, and laser confocal microscopy and flow cytometry were used to detect the binding between them. Ultrasonic diagnostic imaging, MTT assay and flow cytometry were adopted to observe the in vitro imaging performance and killing effect on breast cancer cells after high-intensity focused ultrasound (HIFU) irradiation. Tissue homogenate was used to observe the targeting ability of bifidobacteria. In vivo fluorescence imaging was performed to monitor the targeting of nanoparticles. The 4T1 breast tumor-bearing mice were established and randomly divided into targeted group (n=3) and non-targeted group (n=3) to observe the ultrasound imaging performance of nanoparticles. The tumor-bearing mice were randomly divided into blank control group, PBS+HIFU group, nonoparticles+HIFU group, and nonoparticles+ bifidobacterium+HIFU group (n=3 for each group). The body weight and tumor volume were recorded during treatment process, HE staining was performed 14 d later to observe the morphological changes of the tumor mass. Results Bio-targeted drug loaded nanoparticles were successfully prepared. The nanoparticles had an average size of 218.93±6.56 nm and a zeta potential of 55.00±4.97 mV, and the bifidobacterium had a potential of -28.10±7.52 mV. The connection rate of the nanoparticles and bacterium was (99.04±0.40)%. The nanoparticles showed better ultrasound imaging after HIFU irradiation. The results of MTT assay and flow cytometry showed that the nanoparticles exerted better killing effect on breast cancer cells under hypoxic condition than under normoxia condition (P < 0.05). The results of tissue homogenate demonstrated that bifidobacteria showed good target ability. In vivo fluorescence imaging displayed that the nanoparticles were enriched around the tumor. In vivo ultrasound imaging was achieved in the targeted group after HIFU irradiation. Both the records of tumor volume and results of HE staining indicated that the nonoparticles+bifidobacterium+HIFU group got the best tumor inhibitory effect (P < 0.05). Conclusion The bio-targeted drug loaded nanoparticles can effectively diagnose and treat breast cancer based on hypoxia microenvironment. Our study provides a new thought for the integration of tumor diagnosis and treatment.

The Bozhong Sag is the biggest hydrocarbon rich sag in the Bohai Sea area. However, hydrocarbon resource potential and its distribution are not clear, which restricts petroleum exploration. According to the material balance principle and the hydrocarbon accumulation threshold theory, the resource potential and distribution characteristics of hydrocarbons were evaluated quantitatively with hydrocarbon accumulation systems as evaluation units. The upper and lower plays in the Bozhong Sag and surrounding areas each can be divided into six hydrocarbon accumulation systems. The total afforded accumulation hydrocarbon quantity in the Bozhong Sag and surrounding areas is 60.265×108 t of oil (43.185×108 t in the upper play, 17.080×108 t in the lower play) and 27.03×1011 m3 of gas (17.76×1011 m3 in the upper play and 9.27×1011 m3 in the lower play). The Shijiutuo (I) and Bodong (II) accumulation systems are the further exploration areas with the greatest afforded accumulation hydrocarbon quantity. Key words: Bozhong Sag, hydrocarbon accumulation system, hydrocarbon accumulation threshold, hydrocarbon accumulation quantity, resource evaluation

Objective: To investigate the effects of Bifidobacterium on the acoustic characteristics of tumor tissue and how such acoustic changes affect the efficacy of high-intensity focused ultrasound (HIFU) ablation in nude mice., Methods: Forty mice bearing human breast cancer cell (MDA-MB-231) xenograft were randomized into experimental group ( n =20) and control group ( n =20) for intravenous injection of Bifidobacterium suspension (200 μL, 4 × 10 8 cfu/mL) and PBS (200 μL) for 3 consecutive days, respectively. Before and at 3 and 7 days after the first injection, shear wave elastography was used to evaluate the hardness of the tumor tissue. On day 7 after the first injection, 10 mice from each group were sacrificed and the sound velocity and sound attenuation of the tumor tissues were measured. The changes in the collagen fibers in the tumors were evaluated using Masson staining, and neovascularization in the tumor was assessed with immunohistochemistry for platelet endothelial cell adhesion molecule-1 (PECAM-1/CD31). The remaining 10 tumor-bearing mice in each group were subjected to HIFU ablation, and the ablation efficiency was evaluated by assessing the changes in irradiation gray values, coagulative necrosis volume, energy efficiency factor (EEF) and irradiation area and by pathological examination with HE staining., Results: In the experimental group, the collagen fibers in the tumor tissues were strong and densely aligned, and the tumors contained fewer new blood vessels showing strip-or spot-like morphologies. In the control group, the collagen fibers in the tumors were thin and loosely arranged, and the tumors showed abundant elongated or round new blood vessels. Bifidobacterium colonized in the tumor 7 days after the injection, and the tumor hardness was significantly greater in the experimental group than in the control group ( P =0.01); the acoustic velocity ( P =0.001) and the acoustic attenuation ( P =0.000) of the tumor tissues were also greater in the experimental group. HIFU irradiation resulted in significantly greater changes in the gray scale of tumor ( P =0.0006) and larger coagulative necrosis volume ( P =0.0045) in the experimental group than in the control group, and the EEF was significantly smaller in the experimental group ( P =0.0134)., Conclusions: Bifidobacterium can cause changes in collagen fiber content, acoustic velocity and attenuation in the tumor tissue and reduce the EEF of HIFU irradiation, thereby improving the efficacy of HIFU irradiation.