以天津医科大学药学院本科毕业论文(设计)为例,基于2018—2021年学院本科毕业论文(设计)的整体状况,探究学院本科毕业论文(设计)开展过程中发现的问题,提出了提高学院本科毕业论文(设计)质量的方案,为本校"双一流"专业建设提供助力.

Background Breast cancer is a common malignancy in women. Conventional clinical therapies for breast cancer all display moderate clinical efficacies and limitations. It is urgent to explore the novel and combined therapeutic strategies for breast cancer to meet clinical demand. Methods An iRGD tumor-penetrating peptide-modified nano-delivery system (denoted as iRGD-PSS@PBAE@JQ1/ORI nanoparticles) based on a marine sulfated polysaccharide was developed by codelivery of JQ1 (BET inhibitor) and oridonin (ORI, bioactive diterpenoid derived from traditional Chinese medicine herb). The iRGD-PSS@PBAE@JQ1/ORI NPs, surface modified with iRGD peptide conjugated propylene glycol alginate sodium sulfate (iRGD-PSS). The antitumor efficacy was evaluated both in vitro and in vivo. Results The prepared iRGD-PSS@PBAE@JQ1/ORI NPs effectively enhanced the tumor targeting and cellular internalization of JQ1 and ORI. Thus, JQ1 exerted the reversal effect on immune tolerance by decreasing the expression of PD-L1, while ORI displayed multiple antitumor effects, such as antiproliferation, inhibition of intracellular ROS production and inhibition of lactic acid secretion. Conclusion Our data revealed that iRGD peptide could significantly improve the cellular internalization and tumor penetration of the nano-delivery system. The combination of JQ1 and ORI could exert synergistic antitumor activities. Taken together, this study provides a multifunctional nanotherapeutic system to enhance the anti-tumor efficiency against breast cancer.

ABSTRACT Bone loss induced by mechanical unloading is a common skeletal disease, but the precise mechanism remains unclear. The current study investigated the role of histone methylation, a key epigenetic marker, and its cross-talk with DNA methylation in bone loss induced by mechanical unloading. The expression of G9a, ubiquitin-like with PHD and ring finger domains 1 (UHRF1), and DNA methylation transferase 1 (DNMT1) were increased in hind limb unloading (HLU) rats. This was accompanied by an increased level of histone H3 lysine 9 (H3K9) di-/tri-methylation at lncH19 promoter. Then, alteration of G9a, DNMT1, or UHRF1 expression significantly affected lncH19 level and osteogenic activity in UMR106 cells. Osteogenic gene expression and matrix mineralization were robustly promoted after simultaneous knockdown of G9a, DNMT1, and UHRF1. Furthermore, physical interactions of lncH19 promoter with G9a and DNMT1, as well as direct interactions among DNMT1, G9a, and UHRF1 were detected. Importantly, overexpression of DNMT1, G9a, or UHRF1, respectively, resulted in enrichment of H3K9me2/me3 and 5-methylcytosine at lncH19 promoter. Finally, in vivo rescue experiments indicated that knockdown of DNMT1, G9a, or UHRF1 significantly relieved bone loss in HLU rats. In conclusion, our research demonstrated the critical role of H3K9 methylation and its cross-talk with DNA methylation in regulating lncH19 expression and bone loss in HLU rats. Combined targeting of DNMT1, G9a, and UHRF1 could be a promising strategy for the treatment of bone loss induced by mechanical unloading. © 2021 American Society for Bone and Mineral Research (ASBMR).

Breast cancer is the most common malignant tumor in women. Phototherapy, mainly including photothermal therapy (PTT) and photodynamic therapy (PDT), shows many advantages such as high spatial selectivity, noninvasive nature, and negligible drug resistance for breast cancer treatment. Additionally, recent investigations have shown that nucleus-targeted PTT can kill cancer cells more directly and more efficiently by "burning" cell nuclei closely. In this study, we developed a nucleus-targeting nanoparticle system for combining PTT/PDT and chemotherapy to treat breast cancer. IR780, a near-infrared (NIR) fluorescence dye that has potent anticancer efficacy of PTT and PDT, was firstly conjugated with TAT peptide through substitution reaction between chlorine atom and sulfhydryl group, thus obtained a conjugate TAT-IR780 with notably enhanced water solubility and optical stability. Next, chemotherapeutic drug doxorubicin (DOX) and TAT-IR780 self-assembled in aqueous medium to form TID nanoparticles with a small size of approximately 100 nm. Both in vitro and in vivo, TID nanoparticles showed greatly enhanced PTT/PDT efficiencies as compared with free IR780. Through the mediation of TAT peptide, TID nanoparticles significantly improved the cellular internalization of IR780 in breast cancer cells and delivered it mostly to the perinuclear region. Upon laser irradiation at 785 nm, TID nanoparticles rapidly destroyed the genetic substances and potently induced the apoptosis of breast cancer cells. In the mice bearing breast cancer, intratumoral injection of TID nanoparticles with local laser irradiation realized fluorescence and photothermal imaging-guided combination treatment of nucleus-targeted PTT/PDT and chemotherapy, and achieved significant synergistic effects on breast tumor ablation and recurrence. In summary, this study provides a nucleus-targeting nanoplatform for dual imaging-guided photo-chemotherapy for breast cancer treatment.

Metastasis and chemotherapy resistance are the leading causes of breast cancer mortality. Celecoxib (CXB), a selective cyclooxygenase-2 (COX-2) inhibitor, has antiangiogenetic activity and inhibitory effect on tumor metastasis, and can also enhance the sensitivity of chemotherapeutic drug doxorubicin (DOX) in breast cancer. To combine anticancer effects of DOX and CXB more efficiently, we designed a pH-sensitive nanotherapeutic system based on propylene glycol alginate sodium sulfate (PSS), a marine sulfated polysaccharide that possesses anti-platelet aggregation activity and has been used as a heparinoid drug in China. A facile one-pot nanoprecipitation method was used to prepare this nanotherapeutic system named as PDC nanoparticles, in which DOX and CXB were complexed to form hydrophobic nanocores and PPS coated these nanocores through conjugation with DOX via a highly acid-labile benzoic-imine linker. PDC nanoparticles showed distinct pH-sensitivity and significantly accelerated the release of DOX at the acidic pH mimicking the tumor microenvironment and endocytic-related organelles. Compared to single- and mixed-drug treatments, PDC nanoparticles notably inhibited the growth of mouse breast cancer 4T1 cells and reduced cell migration, invasion and adhesion abilities. In 4T1 tumor-bearing mice, PDC nanoparticles exhibited good tumor-targeting ability and markedly suppressed the tumor growth and metastasis. In summary, this nanotherapeutic system shows a great potential for clinical treatment of metastatic breast cancer by combining chemotherapy and COX-2 inhibitor.

Reactive oxygen species (ROS)-responsive nanoparticles based on a thioketal-containing poly(β-amino ester) show great potential for cancer photodynamic therapy.

Objective To prepare a red blood cells based multifunctional nanoscaled drug delivery system,and to study its in vitro photothermal and photodynamic effects.Methods The indocyanine green (ICG)/doxorubicin (DOX) co-loaded nanoscaled red blood cells (DIRAs) were prepared using an extrusion method.The morphology,particle size,encapsulation efficiency,and stability were determined.The heating related change of particle size was studied using a size and potential tester.The in vitro photothermal effect was studied using an infrared imaging device.The uptake of DIRAs to 4T1 cells was studied using a CLSM examination.The in vitro photodynamic effect was studied using a fluorescence probe and CLSM examination.Results DIRAs were successfully prepared with a uniform and homogeneous size which was about (97.0±20.1) nm.The Zeta potential was about-21.6 mV and the encapsulation efficiency of ICG and DOX were 93.5％ and 95.2％,respectively.The DIRAs had excellent stability within 28 days.This nanoscaled drug delivery system had identical photothermal effect compared to free ICG.The cellular uptake of DOX was significantly improved after the laser irradiation and the photodynamic effect was enhanced.Conclusions The prepared DIRAs have regular shape,suitable particle size,high encapsulation efficiency and high photothermal conversion efficiency.DIRAs can improve the cellular uptake of DOX and enhance the photodynamic efficiency.This biomimetic muhifunctional nano-system could facilitate breast cancer treatment by combining PTT7PDT and chemotherapy.

HN-1, a 12-amino acid peptide, has been reported to possess strong capabilities for targeting and penetrating head and neck squamous cell carcinoma. Here, we designed a simple but effective nanoparticle system for the delivery of doxorubicin (DOX) targeting oral squamous cell carcinoma (OSCC) through the mediation of HN-1. PEGylated DOX (PD) was firstly synthesized by the conjugation of DOX with bis-amino-terminated poly(ethylene glycol) via succinyl linkage, and then PD nanoparticles were prepared by a modified nanoprecipitation method. After that, PD nanoparticles were surface-modified with HN-1 to form HNPD nanoparticles, which had a uniform spherical shape and a small size about 150nm. In human OSCC cells (CAL-27 and SCC-25), HNPD nanoparticles exhibited significantly higher cellular uptakes and cytotoxicities than PD nanoparticles. Furthermore, HNPD nanoparticles showed a certain degree of functional selectivity for CAL-27 and SCC-25 cells as compared to human hepatoma HepG2 cells. In SCC-25 tumor-bearing nude mice, HNPD nanoparticles showed remarkably enhanced tumor-targeting and penetrating efficiencies as compared to PD nanoparticles, and effectively inhibited the tumor growth. In conclusion, our study demonstrated for the first time that HN-1 could be used for mediating the OSCC-targeted delivery of nanoparticles.

目的:建立米拉贝隆原料药中有关物质的高效液相色谱测定方法.方法:采用YMC-Pack ODS-A 色谱柱(250 mm×4.6 mm,5 μm),流动相为缓冲溶液(己烷磺酸钠一水合物5.65 g与磷酸二氢钠2.75 g,加水1 000 ml使溶解,磷酸调节pH值至2.3)-乙腈,梯度洗脱,体积流量为 0.8 ml/min,柱温为 30 ℃,检测波长为 280 nm,进样量:10 μl.结果:在所选定的液相色谱条件下,有关物质与主药分离良好.米拉贝隆、杂质A、杂质 B、杂质C和杂质D 的检出限分别为8.5、4.5、5.4、6.6和10.0 ng.结论:该方法操作简单,重复性好,专属性强,可用于控制米拉贝隆原料药中的有关物质.

IR780, a near-infrared dye, can also be used as a photosensitizer both for photothermal therapy (PTT) and photodynamic therapy (PDT). In this study, we designed a simple but effective nanoparticle system for carrying IR780 and paclitaxel, thus hoping to combine PTT/PDT and chemotherapy to treat hepatocellular carcinoma (HCC). This nanosystem, named PDF nanoparticles, consisted of phospholipid/Pluronic F68 complex nanocores and pullulan shells. IR780 and paclitaxel were loaded separately into PDF nanoparticles to form PDFI and PDFP nanoparticles, which had regular sphere shapes and relatively small sizes. Upon near-infrared laser irradiation at 808 nm, PDFI nanoparticles showed strong PTT/PDT efficacy both in vitro and in vivo. In MHCC-97H cells, the combined treatment of PDFI nanoparticles/laser irradiation and PDFP nanoparticles exhibited significant synergistic effects on inhibiting cell proliferation and inducing cell apoptosis and cell cycle arrest at G2/M phase. In MHCC-97H tumor-bearing mice, PDFI nanoparticles exhibited excellent HCC-targeting and accumulating capability after intravenous injection. Furthermore, the combined treatment of PDFI nanoparticles/laser irradiation and PDFP nanoparticles also effectively inhibited the tumor growth and the tumor angiogenesis in MHCC-97H tumor-bearing mice. In summary, we put forward a therapeutic strategy for HCC treatment by combining PTT/PDT and chemotherapy.

以羧甲基-β-CD(CM-β-CD)为手性添加剂,用毛细管区带电泳法对氢化安息香和联萘酚磷酸酯的消旋体进行了拆分研究.实验考察了CM-β-CD的浓度、背景电解质的pH值、分离电压对对映体分离的影响.结果表明,以100 mmol/L Tris-磷酸为缓冲液,CM-β-CD的浓度在5-30 mg/mL,pH值7.5-10.0之间,电压在10-30 kV之间,温度在25℃时,氢化安息香和联萘酚磷酸酯均能获得基线分离.该方法简便、快速、分离范围宽,可用于氢化安息香和联萘酚磷酸酯的手性分离.

Red blood cells (RBCs)-based vesicles have been widely used for drug delivery due to their unique advantages. Intact RBCs contain a large amount of oxyhemoglobin (oxyHb), which can assist with photodynamic therapy (PDT). Indocyanine green (ICG), a photosensitizer both for photothermal therapy (PTT) and PDT, shows potent anticancer efficacy when combined with chemotherapeutic drug doxorubicin (DOX). In this study, we prepared nanoscaled RBCs (RAs) containing oxyHb and gas-generating agent ammonium bicarbonate (ABC) for co-loading and controlled release of ICG and DOX, thus hoping to achieve synergistic effects of PTT/PDT and chemotherapy against breast cancer. Compared to free ICG, ICG and DOX co-loaded RAs (DIRAs) exhibited nearly identical PTT efficiency both in vitro and in vivo, but meanwhile their PDT efficiency was enhanced significantly. In mouse breast cancer cells, DIRAs significantly inhibited cell growth and induced cell apoptosis after laser irradiation. In breast tumor-bearing mice, intratumoral injection of DIRAs and followed by local laser irradiation almost completely ablated breast tumor and further suppressed tumor recurrence and metastasis. In conclusion, this biomimetic multifunctional nanosystem can facilitate breast cancer treatment by combining PTT/PDT and chemotherapy.

In the present study, a dual pH-responsive multifunctional nanoparticle system was designed for combining immunotherapy and chemotherapy to treat breast cancer through targeting immune cells and cancer cells. A proven anti-tumor immune regulator, R848, was encapsulated with poly(L-histidine) (PHIS) to form PHIS/R848 nanocores. Doxorubicin (DOX) was conjugated to hyaluronic acid (HA) through an acid-cleavable hydrazone bond linkage to synthesize polymeric prodrug HA-DOX, which was subsequently coated outside PHIS/R848 nanocores to form HA-DOX/PHIS/R848 nanoparticles. Ionization of PHIS around pH 6.5 (a pH value close to that of tumor microenvironment) switched the nature of this material from hydrophobic to hydrophilic, and thus triggered the release of R848 to exert immunoregulatory action. The rupture of hydrazone bond in HA-DOX at about pH 5.5 (pH of endo/lysosomes) accelerated the release of DOX to exert cytotoxic effects. In immune cells, PHIS/R848 nanocores exhibited strong immunoregulatory activities similar to those induced by free R848. In breast cancer cells overexpressing CD44, HA-DOX was specially internalized by CD44-mediated endocytosis and significantly inhibited the cell growth. In 4T1 tumor-bearing mice, HA-DOX/PHIS/R848 nanoparticles showed excellent tumor-targeting ability and remarkably inhibited the tumor growth by regulating tumor immunity and killing tumor cells. In summary, this multifunctional nanoparticle system could deliver R848 and DOX respectively to tumor microenvironment and breast cancer cells to achieve synergistic effects of immunotherapy and chemotherapy against breast cancer. Statement of Significance Combination of immunotherapy and chemotherapy is becoming a promising new treatment for cancer. The major challenge is to target cancer and immune cells simultaneously and specifically. In this study, a dual pH-responsive multifunctional nanoparticle system based on poly(L-histidine) and hyaluronic acid was designed for co-loading R848 (immune-regulator) and doxorubicin (chemotherapeutic drug) through different encapsulation modes. By responding to the acidic pHs of tumor microenvironment and intracellular organelles, this multifunctional nanoparticle system could release R848 extracellularly and deliver DOX targetedly to breast cancer cells, thus achieving synergistic effects of immunotherapy and chemotherapy against breast cancer. (C) 2017 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

Sonodynamic therapy (SDT) is an emerging approach that involves a combination of low-intensity ultrasound and specialized chemical agents known as sonosensitizers. Ultrasound can penetrate deeply into tissues and can be focused into a small region of a tumor to activate a sonosensitizer which offers the possibility of non-invasively eradicating solid tumors in a site-directed manner. In this article, we critically reviewed the currently accepted mechanisms of sonodynamic action and summarized the classification of sonosensitizers. At the same time, the breath of evidence from SDT-based studies suggests that SDT is promising for cancer treatment.

建立了大鼠血浆中胡椒碱浓度的UPLC测定法,并研究了不同给药介质对胡椒碱在大鼠体内的药动学特征的影响.大鼠灌胃给予不同给药介质的胡椒碱后,其药动学特征有明显区别,CMC-Na的浓度为0.3％时,胡椒碱达峰较慢,生物利用度较低;而CMC-Na的浓度为1％、3％时,胡椒碱的生物利用度较高,且相差不大,但Tmax和MRT相差较大,以植物油为给药介质灌胃给药后,胡椒碱在大鼠体内吸收缓慢,呈缓释效果,绝对生物利用度较低.因此在进行胡椒碱对其他药物增效作用的体内研究时,应选择适当的给药介质及给药时间.

HPDF nanomicells reversed drug resistance of MCF-7/ADR cells by combining sonodynamic therapy and chemotherapy.

As one of the main active ingredients from Radix Astragali (RA), orally dosed astragaloside IV (AST) is easily transformed to sapogenin-cycloastragenol (CAG) by deglycosylation in the gastrointestinal tract. Because the potential adverse effects of AST and CAG remain unclear, the present study in this article was carried out to investigate the inhibition effects of AST and CAG on UDP-glucuronosyltransferases (UGTs) to explore potential clinical toxicity. An in vitro UGTs incubation mixture was employed to study the inhibition of AST and CAG towards UGT isoforms. Concentrations of 100 μM for each compound were used to initially screen the inhibitory efficiency. Deglycosylation of AST to CAG could strongly increase the inhibitory effects towards almost all of the tested UGT isoforms, with an IC50 of 0.84 μM and 11.28 μM for UGT1A8 and UGT2B7, respectively. Ulteriorly, the inhibition type and kinetics of CAG towards UGT1A8 and UGT2B7 were evaluated depending on the initial screening results. Data fitting using Dixon and Lineweaver–Burk plots demonstrated that CAG competitively inhibited UGT1A8 and noncompetitively inhibited UGT2B7. From the second plot drawn with the slopes from the Lineweaver–Burk plot versus the concentrations of CAG, the inhibition constant (Ki) was calculated to be 0.034 μM and 20.98 μM for the inhibition of UGT1A8 and UGT2B7, respectively. Based on the [I]/Ki standard ([I]/Ki < 0.1, low possibility; 1 > [I]/Ki > 0.1, medium possibility; [I]/Ki > 1, high possibility), it was successfully predicted here that an in vivo herb–drug interaction between AST/CAG and drugs mainly undergoing UGT1A8- or UGT2B7-catalyzed metabolism might occur when the plasma concentration of CAG is above 0.034 μM and 20.98 μM, respectively.

A dual-responsive nanoparticle system was designed for the efficient delivery of genes and chemotherapeutic agents through polymer degradation responding orderly to the tumor intracellular pH and redox state.

Objective:To identify and determine the impurities in amlodipine beslyate tablets.Methods:The main impurities in amlodipine beslyate tablets were identified with LC-MS,NMR and chromatographic methods.Then the main impurities were determined with C18 column as stationary phase and buffer(pH 3.0)-methanol-acetontrile 50∶35∶15 as mobile phase.Results:The main impurity in amlodipine beslyate tablets was proved to be the dehydration product of amlodipine(Impurity A,IM A).IM A could be completely separated with the established method.It was a linear correlation between the area and the concentration in the range of 0.5~10.0 μg / ml.The Limit of Quantification of the method was 10 ng / ml,recovery was 98.2%(n = 9) and the RSD of the method was 0.2%(n = 6).Conclusion:The main impurity in amlodipine beslyate tablets was IM A.The established method is accurate,simple and is suitable for determination of IM A in amlodipine beslyate tablets.