查找使用阿拉丁产品的科研文献

Two‐step flow synthesis of Olaparib in microreactor: Route design, process development and kinetics research

Qilin Xu,Jun Chen,Zihao Wang,Yongjun Zang,Guosi Li,Fucheng Zhu,Dong Liu,Chaoyue Sun

Olaparib is a top-selling pharmaceutical approved for the treatment of ovarian cancer. Herein, a two-step cascaded flow process was developed to synthesize Olaparib in microreactor. Since two different acyl groups are in the piperazine ring of Olaparib, a highly selective monoacylation route of piperazine is crucial for the efficient synthesis of Olaparib. For the first step (i.e., the monoacylation of piperazine), N , N' -carbonyldiimidazole was screened as coupling reagent due to its excellent selectivity , safety and greenness, a high monoacylation yield of 83 % was obtained in the microreactor. To understand the selective monoacylation reaction more deeply, the intrinsic kinetics was investigated based on mechanism cognition and experimental data. The established kinetic model was in good agreement with the experimental results in validation experiments. To further realize continuous manufacturing, the following step (i.e., amidation) was cascaded with the monoacylation in a microreactor system, Olaparib was continuously synthesized in the two-step cascaded microreactor with an overall yield of 78 % within 25 min. Relative to existing processes, the reaction steps were reduced, the economy and efficiency were remarkably improved, indicating efficient process intensification.

Differential expression of DNA damage repair genes after chemoradiotherapy and inhibition rate in different bladder cancer cells

Shujun Sun,Kehua Jiang,Jin Zeng

Background To investigate the potential mechanisms of chemoradiotherapy resistance in patients with bladder cancer. Methods We assessed three bladder cancer cell lines (5637, J82, and TCCSUP) for their sensitivity to chemoradiotherapy. Reverse transcription quantitative PCR (RT-qPCR) was used to detect the expression of specific genes after chemoradiotherapy or combined with olaparib. The Genome Cancer Atlas (TGCA) database was used to analyze possible radioresistance-related genes and the relationship between their expression and bladder cancer survival and prognostic indicators. Results The 5637 cell line showed the most significant sensitivity to chemoradiotherapy. The expression levels of DNA damage repair genes in 5637 cells did not significantly change after chemoradiotherapy. In contrast, the expression levels of BRCA1 and RBBP8 genes significantly increased in J82 and TCCSUP cells after chemoradiotherapy. After combination with olaparib, which is a poly (ADP-ribose) polymerase inhibitor that initiates DNA repair, 5637 cells were significantly inhibited by chemoradiotherapy. However, chemoradiotherapy inhibition on J82 cells was weakened when combined with olaparib. A high reactive expression of BRCA1 and RBBP8 after combination with olaparib suggested that olaparib was ineffective because it did not induce synthetic lethality in which inhibiting PARP by olaparib coincided with suppression of BRCA1/2 expression result in cancer cell death. Conclusions The expression levels of RBBP8 and BRCA1 genes were associated with sensitivity to radiotherapy and chemotherapy in bladder cancer, and an increase in reactive expression after treatment led to worse sensitivity. Therefore, the reactive expression levels of BRCA1 and RBBP8 after chemoradiotherapy may be useful in evaluating the efficacy of olaparib combination therapy.

Improving the physicochemical and pharmacokinetic properties of olaparib through cocrystallization strategy

Xia-Lin Dai,Bo-Wen Pang,Wen-Ting Lv,Jian-Feng Zhen,Lu Gao,Cai-Wen Li,Jing Xiong,Tong-Bu Lu,Jia-Mei Chen

Olaparib (OLA) is the first PARP inhibitor worldwide used for the treatment of ovarian cancer . However, the oral absorption of OLA is extremely limited by its poor solubility. Herein, pharmaceutical cocrystallization strategy was employed to optimize the physicochemical and pharmacokinetic properties. Four cocrystals of OLA with oxalic acid ( OLA-OA ), malonic acid ( OLA-MA ), fumaric acid ( OLA-FA ) and maleic acid ( OLA-MLA ) were successfully discovered and characterized. Fourier transform infrared spectroscopy and X-ray photoelectron spectroscopy confirmed the formation of cocrystals rather than salts, and the possible hydrogen bonding patterns were analyzed through molecular surface electrostatic potential calculations. The in vitro and in vivo evaluations indicate that all of the cocrystals demonstrate significantly improved dissolution performance, oral absorption and tabletability compared to pure OLA. Among them, OLA-FA exhibit sufficient stability and the most increased C max and AUC 0-24h values that were 11.6 and 6.1 times of free OLA, respectively, which has great potential to be developed into the improved solid preparations of OLA.

Silencing TRIP13/KNTC1 inhibits DNA damage repair and enhances Olaparib sensitivity in ovarian cancer

Xingzi Guo,Jie Tang,He Li,Saiping Mao,Yan-Xiang Tang,Zhen-Zi Tang,Lianghui Gong

Ovarian cancer (OC) is associated with high mortality and frequent resistance to poly (ADP-ribose) polymerase (PARP) inhibitors, such as Olaparib, particularly in patients with breast cancer gene (BRCA)-proficient tumors. To explore the potential mechanisms underlying Olaparib resistance, Olaparib-resistant OC cell lines were established through stepwise drug induction. Candidate resistance-related genes were screened using bioinformatic analyses and subsequently validated in clinical specimens. Their biological functions and underlying mechanisms were further investigated through gene silencing, co-immunoprecipitation, immunofluorescence, comet assays, and an OVCAR3 xenograft model. Bioinformatic analyses indicated that TRIP13 and KNTC1 were highly expressed in Olaparib-resistant cells and were associated with poor prognosis. Their elevated expression was further confirmed by RT-qPCR, western blotting, and immunohistochemistry. Functional studies showed that silencing either TRIP13 or KNTC1 inhibited cell proliferation and induced apoptosis in Olaparib-resistant OC cells. Mechanistically, co-immunoprecipitation and immunofluorescence analyses confirmed a cytoplasmic interaction between TRIP13 and KNTC1. TRIP13 knockdown impaired non-homologous end joining (NHEJ)-mediated DNA repair, as evidenced by decreased expression of NHEJ-related proteins, increased γH2AX accumulation, and enhanced comet tail formation. Conversely, TRIP13 overexpression promoted NHEJ repair and reduced Olaparib-induced DNA damage, whereas these effects were partially reversed by the NHEJ inhibitor SCR130. In vivo , TRIP13 overexpression promoted tumor growth and reduced sensitivity to Olaparib, while KNTC1 knockdown reversed these effects. Collectively, these findings suggest that TRIP13 and KNTC1 cooperatively promote NHEJ-mediated DNA repair, thereby contributing to Olaparib resistance in BRCA-proficient OC. Targeting the TRIP13/KNTC1 axis may therefore enhance the therapeutic efficacy of Olaparib and provide a promising strategy for overcoming PARP inhibitor resistance.

Olaparib induces craniofacial cartilage malformations in zebrafish embryos through DNA damage, oxidative stress, and Wnt dysregulation

Min Huang,Nannan Wang,Xianhua Zhang,Qianqian Huang,Fasheng Liu,Xiaoyan Huang,Lingpu Wang,Xinjun Liao,Huiqiang Lu,Lan Liao

Pharmaceutical residues in aquatic environments are a growing concern. Global surveillance has detected these residues in nearly a quarter of the world's rivers, with anticancer drugs drawing particular attention due to their high bioactivity. Olaparib (Ola), a poly(ADP-ribose) polymerase (PARP) inhibitor, is widely used to treat breast and ovarian cancers, but its developmental toxicity to aquatic vertebrates remains unclear. We exposed zebrafish embryos to Ola (5–15 mg/L) from 6 to 120 h post-fertilization (hpf). Ola exposure caused dose-dependent craniofacial cartilage malformations and behavioral abnormalities. Mechanistically, Ola induced DNA damage (Comet assay) and mitochondrial depolarization (JC-10), as well as oxidative stress evidenced by elevated reactive oxygen species (ROS) levels and impaired antioxidant defenses. Ola exposure impaired cranial neural crest cell (CNCC) migration, as shown by reduced sox10:GFP⁺ fluorescence and altered expression of pax 3 a , dlx 2 a , and dlx 5 a . It also reduced chondrogenic differentiation, with lower expression of sox 9 a and col 2 a 1, and increased apoptosis, as indicated by more TUNEL-positive cells. Ola also altered Wnt/β‑catenin pathway gene expression. Pharmacological rescue experiments showed that the antioxidant astaxanthin (60 μg/L) and the Wnt inhibitor C59 (3.79 μg/L) both attenuated craniofacial malformations. Together, these results indicate that Ola induces DNA damage and oxidative stress, impairs CNCC function, and disrupts Wnt signaling, leading to craniofacial cartilage deformities. This study underscores the developmental toxicity of PARP inhibitors as emerging environmental contaminants and offers insights into the mechanisms underlying craniofacial cartilage malformations.

Two Cocrystals of Olaparib with Flavonoids toward Sustained Release: Structure, Dissolution Behavior, and Anticancer Activity Analysis

Chenxin Duan,Yanming Chen,Yuxin Zhang,Feifei Liang,Wenwen Liu,Xinyi Xiao,Cangcang Xu,Tao Zhuang,Chao Hao,Yin Chen

As the first FDA-approved PARP1/2 inhibitor, olaparib (OLA) is a blockbuster anticancer drug, but its use has been limited by the dose-limiting toxicity and short half life of commercially available immediate-release preparations. To realize the sustained release of OLA, the cocrystal of OLA with kaempferol (KAE) and the cocrystal solvate of OLA with quercetin (QUE) were screened and obtained in this study. The cocrystals were characterized by X-ray diffraction, Hirshfeld surface, thermal analysis, and spectroscopic analysis. Intrinsic dissolution rate (IDR) experiments showed that the IDR values of both OLA–KAE and OLA–QUE were 0.40 times that of pure OLA. In dissolution experiments, the dissolution of OLA–KAE and OLA–QUE in pH 6.8 medium was reduced to 21.4% and 18.6% of the original drug, respectively. The stability test indicates that OLA–KAE has excellent physical stability under accelerated conditions for 3 months. Moreover, OLA–KAE and OLA–QUE showed significantly increased inhibiting effects on ovarian cancer cells compared to OLA in MTT assays. This work provides a promising approach for developing sustained-release formulations of OLA via cocrystallization with enhanced pharmacological activity.

Synergistic RU486 and olaparib therapy enhances apoptosis in endometriosis by simultaneously targeting hormonal signalling and DNA repair

Yujie Peng,Meng Zhang,Libo Zhu,Wenqiang Qian,Jingjing Yan,Huidi Jiang,Yu Xin,Ying Zhang,Dongli Sun,Weidong Fei,Mengdan Zhao

Background and Purpose Endometriosis is a chronic, hormone-dependent disorder characterized by ectopic implantation of endometrial tissue, often accompanied by pain and infertility. Although the progesterone receptor modulator RU486 is effective for pain relief, its impact on lesion regression is limited, possibly due to apoptosis resistance and overexpression of PARP1 in endometriotic cells. This study aimed to evaluate the synergistic therapeutic efficacy of combining RU486 with the PARP inhibitor olaparib, focusing on reactivating p53-dependent apoptosis in endometriotic lesions. Experimental Approach Primary ectopic endometrial stromal cells (EESCs) were used to assess the effects of RU486 and olaparib on cytotoxicity, apoptosis, DNA damage, mitochondrial membrane potential, and cell migration. Mechanistic investigations included flow cytometry, western blotting, RT-qPCR, immunofluorescence, and comet assays. A murine endometriosis model was established to evaluate in vivo lesion suppression, pain behaviour, hormone levels, and treatment safety following combination therapy. Key Results RU486 and olaparib exhibited strong synergy at a 1:4 ratio, significantly enhancing apoptosis in EESCs by coactivating p53 through distinct mechanisms—transcriptional up-regulation by RU486 and posttranslational stabilization by olaparib. This synergy intensified Bax/Bcl-2-mediated mitochondrial dysfunction, caspase-3 activation, and PARP1 cleavage. In vivo, the combination therapy achieved a 77.5% lesion weight regression, significantly exceeding monotherapies, while maintaining robust analgesic effects. Histological and molecular analyses confirmed DNA damage and enhanced apoptosis in lesions. Conclusion and Implications The combination medication enhanced apoptotic sensitivity in endometriosis by restoring p53 activity through targeting hormonal signalling and DNA repair pathways. This strategy offered strong potential for clinical translation. Graphical

Hyaluronic acid-coated and Olaparib-loaded PEI − PLGA nanoparticles for the targeted therapy of triple negative breast cancer

Huiping Hu,Yu Zhang,Wenting Ji,Hao Mei,Tingting Wu,Zihao He,Kaiping Wang,Chen Shi

Nanoparticle-based Olaparib delivery enhances its effect, and improves drug sensitivity to cisplatin in triple negative breast cancer

Shentao Zhang,Erjing Li,Zhao Liu,Haitao Shang,Yichi Chen,Hui Jing

Purpose Ultrasound-mediated nanobubbles destruction (UTND) technology could enhance drug transport efficiency and increase the local drug concentration. We structured a novel Olaparib-loaded nanobubbles (Ola-NBs). Then investigated its ability to inhibit triple negative breast cancer (TNBC) cell growth in vitro. Additionally, we observed the change of cisplatin sensitivity before and after Olaparib treatment. Methods The Ola-NBs were prepared using extrusion and thin-film hydration combination methods. Cell viability was checked by CCK-8 assay, and calculated the 50% inhibition concentration (IC 50 ) of Olaparib and cisplatin. Next, Jc-1 staining was used to observe mitochondrial membrane depolarization, and an apoptosis assay was applied to assess the apoptosis in different groups. Finally, a Western blot assay was used to evaluate the inhibition effect of Olaparib on TNBC at the molecular level. Results Ola-NBs were prepared successfully. The zeta potential was −0.617 ± 0.197 mV, and the average diameter was 473.52 ± 17.33 nm. The IC 50 of Olaparib had not significant difference in TNBC cells. However, the IC 95 was higher in cisplatin-resistant MDA-MB-231 cells (MDA-MB-231/CDDP). The cell viability decreased following Olaparib treatment and was more obvious in the Ola-NBs group ( P  < 0.05). In addition, the IC 50 of cisplatin was lower in the post-Olaparib treatment group. Jc-1 results revealed that the mitochondrial membrane decreased more strongly in the Ola-NBs and combination therapy groups. And the results of Jc-1 corroborated the apoptosis assay results. Moreover, Bax protein expression level increased, while Bcl-2 protein expression decreased in the treatment groups. Conclusion Olaparib not only inhibited TNBC cell growth, but it also improved the sensitivity of cisplatin in TNBC cells. And nanobubbles (NBs) might be an effective supporter, because it can enhance the drug efficacy under ultrasound irradiation.

Micelle encapsulation zinc-doped copper oxide nanocomposites reverse Olaparib resistance in ovarian cancer by disrupting homologous recombination repair

Jingyan Yi,Xin Luo,Jinshan Xing,Aharon Gedanken,Xiukun Lin,Chunxiang Zhang,Gan Qiao

Micelle Encapsulation Zinc-doped copper oxide nanocomposites (MEnZn-CuO NPs) is a novel doped metal nanomaterial prepared by our group based on Zinc doped copper oxide nanocomposites (Zn-CuO NPs) using non-micellar beam. Compared with Zn-CuO NPs, MEnZn-CuO NPs have uniform nanoproperties and high stability. In this study, we explored the anticancer effects of MEnZn-CuO NPs on human ovarian cancer cells. In addition to affecting cell proliferation, migration, apoptosis and autophagy, MEnZn-CuO NPs have a greater potential for clinical application by inducing HR repair defects in ovarian cancer cells in combination with poly (ADP-ribose) polymerase inhibitors for lethal effects.

Discovery of dual-targeted molecules based on Olaparib and Rigosertib for triple-negative breast cancer with wild-type BRCA

Zhikun Liu,Shining Mao,Lumei Dai,Rizhen Huang,Weiwei Hu,Chunhao Yu,Yong Yang,Guoxiu Cao,Xiaochao Huang

PARP inhibitors (PARPis) demonstrate significant potential efficacy in the clinical treatment of BRCA-mutated triple-negative breast cancer (TNBC). However, a majority of patients with TNBC do not possess BRCA mutations, and therefore cannot benefit from PARPis. Previous studies on multi-targeted molecules derived from PARPis or disruptors of RAF-RAF pathway have offered an alternative approach to develop novel anti-TNBC agents. Hence, to broaden the application of PARP inhibitors for TNBC patients with wild-type BRCA, a series of dual-targeted molecules were constructed via integrating the key pharmacophores of Olaparib (Ola) and Rigosertib into a single entity. Subsequent studies exhibited that the resulting compounds 13a – 14c obtained potential anti-proliferative activity against BRCA-defected or wild-type TNBC cells. Among them, an optimal compound 13b showed good inhibitory activity toward PARP-1, displayed approximately 34-fold higher inhibitory activity than that of Ola in MDA-MB-231 cells, and exerted multi-functional mechanisms to induce apoptosis. Moreover, 13b displayed superior antitumor efficacy (TGI, 61.3 %) than the single administration of Ola (TGI, 38.5 %), 11b (TGI, 51.8 %) or even their combined administration (TGI, 56.7 %), but did not show significant systematic toxicity. These findings suggest that 13b may serve as a potential candidate for BRCA wild-type TNBC.

Affinity Chromatographic Method for Determining Drug–Protein Interaction with Enhanced Speed Than Typical Frontal Analysis

Yuanyuan Ou,Sai Qiao,Ting Li,Xinxin Zheng,Xue Zhao,Lejing Qu,Xinfeng Zhao,Yajun Zhang

Revealing drug–protein interaction is highly important to select a drug candidate with improved drug-like properties in the early stages of drug discovery. This highlights the urgent need to develop assays that enable the analysis of drug–protein interaction with high speed. Herein, this purpose was realized by the development of an affinity chromatographic method with a two-fold higher speed than typical assays like frontal analysis and zonal elution. The method involved synthesis of a stationary phase by immobilizing poly(ADP-ribose) polymerase-1 (PARP1) onto macroporous silica gel through a one-step bioorthogonal reaction, characterization of mutual displacement interaction of two canonical drugs to the immobilized PARP1, determination of the interaction between three (iniparib, rucaparib, and olaparib) drugs and the protein, and validation of these parameters by typical frontal analysis. The numbers of binding sites on the column were (2.85 ± 0.05) × 10–7, (1.89 ± 0.71) × 10–6, and (1.49 ± 0.06) × 10–7 M for iniparib, rucaparib, and olaparib, respectively. On these sites, the association constants of the three drugs to the protein were (9.85 ± 0.56) × 104, (2.85 ± 0.34) × 104, and (1.07 ± 0.35) × 105 M–1. The determined parameters presented a good agreement with the calculation by typical frontal analyses, which indicated that the current continuous competitive frontal analysis method was reliable for determining drug–protein interaction. Application of the methods was achieved by screening tubeimosides I and II as the bioactive compounds against breast cancer in Bolbostemma paniculatum. Their mechanism may be the interference of DNA repair via down-regulating PARP1 and meiotic recombination 11 expressions, thus leading to oncogene mutations and death of cancer cells. The method was high speed since it allowed simultaneous determination of binding parameters between two drugs and a protein with a smaller number of experiments to be performed. Such a feature made the method an attractive alternative for high-speed analysis of drug–protein interaction or the other bindings in a binary system.