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Banoxantrone dihydrochloride (AQ4N dihydrochloride) Sale

(Synonyms: AQ4N dihydrochloride) 目录号 : GC34085

Banoxantrone dihydrochloride (AQ4N dihydrochloride) 是一种缺氧活化拓扑异构酶 II 抑制剂,AQ4N 以非共价方式与 DNA 结合,促进缺氧和缺氧肿瘤细胞的抗肿瘤活性。

Banoxantrone dihydrochloride (AQ4N dihydrochloride) Chemical Structure

Cas No.:252979-56-9

规格 价格 库存 购买数量
10mM (in 1mL Water)
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5mg
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25mg
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实验参考方法

Cell experiment [1]:

Cell lines

9L rat gliosarcoma and H460 human non-small-cell lung carcinoma cells

Preparation Method

Cells were treated with Banoxantrone dihydrochloride (AQ4N dihydrochloride) (0-0.25 mM) for 24 hours under normoxia or 0.1% O2. The culture medium was then changed to drug-free medium, and the cells were additionally cultured for 3 days under normoxia. Relative cell survival was determined by crystal violet staining of the cells remaining at the end of the experiment (A595 nm).

Reaction Conditions

0-0.25 mM;24h

Applications

Banoxantrone dihydrochloride showed 8-fold higher cytotoxicity under hypoxia than normoxia in cultures of 9L rat gliosarcoma and H460 human non-small-cell lung carcinoma cells.

Animal experiment [2]:

Animal models

8-12 week old male BD2F1 mice

Preparation Method

Tumor( poorly differentiated T50/80 murine mammary carcinoma) grafting in mice,AQ4N was administered as a single i.p. injection at a dose of 200 mg/kg. The drug was given 30 min before a single dose of X-irradiation of 12 Gy. Tumours were excised at a range of times following treatment and placed on ice. The tumor was enzymolysis into single cells and detected by comet assay.

Dosage form

200 mg/kg; i.p.; 30 minutes before radiation

Applications

AQ4N was combined with radiation, considerable DNA damage was detected in T50/80 tumors implanted in BDF mice after immediate excision.

References:

[1]. Manley E Jr, Waxman DJ. Impact of tumor blood flow modulation on tumor sensitivity to the bioreductive drug banoxantrone. J Pharmacol Exp Ther. 2013 Feb;344(2):368-77. doi: 10.1124/jpet.112.200089. Epub 2012 Nov 28. PMID: 23192656; PMCID: PMC3558827.
[2]. Hejmadi MV, McKeown SR, et,al. DNA damage following combination of radiation with the bioreductive drug AQ4N: possible selective toxicity to oxic and hypoxic tumour cells. Br J Cancer. 1996 Feb;73(4):499-505. doi: 10.1038/bjc.1996.87. PMID: 8595165; PMCID: PMC2074454.

产品描述

Banoxantrone dihydrochloride (AQ4N dihydrochloride) is an oxygen-depleted activated topoisomerase II inhibitor, AQ4N binds to DNA in a non-covalent manner and promotes antitumor activity of hypoxic and hypoxic tumor cells[1-4].

AQ4N(0-0.25 mM;24h) showed 8-fold higher cytotoxicity under hypoxia than normoxia in cultures of 9L rat gliosarcoma and H460 human non-small-cell lung carcinoma cells[5].

AQ4N(200 mg/kg; i.p.; 30 minutes before radiation) was combined with radiation, considerable DNA damage was detected in T50/80 tumors implanted in BDF mice after immediate excision[2,6].Activation of AQ4N cytotoxicity in mice requires extensive and prolonged tumor hypoxia[5]. AQ4N inhibited HMEC-1 cell contacts on Matrigel, HMEC-1 cell invasion, and sprouting in rat aorta explants. When AQ4N (20 mg/kg) was given in vivo for 5 days, microvessels disappeared in LNCaP tumors grown in a dorsal skin flap[7].

References:
[1]. Newell DR, Searle KM, Westwood NB, Burtles SS; Cancer Research UK Phase I/II Clinical Trials Committee. Professor Tom Connors and the development of novel cancer therapies by the Phase I/II Clinical Trials Committee of Cancer Research UK. Br J Cancer. 2003 Aug 4;89(3):437-54. doi: 10.1038/sj.bjc.6601106. PMID: 12888809; PMCID: PMC2394365.
[2]. Hejmadi MV, McKeown SR, et,al. DNA damage following combination of radiation with the bioreductive drug AQ4N: possible selective toxicity to oxic and hypoxic tumour cells. Br J Cancer. 1996 Feb;73(4):499-505. doi: 10.1038/bjc.1996.87. PMID: 8595165; PMCID: PMC2074454.
[3]. Patterson LH, McKeown SR, et,al. Enhancement of chemotherapy and radiotherapy of murine tumours by AQ4N, a bioreductively activated anti-tumour agent. Br J Cancer. 2000 Jun;82(12):1984-90. doi: 10.1054/bjoc.2000.1163. PMID: 10864207; PMCID: PMC2363261.
[4]. Patterson LH, McKeown SR. AQ4N: a new approach to hypoxia-activated cancer chemotherapy. Br J Cancer. 2000 Dec;83(12):1589-93. doi: 10.1054/bjoc.2000.1564. PMID: 11104551; PMCID: PMC2363465.
[5]. Manley E Jr, Waxman DJ. Impact of tumor blood flow modulation on tumor sensitivity to the bioreductive drug banoxantrone. J Pharmacol Exp Ther. 2013 Feb;344(2):368-77. doi: 10.1124/jpet.112.200089. Epub 2012 Nov 28. PMID: 23192656; PMCID: PMC3558827.
[6]. McKeown SR, Hejmadi MV, et,al. AQ4N: an alkylaminoanthraquinone N-oxide showing bioreductive potential and positive interaction with radiation in vivo. Br J Cancer. 1995 Jul;72(1):76-81. doi: 10.1038/bjc.1995.280. PMID: 7599069; PMCID: PMC2034137.
[7]. O'Rourke M, Ward C, et,al. Evaluation of the antiangiogenic potential of AQ4N. Clin Cancer Res. 2008 Mar 1;14(5):1502-9. doi: 10.1158/1078-0432.CCR-07-1262. PMID: 18316575.

Banoxantrone dihydrochloride (AQ4N dihydrochloride) 是一种缺氧活化拓扑异构酶 II 抑制剂,AQ4N 以非共价方式与 DNA 结合,促进缺氧和缺氧肿瘤细胞的抗肿瘤活性[1-4]。

AQ4N(0-0.25 mM;24h) 在 9L 大鼠神经胶质肉瘤和 H460 人非小细胞肺癌细胞培养物中表现出缺氧条件下比常氧条件下高 8 倍的细胞毒性[5]。

AQ4N (200 mg/kg;i.p.;放疗前 30 分钟)与放疗相结合,在立即切除后植入 BDF 小鼠的 T50/80 肿瘤中检测到相当大的 DNA 损伤 [2,6]。在小鼠中激活 AQ4N 细胞毒性需要广泛和长期肿瘤缺氧[5]。 AQ4N 抑制基质胶上的 HMEC-1 细胞接触、HMEC-1 细胞侵袭和大鼠主动脉外植体的发芽。体内给予 AQ4N (20 mg/kg) 5 天后,生长在背侧皮瓣的 LNCaP 肿瘤中微血管消失[7]。

Chemical Properties

Cas No. 252979-56-9 SDF
别名 AQ4N dihydrochloride
Canonical SMILES O=C1C2=C(C(O)=CC=C2O)C(C3=C(NCC[N+](C)(C)[O-])C=CC(NCC[N+](C)(C)[O-])=C13)=O.Cl.Cl
分子式 C22H30Cl2N4O6 分子量 517.4
溶解度 Water : 25 mg/mL (48.32 mM) 储存条件 Store at -20°C, protect from light, stored under nitrogen
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1 mM 1.9327 mL 9.6637 mL 19.3274 mL
5 mM 0.3865 mL 1.9327 mL 3.8655 mL
10 mM 0.1933 mL 0.9664 mL 1.9327 mL
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Research Update

Supramolecular Radiosensitizer Based on Hypoxia-Responsive Macrocycle

Adv Sci (Weinh) 2022 Feb;9(6):e2104349.PMID:34994113DOI:10.1002/advs.202104349.

Radiotherapy (RT) has been viewed as one of the most effective and extensively applied curatives in clinical cancer therapy. However, the radioresistance of tumor severely discounts the radiotherapy outcomes. Here, an innovative supramolecular radiotherapy strategy, based on the complexation of a hypoxia-responsive macrocycle with small-molecule radiosensitizer, is reported. To exemplify this tactic, a carboxylated azocalix[4]arene (CAC4A) is devised as molecular container to quantitatively package tumor sensitizer Banoxantrone dihydrochloride (AQ4N) through reversible host-guest interaction. Benefited from the selective reduction of azo functional groups under hypoxic microenvironment, the supramolecular prodrug CAC4A•AQ4N exhibits high tumor accumulation and efficient cellular internalization, thereby significantly amplifying radiation-mediated tumor destruction without appreciable systemic toxicity. More importantly, this supramolecular radiotherapy strategy achieves an ultrahigh sensitizer enhancement ratio (SER) value of 2.349, which is the supreme among currently reported noncovalent-based radiosensitization approach. Further development by applying different radiosensitizing drugs can make this supramolecular strategy become a general platform for boosting therapeutic effect in cancer radiotherapies, tremendously promising for clinical translation.

A Tumor Vascular-Targeted Interlocking Trimodal Nanosystem That Induces and Exploits Hypoxia

Adv Sci (Weinh) 2018 May 28;5(8):1800034.PMID:30128230DOI:10.1002/advs.201800034.

Vascular-targeted photodynamic therapy (VTP) is a recently approved strategy for treating solid tumors. However, the exacerbated hypoxic stress makes tumor eradication challenging with such a single modality approach. Here, a new graphene oxide (GO)-based nanosystem for rationally designed, interlocking trimodal cancer therapy that enables VTP using photosensitizer verteporfin (VP) (1) with codelivery of Banoxantrone dihydrochloride (AQ4N) (2), a hypoxia-activated prodrug (HAP), and HIF-1α siRNA (siHIF-1α) (3) is reported. The VTP-induced aggravated hypoxia is highly favorable for AQ4N activation into AQ4 (a topoisomerase II inhibitor) for chemotherapy. However, the hypoxia-induced HIF-1α acts as a "hidden brake," through downregulating CYP450 (the dominant HAP-activating reductases), to substantially hinder AQ4N activation. siHIF-1α is rationally adopted to suppress the HIF-1α expression upon hypoxia and further enhance AQ4N activation. This trimodal nanosystem significantly delays the growth of PC-3 tumors in vivo compared to the control nanoparticles carrying VP, AQ4N, or siHIF-1α alone or their pairwise combinations. This multimodal nanoparticle design presents, the first example exploiting VTP to actively induce hypoxia for enhanced HAP activation. It is also revealed that HAP activation is still insufficient under hypoxia due to the hidden downregulation of the HAP-activating reductases (CYP450), and this can be well overcome by GO nanoparticle-mediated siHIF-1α intervention.

Genetically engineered bacteria-mediated multi-functional nanoparticles for synergistic tumor-targeting therapy

Acta Biomater 2022 Sep 15;150:337-352.PMID:35931281DOI:10.1016/j.actbio.2022.07.056.

Focused ultrasonic ablation surgery (FUAS) for tumor treatment has emerged as an effective non-invasive therapeutic approach, but its widespread clinical utilization is limited by its low therapeutic efficiency caused by inadequate tumor targeting, single imaging modality, and possible tumor recurrence following surgery. Therefore, this study aimed to develop a biological targeting synergistic system consisting of genetically engineered bacteria and multi-functional nanoparticles to overcome these limitations. Escherichia coli was genetically modified to carry an acoustic reporter gene encoding the formation of gas vesicles (GVs) and then target the tumor hypoxic environment in mice. After E. coli producing GVs (GVs-E. coli) colonized the tumor target area, ultrasound imaging and collaborative FUAS were performed; multi-functional nanoparticles were then enriched in the tumor target area through electrostatic adsorption. Multi-functional cationic lipid nanoparticles containing IR780, perfluorohexane, and Banoxantrone dihydrochloride (AQ4N) were coloaded in the tumor to realize targeted multimodal imaging and enhance the curative effect of FUAS. AQ4N was stimulated by the tumor hypoxic environment and synergistically cooperated with FUAS to kill tumor cells. In sum, synergistic tumor therapy involving multi-functional nanoparticles mediated by genetically engineered bacteria overcomes the limitations and improves the curative effect of existing FUAS. STATEMENT OF SIGNIFICANCE: Inadequate tumor targeting, single image monitoring mode, and prone tumor recurrence following surgery remain significant challenges yet critical for tumor therapy. This study proposes a strategy for genetically engineered bacteria-mediated multifunctional nanoparticles for synergistic tumor therapy. The multifunctional genetically engineered biological targeting synergistic agent can accomplish tumor-targeting therapy, synergistic FUAS ablation, hypoxia-activated chemotherapy combined with FUAS ablation, and multiple-imaging guidance and monitoring all at the same time, thereby compensating for the shortcomings of FUAS treatment. This strategy could pave the way for the progress of tumor therapy.

Ultralong circulating choline phosphate liposomal nanomedicines for cascaded chemo-radiotherapy

Biomater Sci 2019 Mar 26;7(4):1335-1344.PMID:30816393DOI:10.1039/c9bm00051h.

Cancer radiation therapy (RT) is limited by endogenous DNA repair of tumor cells and microenvironmental hypoxia in tumor tissues. Herein, we demonstrated an effective cancer chemo-radiotherapy strategy based on choline phosphate liposomal nanomedicines, which inhibit the intrinsic radioresistance of RT and concomitantly harness the RT-induced hypoxia to produce additional toxicity to overcome post-RT radioresistance. To achieve this strategy, a radiotherapy sensitizer, vorinostat, and a hypoxia-activated Banoxantrone dihydrochloride (AQ4N) were simultaneously delivered to a tumor using liposomes composed of an inverted polarity lipid 2-((2,3-bis(oleoyloxy)propyl)dimethylammonio)ethyl ethyl phosphate (DOCPe). The DOCPe liposomes exhibited a longer blood circulation time and enhanced tumor accumulation, compared to their zwitterionic phosphocholine counterpart. The RT was sensitized by vorinostat to kill non-tolerant normoxic tumor cells efficiently. The irradiation aggravated hypoxia-activated AQ4N to further potentiate RT treatment. This chemo-radiotherapy combination showed excellent tumor treatment efficacy and is promising for future clinical translation.

Glucose & oxygen exhausting liposomes for combined cancer starvation and hypoxia-activated therapy

Biomaterials 2018 Apr;162:123-131.PMID:29438880DOI:10.1016/j.biomaterials.2018.02.004.

Starvation therapy to slow down the tumor growth by cutting off its energy supply has been proposed to be an alternative therapeutic strategy for cancer treatment. Herein, glucose oxidase (GOx) is loaded into stealth liposomes and act as the glucose and oxygen elimination agent to trigger the conversion of glucose and oxygen into gluconic acid and H2O2. Such liposome-GOx after intravenous injection with effective tumor retention is able to exhaust glucose and oxygen within the tumor, producing cytotoxic H2O2 and enhancing hypoxia, as vividly visualized by non-invasive in vivo photoacoustic imaging. By further combination treatment with stealth liposomes loaded with Banoxantrone dihydrochloride (AQ4N), a hypoxia-activated pro-drug, a synergistically enhanced tumor growth inhibition effect is achieved in the mouse model of 4T1 tumor. Hence, by combining starvation therapy and hypoxia-activated therapy tactfully utilizing liposomal nanocarriers to co-deliver both enzymes and prodrugs, an innovative strategy is presented in this study for effective cancer treatment.