RESUMO
Given that precise/rapid intraoperative tumor margin identification is still challenging, novel fluorescent probes HY and HYM, based on acidic tumor microenvironment (TME) activation and organic anion transporting polypeptide (OATPs)-mediated selective uptake, were constructed and synthesized. Both of them possessed acidic pH-activatable and reversible fluorescence as well as large Stokes shift. Compared with HY, HYM had a higher (over 9-fold) enhancement in fluorescence with pH ranging from 7.6 to 4.0, and the fluorescence quantum yield of HYM (ΦF = 0.49) at pH = 4.0 was 8-fold stronger than that (ΦF = 0.06) at pH = 7.4. Mechanism research demonstrated that acidic TME-induced protonation of the pyridine N atom on ß-carbolines accounted for the pH-sensitive fluorescence by influencing the intramolecular charge transfer (ICT) effect. Furthermore, HYM selectively lit up cancer cells and tumor tissues not only by "off-on" fluorescence but also by OATPs (overexpressed on cancer cells)-mediated cancer cellular internalization, offering dual tumor selectivity for precise visualization of tumor mass and intraoperative guidance upon in situ spraying. Most importantly, HYM enabled rapid and high-contrast (tumor-to-normal tissue ratios > 6) human tumor margin identification in clinical tumor tissues by simple spraying within 6 min, being promising for aiding in clinical surgical resection.
Assuntos
Corantes Fluorescentes , Neoplasias , Humanos , Corantes Fluorescentes/química , Neoplasias/diagnóstico por imagem , Carbolinas , Fluorescência , Microambiente TumoralRESUMO
Photodynamic therapy (PDT) is a clinically approved treatment for cancer due to its high spatiotemporal selectivity and non-invasive modality. However, its therapeutic outcomes are always limited to the severe hypoxia environment of the solid tumor. Herein, two novel photosensitizers HY and HYM based on naturally antitumor alkaloids ß-carboline were designed and synthesized. Through a series of experiments, we found HY and HYM can produce type II ROS (singlet oxygen) after light irradiation. HYM had higher singlet oxygen quantum yield and molar extinction coefficient than HY, as well as type I PDT behavior, which further let us find that HYM could exhibit robust phototoxicity activities in both normoxia and hypoxia. Meanwhile, HYM showed tumor-selective cytotoxicity with minimal toxicity toward normal cells. Notably, thanks to HYM's hypoxia-tolerant type I/II PDT and tumor selective chemotherapy, HYM showed synergistic inhibitory effect on tumor growth (inhibition rate > 91%). Our research provides a promising photosensitizer for hypoxia-tolerant chemo-photodynamic therapy, and may also give a novel molecular skeleton for photosensitizer design.
Assuntos
Neoplasias , Fotoquimioterapia , Humanos , Fármacos Fotossensibilizantes/farmacologia , Fármacos Fotossensibilizantes/uso terapêutico , Oxigênio Singlete , Hipóxia/tratamento farmacológico , Neoplasias/tratamento farmacológico , Carbolinas/farmacologia , Carbolinas/uso terapêutico , Linhagem Celular TumoralRESUMO
A novel class of aminopyrimidine-based Bruton's tyrosine kinase (BTK) and FMS-like tyrosine kinase 3 (FLT3) dual-target inhibitors based on the BTK inhibitor spebrutinib was designed for the treatment of acute myeloid leukemia. Representative compounds 14d, 14g, 14j and 14m effectively inhibited BTK, FLT3, and FLT3(D835Y) mutant activities with low nanomolar IC50's. These compounds displayed potent antiproliferative activities against leukemia cells with IC50's of 0.29-950 nM. In particular, 14m had IC50 values 101-1045 times lower than those of spebrutinib against all cancer cell lines tested. Compound 14m effectively induced autophagy and apoptosis in MV-4-11 cells through regulating related proteins in a dose-dependent manner. Finally, intraperitoneal administration of 14m at 20 mg/kg significantly repressed the growth of MV-4-11 cells with a TGI value of 95.68% with no apparent toxicity. These BTK/FLT3 dual-target inhibitors represent promising leads for further structural optimization and antitumor mechanism studies.
Assuntos
Antineoplásicos , Leucemia Mieloide Aguda , Humanos , Linhagem Celular Tumoral , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/metabolismo , Pirimidinas/química , Tirosina Quinase da Agamaglobulinemia , Inibidores de Proteínas Quinases/química , Proliferação de Células , Apoptose , Antineoplásicos/química , Tirosina Quinase 3 Semelhante a fmsRESUMO
A series of novel nitric oxide (NO)-releasing 5,8-quinolinedione/furoxan hybrids (8a-h and 9a-h) were designed and synthesized through coupling different alkanolamine substituted phenylsulfonyl furoxan with 5,8-quinolinedione. Most compounds displayed high cytotoxic activity against drug-sensitive/-resistant cancer cells. In particular, the IC50 of 9a (0.42 µM) was about 9-fold lower than that of ß-lap (3.69 µM) and 12-fold lower than that of SAHA (5.24 µM) in drug-resistant cancer cells. Also, 9a was demonstrated to selectively inhibit the growth of Bel7402/5-FU cancer cells. Mechanistic studies demonstrated that 9a could serve as an NO donor and nicotinamide quinone oxidoreductase 1 (NQO1) inhibitor (IC50 = 0.8 µM), which could induce the highest level of NO and reactive oxygen species (ROS) in Bel-7402/5-FU cancer cells. Furthermore, 9a could promote tumor cell apoptosis and autophagy via regulation of apoptosis-related protein (Bax, Bcl-2, and Caspase 3) and autophagy-associated proteins (LC3 and p62) in Bel-7402/5-FU cells. Taken together, 9a may be considered as a promising candidate for a further comprehensive study involving drug-resistant hepatocellular carcinoma.
Assuntos
Antineoplásicos , Neoplasias Hepáticas , Humanos , Óxido Nítrico/metabolismo , Niacinamida/farmacologia , Linhagem Celular Tumoral , Antineoplásicos/farmacologia , Antineoplásicos/metabolismo , Apoptose , Neoplasias Hepáticas/tratamento farmacológico , Fluoruracila/farmacologia , Proliferação de Células , NAD(P)H Desidrogenase (Quinona)RESUMO
Computer-aided drug design and structure-based drug design techniques were used to find 18 novel hydrazidoarylaminopyrimidine-based BTK/FLT3 dual inhibitors. At 1 µM and 0.05 µM, the majority of the target compounds inhibited BTK and FLT3 by more than 80%, respectively. Among these, compound RSH-7 inhibited BTK and FLT3 most effectively, with IC50 values of 47 and 12 nM, respectively, which were superior to spebrutinib (BTK IC50 = 54 nM) and sorafenib (FLT3 IC50 = 33 nM). RSH-7 effectively inhibited the proliferation of multiple hematological malignancy cells with IC50 values ranging from 3 to 17 nM, which were 81-133 folds lower than spebrutinib. Furthermore, RSH-7 strongly inhibited BTK and FLT3 signaling and induced apoptosis in jeko-1 cells by upregulating pro-apoptotic proteins and downregulating Bcl-2 levels. RSH-7 showed moderate in vitro ADME properties. Importantly, RSH-7 demonstrated highly efficacious and well-tolerated in jeko-1 (50 mg/kg, TGI = 79.78%) and MV4-11 (20 mg/kg, TGI = 94.84%) xenograft models. These findings indicated that RSH-7 may be a promising lead compound for the treatment of hematological malignancies.
Assuntos
Neoplasias Hematológicas , Humanos , Animais , Neoplasias Hematológicas/tratamento farmacológico , Acrilamidas , Apoptose , Modelos Animais de Doenças , Tirosina Quinase 3 Semelhante a fmsRESUMO
Chemodynamic therapy (CDT) utilizing toxic hydroxyl radicals (·OH) to kill cancer cells exhibits huge potentiality in antitumor treatment. However, inadequate acidity, insufficient hydrogen peroxide (H2O2) amount, and overexpressed reduced glutathione (GSH) inside cancer cells severely restrict the efficacy of CDT. Although numerous efforts have been made, fabricating a versatile CDT material for surmounting these obstacles simultaneously is still a great challenge, especially for supramolecular materials owing to lacking an active metal unit for the Fenton reaction. Here, we intriguingly proposed a powerful supramolecular nanoagent (GOx@GANPs) based on the host-guest interaction between pillar[6]arene and ferrocene for all-sided boosting CDT efficacy via in situ cascade reactions. GOx@GANPs could stimulate intracellular glucose conversion into H+ and H2O2 to optimize the in situ Fenton reaction conditions and continuously produce sufficient â¢OH. Meanwhile, consumption of the original intracellular GSH pool and inhibition of GSH regeneration were synchronously achieved through the GSH-responsive gambogic acid prodrug and cutting off adenosine triphosphate (ATP) supply for GSH resynthesis, respectively. This complete GSH exhausting characteristic of GOx@GANPs effectively suppressed â¢OH elimination, ultimately resulting in a superior CDT effect. Furthermore, GOx@GANPs also produced synergistic effects of starvation therapy, chemotherapy, and CDT, exhibiting low toxicity toward normal tissues. Thus, this work introduces a valuable way for optimizing and elevating CDT efficiency and synergistic treatment of tumors.
Assuntos
Peróxido de Hidrogênio , Neoplasias , Humanos , Peróxido de Hidrogênio/farmacologia , Trifosfato de Adenosina , Glucose , Radical Hidroxila , Neoplasias/tratamento farmacológico , Linhagem Celular TumoralRESUMO
Tumor selective near-infrared (NIR) fluorescent contrast agents has the potential to greatly enhance the efficiency and precision of tumor surgery by enabling real-time tumor margin identification for tumor resection guided by imaging. However, the development of these agents is still challenging. In this study, based on the acidic tumor microenvironment (TME), we designed and synthesized a novel pH-sensitive NIR fluorescent contrast agent OBD from ß-carboline. The fluorescence quantum yield of OBD exhibited a notable increase at pH 3.6, approximately 12-fold higher compared to its value at pH 7.4. After cellular uptake, OBD lighted up the cancer cells with high specificity and accumulated in the mitochondria. Spraying OBD emitted selective fluorescence in xenograft tumor tissues with tumor-to-normal tissue ratios (TNR) as high as 11.18, implying successful image-guided surgery. Furthermore, OBD was also shown to track metastasis in spray mode. After simple topical spray, OBD rapidly and precisely visualized the tumor margins of clinical colon and liver tissues with TNR over 4.2. Therefore, the small-molecule fluorescent contrast agent OBD has promising clinical applications in tumor identification during surgery.
Assuntos
Meios de Contraste , Neoplasias , Humanos , Microambiente Tumoral , Neoplasias/diagnóstico por imagem , Corantes Fluorescentes/química , Fluorescência , Imagem Óptica/métodosRESUMO
Rationale: Challenges such as developing a universal tumor-specific probe for tumor margin identification in diverse tumors with an easy-operative and fast-imaging pattern still exist. Hence, in the present study, a rapidly "off-on" near-infrared (NIR) fluorescent probe NBD with pH-activatable fluorescence and a large Stokes shift was constructed for spray mediated near-instant and precise clinical tumor margins identification. Methods: NBD was designed and synthesized by introducing both diphenyl amino group and benzo[e]indolium to ß-carboline at C-6 and C-3 positions respectively. The optical properties of NBD was characterized by absorption spectra, fluorescence spectra. Subsequently, we investigated its pH-dependent mechanism by 1H NMR and density functional theory (DFT) calculation. NBD was further under deeper investigation into its imaging performance in nude mice models (subcutaneous, orthotopic, metastatic tumor), and clinical tissues from patients with three clinically representative tumors (liver cancer, colon cancer, and lung cancer). Results: It was found that NBD had NIR fluorescence (742 nm), a large Stokes shift (160 nm), and two-photon absorbance (1040 nm). Fluorescence quantum yield (ФF) increased by 5.5-fold when pH decreased from 7.4 to 4.0, to show pH-dependent property. Furthermore, NBD could not only selectively light up all four cancer cell lines, but also delineate xenograft tumor and orthotopic microtumor to guide surgical tumor resection, and track metastatic tissues. Particularly, after simple topical spray (three minutes later), NBD could rapidly and precisely distinguish the boundary ranges of three kinds of clinical cancer specimens including liver, colon, and lung cancers, with high tumor-to-normal tissue signal ratios (6.48~9.80). Conclusions: Therefore, the proposed fluorescent probe NBD may serve as a versatile NIR fluorogenic spray for the near-instant visualization of tumor margins and assisting surgeons in surgerical resection of clinical cancers.