Conquering the Hypoxia Limitation for Photodynamic Therapy

Advanced Materials, Journal Year: 2021, Volume and Issue: 33(48)

Published: Sept. 27, 2021

Photodynamic therapy (PDT) has aroused great research interest in recent years owing to its high spatiotemporal selectivity, minimal invasiveness, and low systemic toxicity. However, due the hypoxic nature characteristic of many solid tumors, PDT is frequently limited therapeutic effect. Moreover, consumption O2 during may further aggravate tumor condition, which promotes proliferation, metastasis, invasion resulting poor prognosis treatment. Therefore, numerous efforts have been made increase content with goal enhancing efficacy. Herein, these strategies developed past decade are comprehensively reviewed alleviate hypoxia, including 1) delivering exogenous directly, 2) generating situ, 3) reducing cellular by inhibiting respiration, 4) regulating TME, (e.g., normalizing vasculature or disrupting extracellular matrix), 5) hypoxia-inducible factor 1 (HIF-1) signaling pathway relieve hypoxia. Additionally, -independent Type-I also discussed as an alternative strategy. By reviewing progress, it hoped that this review will provide innovative perspectives new nanomaterials designed combat hypoxia avoid associated limitation PDT.

Language: Английский

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ImmunoPET: Concept, Design, and Applications

Chemical Reviews, Journal Year: 2020, Volume and Issue: 120(8), P. 3787 - 3851

Published: March 23, 2020

Immuno-positron emission tomography (immunoPET) is a paradigm-shifting molecular imaging modality combining the superior targeting specificity of monoclonal antibody (mAb) and inherent sensitivity PET technique. A variety radionuclides mAbs have been exploited to develop immunoPET probes, which has driven by development optimization radiochemistry conjugation strategies. In addition, tumor-targeting vectors with short circulation time (e.g., Nanobody) or an enhanced binding affinity bispecific antibody) are being used design novel probes. Accordingly, several such as

Language: Английский

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Carbonic anhydrase inhibitors as emerging agents for the treatment and imaging of hypoxic tumors

Expert Opinion on Investigational Drugs, Journal Year: 2018, Volume and Issue: 27(12), P. 963 - 970

Published: Nov. 14, 2018

Introduction: Hypoxic tumors overexpress two carbonic anhydrases (CA, EC 4.2.1.1), CA IX and XII, involved in complex processes connected to tumorigenesis (pH regulation, metabolism, invasion, dissemination of the tumor). The biochemical rationale behind these is orchestrated by transcription factor hypoxia inducible 1 (HIF-1).Areas covered: XII have been validated as antitumor/antimetastatic drug targets may be used for imaging hypoxic tumors. Many inhibitors (CAIs) belonging sulfonamide, coumarin sulfocoumarin classes selectively inhibit isoforms. IX/XII growth primary formation metastases deplete cancer stem cell population, alone or combination with other agents. These are three beneficial antitumor mechanisms that make them unique among anticancer drugs available.Expert opinion: Indisulam entered clinical trials an sulfonamide; it progressed Phase II but was terminated 2016. However, SLC-0111, a sulfonamide inhibitor 1, recently completed successful I trial treatment advanced, metastatic solid This compound now Ib/II being assessed monotherapy agents such gemcitabine. synergistic (cisplatin, proton pump inhibitors, doxorubicin, temozolamide) versatile, emerging class drugs.

Language: Английский

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Progress in the development of human carbonic anhydrase inhibitors and their pharmacological applications: Where are we today?

Medicinal Research Reviews, Journal Year: 2020, Volume and Issue: 40(6), P. 2485 - 2565

Published: July 21, 2020

Carbonic anhydrases (CAs, EC 4.2.1.1) are widely distributed metalloenzymes in both prokaryotes and eukaryotes. They efficiently catalyze the reversible hydration of carbon dioxide to bicarbonate H+ ions play a crucial role regulating many physiological processes. CAs well-studied drug target for various disorders such as glaucoma, epilepsy, sleep apnea, high altitude sickness. In past decades, large category diverse families CA inhibitors (CAIs) have been developed them showed effective inhibition toward specific isoforms, effectiveness pathological conditions preclinical clinical settings. The discovery isoform-selective CAIs last decade led diminished side effects associated with off-target isoforms inhibition. new classes compounds will be discussed review, together strategies their development. Pharmacological advances newly emerged diseases not usually (neuropathic pain, arthritis, cerebral ischemia, cancer) also discussed.

Language: Английский

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Regulation of pH by Carbonic Anhydrase 9 Mediates Survival of Pancreatic Cancer Cells With Activated KRAS in Response to Hypoxia

Gastroenterology, Journal Year: 2019, Volume and Issue: 157(3), P. 823 - 837

Published: May 9, 2019

Most pancreatic ductal adenocarcinomas (PDACs) express an activated form of KRAS, become hypoxic and dysplastic, are refractory to chemo radiation therapies. To survive in the environment, PDAC cells upregulate enzymes transporters involved pH regulation, including extracellular facing carbonic anhydrase 9 (CA9). We evaluated effect blocking CA9, combination with administration gemcitabine, mouse models cancer.We knocked down expression KRAS human (PK-8 PK-1) small hairpin RNAs. Human (KrasG12D/Pdx1-Cre/Tp53/RosaYFP) were incubated inhibitors MEK (trametinib) or signal-regulated kinase (ERK), some cultured under conditions. measured levels stability hypoxia-inducible factor 1 subunit alpha (HIF1A), endothelial PAS domain protein (EPAS1, also called HIF2A), solute carrier family 16 member 4 (SLC16A4, MCT4), SLC2A1 (also GLUT1) by immunoblot analyses. analyzed intracellular (pHi) metabolic flux. CA9 cells, inhibited SLC-0111, them assessed pHi, flux, cytotoxicity normoxic Cells injected into either immune-compromised immune-competent mice growth xenograft tumors was assessed. Tumor fragments derived from patients surgically ligated pancreas performed tissue microarray analyses 205 samples measure associated genes that regulate hypoxia outcomes using Cancer Genome Atlas database.Under conditions, had increased HIF1A HIF2A, upregulated glycolysis. Knockdown incubation trametinib, reduced posttranscriptional stabilization upregulation glycolysis response hypoxia. expressed 66% analyzed; high adaptation hypoxia, correlated significantly survival times patients. pharmacologic inhibition pHi decreased gemcitabine-induced glycolysis, their sensitivity gemcitabine. knockdown formed smaller mice, injection gemcitabine tumor mice. In grown oral SLC-0111 intratumor acidosis cell death. These tumors, patient-derived fragments, grew more slowly than given control agents, resulting longer times. KrasG12D/Pdx1-Cre/Tp53/RosaYFP genetically modified numbers B tumors.In increase via Disruption this pathway slows might be developed for treatment cancer.

Language: Английский

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A Phase 1 Study of SLC-0111, a Novel Inhibitor of Carbonic Anhydrase IX, in Patients With Advanced Solid Tumors

American Journal of Clinical Oncology, Journal Year: 2020, Volume and Issue: 43(7), P. 484 - 490

Published: April 2, 2020

Objectives: SLC-0111 is an ureido-substituted benzenesulfonamide small molecule inhibitor of carbonic anhydrase IX. The objectives this first-in-human Phase 1 study were to determine the safety and tolerability in patients with advanced solid tumors establish recommended 2 dose for future clinical investigations. Materials Methods: Using a 3+3 design, escalation started at 500 mg oral daily dosing cohort increased 1000 2000 cohorts 3. Drug-related adverse events (AEs) monitored tolerability. Pharmacokinetic analyses assessed plasma concentrations single repeated doses SLC-0111. RECIST 1.1 criteria used assess disease progression. Results: No dose-limiting toxicities reported dosed ≤1000 exhibited fewer drug-related AEs ≥ grade 3 such as nausea vomiting, compared 2000-mg cohort. Forty-one percent experienced interruptions or discontinuation majority (71%) these occurred Mean C max AUC (0-24) values similar 1000-mg levels. T 1/2 after dosing. Power-law analysis 0-24 showed that exposure was generally proportional. objective responses observed, but stable >24 weeks observed patients. Conclusions: safe previously treated, tumors. pharmacokinetic data support mg/d phase

Language: Английский

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Carbonic anhydrase inhibitors as antitumor/antimetastatic agents: a patent review (2008–2018)

Expert Opinion on Therapeutic Patents, Journal Year: 2018, Volume and Issue: 28(10), P. 729 - 740

Published: Aug. 3, 2018

Introduction: Human carbonic anhydrases (CA, EC 4.2.1.1) IX and XII are tumor-associated proteins, being part of the molecular machinery that tumor cells build as adaptive responses to hypoxia acidic conditions characteristic ‘glycolytic shift’ many tumors. A wealth research depicts CA biomarkers therapeutic targets for various cancer types.Areas covered: The review presents an overview role in hypoxic tumors physio-pathology well principal molecular, structural, catalytic features both isozymes. then covers patent literature medically relevant inhibitors CAs produced during period 2008–2018.Expert opinion: variety approaches design strategies were reported which afford IX/XII-specific avoid compromising effects isoforms-promiscuous compounds. Access crystal structures human isoforms have improved structure-based drug campaigns related zinc-binder chemotypes. Nevertheless, great potential still resides non-classical CAIs exhibit alternative binding mechanisms able further distinguish active sites architecture. hybrids/conjugates increasingly emerging field promising tools combine inhibition anticancer other moieties or antitumor drugs.

Language: Английский

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Carbonic anhydrase IX and acid transport in cancer

British Journal of Cancer, Journal Year: 2019, Volume and Issue: 122(2), P. 157 - 167

Published: Dec. 10, 2019

Alterations in tumour metabolism and acid/base regulation result the formation of a hostile environment, which fosters growth metastasis. Acid/base homoeostasis cancer cells is governed by concerted interplay between carbonic anhydrases (CAs) various transport proteins, either mediate proton extrusion or shuttling equivalents, such as bicarbonate lactate, across cell membrane. Accumulating evidence suggests that some these transporters interact both directly functionally with CAIX to form protein complex coined 'transport metabolon'. Transport metabolons formed require CA catalytic activity have function migration invasion. Another type metabolon monocarboxylate transporters. In this complex, functions antenna for transporter, drives export lactate protons from cell. Since almost exclusively expressed cells, might serve promising targets interfere pH energy metabolism. This review provides an overview current state research on discusses how could be exploited modern therapy.

Language: Английский

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Advances in the structural annotation of human carbonic anhydrases and impact on future drug discovery

Expert Opinion on Drug Discovery, Journal Year: 2019, Volume and Issue: 14(11), P. 1175 - 1197

Published: Aug. 22, 2019

Introduction: Of the 15 human carbonic anhydrase (CA, EC 4.2.1.1) isoforms known to date, for 11 crystal structure is known. Many different classes of CA inhibitors (CAIs) were reported in last decade, with a wealth inhibition mechanisms, where apart from classical one, do not bind zinc ion active site. The binders (sulfonamides, dithiocarbamates and their isosteres, thiols, selenols, carboxylates, hydroxamates, carbamates) are isoform-selective inhibitors, but specificity action may be achieved by decorating scaffolds tails that interact amino acids at entrance site.Areas covered: Herein, authors review advances structural annotation CAs. Furthermore, look impact on drug discovery efforts as well providing expert perspectives.Expert opinion: CAs unique example among metalloenzymes which all regions spacious sites used inhibitor/activator binding, leading variety mechanisms profiles many chemotypes modulating activity. This exploited design increasingly efficient useful pharmacological applications.

Language: Английский

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Carbonic Anhydrase Inhibitors Targeting Metabolism and Tumor Microenvironment

Metabolites, Journal Year: 2020, Volume and Issue: 10(10), P. 412 - 412

Published: Oct. 14, 2020

The tumor microenvironment is crucial for the growth of cancer cells, triggering particular biochemical and physiological changes, which frequently influence outcome anticancer therapies. rationale behind many these phenomena resides in activation transcription factors such as hypoxia-inducible factor 1 2 (HIF-1/2). In turn, HIF pathway activates a number genes including those involved glucose metabolism, angiogenesis, pH regulation. Several carbonic anhydrase (CA, EC 4.2.1.1) isoforms, CA IX XII, actively participate processes were validated antitumor/antimetastatic drug targets. Here, we review field inhibitors (CAIs), selectively inhibit cancer-associated isoforms. Particular focus was on identification lead compounds various inhibitor classes, measurement inhibitory on-/off-target effects. addition, preclinical data that resulted SLC-0111, sulfonamide Phase Ib/II clinical trials treatment hypoxic, advanced solid tumors, are detailed.

Language: Английский

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