Tirazone (tirapazamine)

Apart HIF itself, other potential molecular targets such as prolyl-hydroxylases (PHD), von Hippel-Lindau protein (VHL), monocarboxylate transporters (MCTs), Na+ /H+ exchangers (NHEs), vacuolar ATPases (V-ATPase), anion exchangers (AEs), Na+ /HCO₃- co-transporters (NBCs), vascular endothelial growth factor (VEGF) and carbonic anhydrases were identified as being involved in tumorigenesis. HIF-1α inhibitors (topotecan, digoxin, PX-478), hypoxia-activated prodrugs (evofosfamide, apaziquone, porfiromycin, tirapazamine, banoxantrone) and carbonic anhydrase IX/XII inhibitors (SLC-0111) are either used clinically or in clinical development for the management of hypoxic breast cancers.

P1/2, N=25, Recruiting, Teclison Ltd. | Trial completion date: Dec 2025 --> Sep 2028 | Trial primary completion date: Dec 2025 --> Mar 2028

P2, N=54, Recruiting, Teclison Ltd. | Trial completion date: Dec 2025 --> Jun 2027 | Trial primary completion date: Dec 2025 --> Dec 2026

P2, N=110, Recruiting, Teclison Ltd. | Trial completion date: Dec 2025 --> Sep 2027 | Trial primary completion date: Dec 2025 --> Mar 2027

Furthermore, tirapazamine (TPZ), a hypoxia-activated chemotherapeutic drug, was encapsulated into DT-COF pores with anastomosing dimensions (drug loading efficiency = 76.2%)...Additionally, DT-COF consumed the limited intratumoral oxygen to generate singlet oxygen, which further cooperated with the hypoxic tumor microenvironment to promote the activation of TPZ, thereby achieving synergistic antitumor therapy through the combination of photodynamic therapy and chemotherapy. This study provides a new strategy for the development of MPAPSs and demonstrates their potential in cancer theranostics.

Herein, we develop a dual pH/reactive oxygen species-responsive dendrimer nanogel (DNG) platform based on generation 3 poly(amidoamine) (G3 PAMAM) dendrimers for co-delivery of the hypoxia-activated prodrug tirapazamine (TPZ) and the immunomodulatory cytokine interferon-gamma (IFN-γ)...Leveraging the rich hydroxyl groups and the enhanced permeability and retention effect of DNGs, the DNGs-TPZ/IFN-γ can penetrate the BBB and demonstrate potent therapeutic efficacy in an orthotopic mouse glioma model. The developed DNGs-TPZ/IFN-γ with a simple composition may be developed to co-deliver drugs and cytokines to tackle other cancer types.

This study has constructed a nanomicelle (HACA/GOx@AF/TPZ) that is composed of a coassembly of hyaluronic acid-cinnamaldehyde Schiff base (HACA), glucose oxidase (GOx), tirapazamine (TPZ), and acriflavine (AF)...Meanwhile, AF can specifically inhibit HIF-1α through a multistage response, downregulating the expression of VEGF and facilitating the conversion of the tumor microenvironment (TME) to an antitumor TME, inducing dendritic cell maturation and polarization of M2 macrophages to M1. The "hypoxia-activated immune modulation" combination therapy strategy using HACA/GOx@AF/TPZ may provide more possibilities for combined tumor treatment.

This platform codelivered β-lapachone (Lap) and the hypoxia-activated prodrug tirapazamine (TPZ) within a pH-responsive, biodegradable, copper-doped, zeolitic imidazolate framework...The H2O2 generated from this process served as a substrate for Cu+-mediated Fenton-like reactions, leading to the production of highly cytotoxic hydroxyl radicals and thereby enhancing the effect of chemodynamic therapy (CDT). The experimental findings confirmed that this strategy effectively integrates hypoxia-activated chemotherapy with CDT, resulting in significantly improved therapeutic outcomes compared to monotherapies.

Furthermore, the spheroid size test demonstrates the superior penetration capability of N@P/T, leading to significant alterations in tumor spheroid size and morphology. Our integrated computational and experimental approach demonstrates that N@P/T effectively targets hypoxic cancer cells through specific molecular interactions, offering a promising strategy for BC treatment.

Here, a vaccine-integrated hollow MnO2 nanoplatform (TMLV), co-loaded with tirapazamine (TPZ) and lactate oxidase (LOX), is developed to orchestrate lactate-activatable multiple immune regulations against tumor...The activation of cGAS-STING pathway will further promote the cross-presentation between activated APCs and CD8+ T cells, significantly strengthening the adaptive immunity. This adjuvant-free design enabling multi-pathway immune activation might offer a novel strategy to overcome key challenges in antitumor immunotherapy.

The scaffold, composed of soybean isolate protein, polyvinyl alcohol, sodium alginate, and magnesium acetate, was loaded with doxorubicin (DOX) and tirapazamine (TPZ) to establish a sequential therapeutic cascade...Furthermore, magnesium acetate serves a dual immunomodulatory role by functioning as an immune adjuvant that facilitates CD8+ T cell activation and promotes tumor-associated macrophage repolarization towards the M1 phenotype. This multifunctional dual-drug depot demonstrates potential as an effective therapeutic platform for preventing tumor recurrence and addressing the limitations of conventional postoperative therapies.

Here, MnO2 nanosheets are synthesized with oxidase-like activity using fucoidan as a protective agent, and construct a multifunctional delivery system MnO2@DNAzyme-TPZ (MDT) by loading DNAzymes and hypoxia-activated prodrug Tirapazamine (TPZ) for tumor treatment and metastasis inhibition...MDT significantly inhibits tumor growth and metastasis in vivo in an in situ tumor model. The strategy of combining selective gene silencing based on DNAzymes with nanozymes and hypoxia-activated prodrug provides a new approach to anti-tumor metastasis therapy.