Neuroinflammation is a prominent feature of Alzheimer\'s disease (AD). Activated microglia undergo a reprogramming of cellular metabolism necessary to power their cellular activities during disease. Thus, selective targeting of microglial immunometabolism might be of therapeutic benefit for treating AD. In the AD brain, the levels of microglial hexokinase 2 (HK2), an enzyme that supports inflammatory responses by promoting glycolysis, are significantly increased. In addition, HK2 displays non-metabolic activities that extend its inflammatory role beyond glycolysis. The antagonism of HK2 affects microglial phenotypes and disease progression in a gene-dose-dependent manner. HK2 complete loss fails to improve pathology by exacerbating inflammation, while its haploinsufficiency reduces pathology in 5xFAD mice. We propose that the partial antagonism of HK2 is effective in slowing disease progression by modulating NF-κB signaling through its cytosolic target, IKBα. The complete loss of HK2 affects additional inflammatory mechanisms related to mitochondrial dysfunction.

Cancer development is related to genetic mutations in primary cells, where 5-10% of all cancers are derived from acquired genetic defects, most of which are a consequence of the environment and lifestyle. As it turns out, over half of cancer deaths are due to the generation of drug resistance. The local delivery of chemotherapeutic drugs may reduce their toxicity by increasing their therapeutic dose at targeted sites and by decreasing the plasma levels of circulating drugs. Nanobubbles have attracted much attention as an effective drug distribution system due to their non-invasiveness and targetability. This review aims to present the characteristics of nanobubble systems and their efficacy within the biomedical field with special emphasis on cancer treatment. In vivo and in vitro studies on cancer confirm nanobubbles\' ability and good blood capillary perfusion; however, there is a need to define their safety and side effects in clinical trials.

Prostate cancer is a multi-focal disease that can be treated using surgery, radiation, androgen deprivation, and chemotherapy, depending on its presentation. Standard dose-escalated radiation therapy (RT) in the range of 70-80 Gray (GY) is a standard treatment option for prostate cancer. It could be used at different phases of the disease (e.g., as the only primary treatment when the cancer is confined to the prostate gland, combined with other therapies, or as an adjuvant treatment after surgery). Unfortunately, RT for prostate cancer is associated with gastro-intestinal and genitourinary toxicity. We have previously reported that the metabolic modulator lonidamine (LND) produces cancer sensitization through tumor acidification and de-energization in diverse neoplasms. We hypothesized that LND could allow lower RT doses by producing the same effect in prostate cancer, thus reducing the detrimental side effects associated with RT. Using the Seahorse XFe96 and YSI 2300 Stat Plus analyzers, we corroborated the expected LND-induced intracellular acidification and de-energization of isolated human prostate cancer cells using the PC3 cell line. These results were substantiated by non-invasive 31P magnetic resonance spectroscopy (MRS), studying PC3 prostate cancer xenografts treated with LND (100 mg/kg, i.p.). In addition, we found that LND significantly increased tumor lactate levels in the xenografts using 1H MRS non-invasively. Subsequently, LND was combined with radiation therapy in a growth delay experiment, where we found that 150 µM LND followed by 4 GY RT produced a significant growth delay in PC3 prostate cancer xenografts, compared to either control, LND, or RT alone. We conclude that the metabolic modulator LND radio-sensitizes experimental prostate cancer models, allowing the use of lower radiation doses and diminishing the potential side effects of RT. These results suggest the possible clinical translation of LND as a radio-sensitizer in patients with prostate cancer.

Phototherapy, including photodynamic therapy (PDT) and photothermal therapy (PTT), has great promise in the treatment of cancer. However, there are many obstacles that can restrict the therapeutic efficacy of phototherapy. The hypoxic tumor microenvironment can restrict the production of reactive oxygen species (ROS) in PDT. As for PTT, the thermotolerance of cancer cells may lead to ineffective PTT. In this study, IR780 and glycolysis inhibitor lonidamine (LND)-encapsulated liposomes are prepared for photodynamic and photothermal therapy of hepatocellular carcinoma. IR780 can be used as a photosensitizer and photothermal agent for simultaneous PDT and PTT after being irradiated with 808 nm laser. LND can reduce the oxygen consumption of cancer cells by inhibiting glycolysis, which will relieve tumor hypoxia and produce more ROS for PDT. On the other hand, energy supply can be blocked by LND-induced glycolysis inhibition, which will inhibit the production of heat shock proteins (HSPs), reduce the thermotolerance of tumor cells, and finally enhance the therapeutic efficacy of PTT. The enhanced PTT is studied by measuring intracellular HSPs, ATP level, and mitochondrial membrane potential. The antitumor effect of IR780 and LND co-loaded liposomes is extensively investigated by in vitro and in vivo experiments. This research provides an innovative strategy to simultaneously enhance the therapeutic efficacy of PDT and PTT by inhibiting glycolysis, which is promising for future creative approaches to cancer phototherapy.

Photodynamic therapy (PDT) is an effective approach for treating melanoma. However, the photosensitizers employed in PDT can accumulate in healthy tissues, potentially causing harm to normal cells and resulting in side effects such as heightened photosensitivity. To address this, an activatable photosensitizer (PSD) by linking PpIX with a fluorescence quencher using a disulfide bond is designed. PSD responded to endogenous GSH, showing high selectivity for A375 cells. To enhance PSD\'s bioavailability and anticancer efficacy, an enzyme-responsive nanoplatform based on a lonidamine-derived self-assembling peptide is developed. Initially, PSD and the peptide self-assembled into nanoparticles, displaying potent tumor targeting of PSD in vivo. Upon cell uptake, these nanoparticles specifically responded to elevated cathepsin B, causing nanoparticle disintegration and releasing PSD and lonidamine prodrug (LND-1). PSD is selectively activated by GSH for cancer-specific fluorescence imaging and precision PDT, while LND-1 targeted mitochondria, forming a fibrous lonidamine depot in situ and intensifying photosensitizer\'s cytotoxicity through ROS generation, mitochondrial dysfunction, and DNA damage. Notably, intravenous administration of LND-1-PEG@PSD with light irradiation significantly suppressed A375-xenografted mouse tumor growth, with minimal systemic toxicity. Together, the synergy of activatable photosensitizer and enzyme-responsive nanoplatform elevates PDT precision and diminishes side effects, showcasing significant potential in the realm of cancer nanomedicine.

Microgliosis and neuroinflammation are prominent features of Alzheimer\'s disease (AD). Disease-responsive microglia meet their increased energy demand by reprogramming metabolism, specifically, switching to favor glycolysis over oxidative phosphorylation. Thus, targeting of microglial immunometabolism might be of therapeutic benefit for treating AD, providing novel and often well understood immune pathways and their newly recognized actions in AD. We report that in the brains of 5xFAD mice and postmortem brains of AD patients, we found a significant increase in the levels of Hexokinase 2 (HK2), an enzyme that supports inflammatory responses by rapidly increasing glycolysis. Moreover, binding of HK2 to mitochondria has been reported to regulate inflammation by preventing mitochondrial dysfunction and NLRP3 inflammasome activation, suggesting that its inflammatory role extends beyond its glycolytic activity. Here we report, that HK2 antagonism selectively affects microglial phenotypes and disease progression in a gene-dose dependent manner. Paradoxically, complete loss of HK2 fails to improve AD progression by exacerbating inflammasome activity while its haploinsufficiency results in reduced pathology and improved cognition in the 5XFAD mice. We propose that the partial antagonism of HK2, is effective in slowed disease progression and inflammation through a non-metabolic mechanism associated with the modulation of NFKβ signaling, through its cytosolic target IKBα. The complete loss of HK2 affects additional inflammatory mechanisms associated to mitochondrial dysfunction.

Tumor proliferation and metastasis rely on energy provided by mitochondria. The hexokinase inhibitor lonidamine (LND) could suppress the activities in mitochondria, being a potential antitumor drug. However, limited water-solubility of LND may hinder its biomedical applications. Besides, the cancer-killing effect of LND is compromised by the high level of glutathione (GSH) in cancer cells. Therefore, it is urgent to find a proper method to simultaneously deliver LND and deplete GSH as well as monitor GSH level in cancer cells. Herein, a host polymer β-cyclodextrin-polyethylenimine (β-CD-PEI) and a guest polymer dextran-5-dithio-(2-nitrobenzoic acid) (Dextran-SS-TNB) were synthesized and allowed to form LND-loaded GSH-responsive nanoparticles through host-guest inclusion complexation between β-CD and TNB as host and guest molecular moieties, respectively, which functioned as a system for simultaneous delivery of LND and -SS-TNB species into cancer cells. As a result, the delivery system could deplete GSH and elevate reactive oxygen species (ROS) level in cancer cells, further induce LND-based mitochondrial dysfunction and ROS-based immunogenic cell death (ICD), leading to a synergistic and efficient anticancer effect. In addition, -SS-TNB reacted with GSH to release TNB2-, which could be a probe with visible light absorption at 410 nm for monitoring the GSH level in the cells.

UNASSIGNED: Mitochondria are a significant target of lonidamine (LND). However, its limited solubility and inability to specifically target mitochondria, LND can lead to hepatic toxicity and has shown only modest anticancer activity. The objective of this study is to establish a glutathione programmed mitochondria targeted delivery of LND for the effective treatment of triple negative breast cancer (TNBC).
UNASSIGNED: In this study, LND was encapsulated in poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) wrapped with mitochondria-targeting short-chain triphenylphosphonium-tocopherol polyethylene glycol succinate (TPP-TPGS, TPS) and tumor-targeting long-chain 1, 2-distearoyl-sn-glycero-3-phosphoethanolamine-S-S-polyethylene glycol-R6RGD (DSPE-S-S-PEG2000-R6RGD, DSSR), which were designated as LND-PLGA/TPS/DSSR NPs. The release behavior was evaluated, and cellular uptake, in vitro and in vivo antitumor activity of nanoparticles were investigated. The mechanism, including apoptosis of tumor cells and mitochondrial damage and respiratory rate detection, was also further investigated.
UNASSIGNED: LND-PLGA/TPS/DSSR NPs were successfully prepared, and characterization revealed that they are globular particles with smooth surfaces and an average diameter of about 250 nm. Long-chain DSSR in LND-PLGA/TPS/DSSR NPs prevented positively charged LND-PLGA/TPS NPs from being cleared by the reticuloendothelial system. Furthermore, LND release rate from NPs at pH 8.0 was significantly higher than that at pH 7.4 and 5.5, which demonstrated specific LND release in mitochondria and prevented LND leakage in cytoplasm and lysosome. NPs could locate in mitochondria, and the released LND triggered apoptosis of tumor cells by damaging mitochondria and releasing apoptosis-related proteins. In addition, in TNBC mice model, programmed mitochondria targeted NPs improved efficacy and reduced LND toxicity.
UNASSIGNED: LND-PLGA/TPS/DSSR NPs may be a useful system and provide an effective approach for the treatment of TNBC.

The combination of one molecule of organic and metal-based fragments that exhibit antitumor activity is a modern approach in the search for new promising drugs. In this work, biologically active ligands based on lonidamine (a selective inhibitor of aerobic glycolysis used in clinical practice) were introduced into the structure of an antitumor organometallic ruthenium scaffold. Resistant to ligand exchange reactions, compounds were prepared by replacing labile ligands with stable ones. Moreover, cationic complexes containing two lonidamine-based ligands were obtained. Antiproliferative activity was studied in vitro by MTT assays. It was shown that the increase in the stability in ligand exchange reactions does not influence cytotoxicity. At the same time, the introduction of the second lonidamine fragment approximately doubles the cytotoxicity of studied complexes. The ability to induce apoptosis and caspase activation in tumour cell MCF7 was studied by employing flow cytometry.

Pyroptosis is accompanied by immunogenic mediators\' release and serves as an innovative strategy to reprogram tumor microenvironments. However, damaged mitochondria, the origin of pyroptosis, are frequently eliminated by mitophagy, which will severely impair pyroptosis-elicited immune activation. Herein, black phosphorus nanosheets (BP) are employed as a pyroptosis inducer delivery and mitophagy flux blocking system since the degradation of BP could impair lysosomal function by altering the pH within lysosomes. The pyroptosis inducer of lonidamine (LND) was precoupled with the mitochondrial target moiety of triphenylphosphonium to facilitate the occurrence of pyroptosis. The mitochondria-targeting LND-modified BP (BPTLD) were further encapsulated into the macrophage membrane to endow the BPTLD with blood-brain barrier penetration and tumor-targeting capability. The antitumor activities of membrane-encapsulated BPTLD (M@BPTLD) were investigated using a murine orthotopic glioblastoma model. The results demonstrated that the engineered nanosystem of M@BPTLD could target the mitochondria, and induce as well as reinforce pyroptosis via mitophagy flux blocking, thereby boosting the release of immune-activated factors to promote the maturation of dendritic cells. Furthermore, upon near-infrared (NIR) irradiation, M@BPTLD induced stronger mitochondrial oxidative stress, which further advanced robust immunogenic pyroptosis in glioblastoma cells. Thus, this study utilized the autophagy flux inhibition and phototherapy performance of BP to amplify LND-mediated pyroptosis, which might greatly contribute to the development of pyroptosis nanomodulators.