Biology subjects

Kannan, R. M.

Publications and source records attributed to Kannan, R. M..

5 recordsLinked to original sources

bioRxiv2026

Gut-derived metabolic reprogramming drives immune aging and tissue degeneration

Aging is characterized by changes in gut microbiome, metabolic imbalance and chronic inflammation, yet how these processes integrate to drive tissue degeneration remains poorly defined. Using age-related macular degeneration (AMD) as a model of tissue aging, we identify a diet-induced metabolic-immune axis that promotes systemic and retinal degeneration. In mice, a high-fat, cholesterol-enriched (HFC) diet induced perturbations in the gut structural integrity and microbiome repertoire, as well as systemic metabolic aging signatures, prominently marked by reduced circulating histidine. Plasma histidine levels were similarly decreased in AMD patients and inversely correlated with body mass index (BMI) in control donors. These diet-induced gut microbiome changes and subsequent metabolic alterations promoted peripheral innate immune reprogramming, with expansion of inflammatory neutrophils and monocytes that infiltrated the outer retina in a mouse model. Mechanistically, the gut-derived IGF1R/AKT2 signaling acts as a central regulator of global epigenetic remodeling and systemic immune aging under high-fat conditions in C. elegans. In a mouse model with an age-dependent dry AMD-like pathology, distinct retinal pigment epithelium (RPE) subpopulations exhibited downregulation of the histidine transporter SLC7A5, linking metabolic stress to activation of MIF/CD74-dependent inflammatory signaling between RPE and infiltrating immune cells. Histidine supplementation or AKT2 phospho-state modulation attenuated systemic immune activation and rescued retinal degeneration. These findings identify histidine-axis dysregulation as a mechanistic bridge between diet-induced microbiome changes, metabolic stress, immune aging, and retinal degeneration.

cell biology↗

bioRxiv2025

Actinium-225 dendrimer-radioconjugates combined with low-dose standard-of-care chemotherapy: site-independent treatment of triple negative breast cancer metastases

PURPOSEMetastatic triple negative breast cancer (mTNBC) is incurable largely due to the development of drug resistance, the lack of selective cell targeting, and/or limitations in tumor drug delivery that vary depending on the different (metastatic) tumor locations. METHODSThe potential of a single type of systemic, targeted alpha-particle therapy (TAT) was investigated for addressing the above challenges of TNBC tumors implanted at different anatomic sites in mice. Actinium-225 dendrimer-radioconjugates alone, and/or after pretreatment with low-dose standard-of-care cisplatin, were assessed in vitro and on immune-competent 4T1-Balb/c mouse models with tumors implanted intracranially, orthotopically or subcutaneously. RESULTSIn vitro, TATs efficacy was enhanced by cisplatin. In vivo, treatment was initiated well after tumors had grown (Vto = 39 {+/-} 14 mm3 in the intracranial model, and Vto=100mm3 in the orthotopic and subcutaneous models). Across all tumor implantation sites, a unified correlation was observed between animal mean survival and the dendrimer-delivered tumor absorbed doses, which were selectively increased by low-dose cisplatin pretreatment. Importantly, in all animal models, the mean survival following systemic treatment with both modalities was significantly longer vs. each modality alone and/or vs. no treatment, at injected doses that did not cause long-term (10-month) toxicities in tumor-free mice. CONCLUSIONSystemically-injected dendrimer-delivered TAT, combined with low-dose cisplatin pretreatment, can safely extend survival independent of mTNBC tumors anatomic site, potentially presenting a single type of therapy to simultaneously treat multi-site mTNBC.

bioengineering↗

bioRxiv2024

Glioblastoma Treatment by Systemic Actinium-225 alpha-particle Dendrimer-radioconjugates is Improved by Chemotherapy

RATIONALEThe poor prognosis of glioblastoma is largely due to drug resistance and tumor location that, together, make it difficult to treat aggressively without affecting the rest of the brain. METHODOLOGYHigh-energy, short-range (40-80{micro}m) dendrimer-delivered -particles could address both challenges, because (1) they cause complex, highly cytotoxic double-strand DNA breaks, and (2) irradiation of the neighboring brain is minimal, since dendrimers selectively delivers them to tumors. Since cancer cells that are not directly hit by -particles will likely not be killed, the patterns of tumor irradiation affect efficacy. Systemically injected dendrimers extensively accumulate in glioblastomas, where they are taken up by tumor associated macrophages (TAMs), which tend to infiltrate tumors. We hypothesized that dendrimers labeled with -particle emitters, when being carried by TAMs, could more evenly irradiate glioblastomas, improving survival. In this study, the efficacy of dendrimers radiolabeled with the -particle emitter actinium-225 (dendrimer-radioconjugates) was evaluated when administered alone and/or after temozolomide, in a syngeneic immune-competent orthotopic GL261-C57BL/6 mouse model. RESULTSSystemically-administered dendrimer-radioconjugates, at activities that did not result in long-term toxicities, prolonged survival of mice with orthotopic GL261 tumors, compared to standard-of-care temozolomide (39 vs 31 days mean survival, p=0.0061) and non-treated animals (30 days, p=0.0009). Importantly, injection of temozolomide 24 hours before administration of dendrimer-radioconjugates further improved survival remarkably (44 days). This improvement in efficacy was attributed to: (1) the significant increase (by 33%) in tumor absorbed doses delivered by dendrimer-radioconjugates when injected after chemotherapy, without altering normal organ dosimetry, while sparing the tumor-surrounding healthy brain; (2) the potentially deeper tumor penetration of dendrimer-radioconjugates, suggested by the enhancement of dendrimer penetration within GL261-spheroids, employed as model tumor-avascular regions and/or TAM-free regions; and/or (3) the formation of a more lethal cocktail when both modalities acted on same cancer cells, that was correlated with increased levels of dendrimer-radioconjugates associating with GL261 cells in vitro and with greater incidences of karyomegaly in vivo. CONCLUSIONSThis study demonstrates the potential of a brain tumor targeted systemic actinium-225 radiopharmaceutical therapy that inhibits growth of glioblastoma cells and prolongs survival of mice with orthotopic brain tumors, further improved by standard-of-care temozolomide, without notable toxicities.

bioengineering↗

bioRxiv2020

Dendrimer-targeted immunosuppression of microglia reactivity super-accelerates photoreceptor regeneration in the zebrafish retina

Muller glia (MG) function as injury-induced retinal stem cells in zebrafish but not mammals. Insights from zebrafish, however, have been used to stimulate limited regenerative responses from mammalian MG. Microglia/macrophages regulate MG stem cell activity in the chick, zebrafish and mouse. We previously showed that dexamethasone can accelerate retinal regeneration in zebrafish. Similarly, microglia ablation enhances regenerative outcomes in the mouse retina. Targeted immunomodulation may therefore enhance the regenerative potential of human MG. Nanoparticle-based immunomodulation is an emerging field with immense therapeutic potential. Here, we investigated how regeneration-enhancing dexamethasone treatments alter microglia behavior and how dendrimer-based targeting of dexamethasone to reactive microglia impact retinal regeneration kinetics. Intravital time-lapse imaging revealed specific dexamethasone-induced changes in microglia reactivity. Dendrimer-conjugated dexamethasone treatments resulted in: 1) decreased toxicity, 2) selective targeting of reactive microglia and, 3) "super-accelerated" retinal regeneration kinetics. These data support the use of dendrimer-based drug formulations for modulating microglia reactivity in degenerative disease contexts, especially as therapeutic strategies for promoting regenerative responses to neuronal cell loss.

neuroscience↗

bioRxiv2020

Microglia-targeted dendrimer-2PMPA therapy robustly inhibits GCPII and improves cognition in a mouse model of multiple sclerosis

Roughly half of all individuals with multiple sclerosis (MS) experience cognitive impairment, but there are no approved treatments that target this aspect of the disease. Recent studies link reduced brain N-acetylaspartylglutamate (NAAG) levels to impaired cognition in various neurological diseases, including MS. NAAG levels are regulated by glutamate carboxypeptidase II (GCPII), which hydrolyzes the neuropeptide to N-acetyl-aspartate (NAA) and glutamate. Although several GCPII inhibitors, such as 2-(phosphonomethyl)-pentanedioic acid (2-PMPA), elevate brain NAAG levels and restore cognitive function in preclinical studies when given at high systemic doses or via direct brain injection, no GCPII inhibitors are clinically available due to poor bioavailability and limited brain penetration. Systemic hydroxyl dendrimers (~4 nm) have been successfully used to enhance brain delivery of drugs selectively to activated glia. We recently discovered that GCPII is highly upregulated in activated microglia after brain injury. To determine if dendrimer conjugation could enhance the brain delivery of GCPII inhibitors, specifically in the context of MS, we attached 2-PMPA to hydroxyl polyamidoamicne (PAMAM) dendrimers (D-2PMPA) using a highly efficient click chemistry approach. Targeted uptake of D-2PMPA into activated glia was subsequently confirmed in glial cultures where it showed robust anti-inflammatory activity, including an elevation in TGF{beta} and a reduction in TNF. Given these positive effects, D-2PMPA (20mg/kg) or vehicle dendrimer were dosed twice weekly to experimental autoimmune encephalomyelitis (EAE)-immunized mice starting at disease onset (therapeutic paradigm). D-2PMPA significantly improved cognition in EAE as assessed by Barnes maze performance, even though physical severity was not impacted. Glial target engagement was confirmed, as CD11b+ enriched cells isolated from hippocampi in D-2PMPA-treated mice exhibited almost complete loss of GCPII activity. These data demonstrate the utility of hydroxyl dendrimers to enhance brain penetration and support the development of D-2PMPA to treat cognitive impairment in MS. FundingThis work was funded by the National Multiple Sclerosis Society (RG-1507-05403 to BSS), the National Institute of Health NINDS (R01NS093416 to SK, RM and BSS), and Ashvattha Therapeutics. We would also like to acknowledge support for the statistical analysis from the National Center for Research Resources and NIH NCATS (1UL1TR001079). HighlightsO_LIThe GCPII inhibitor 2-PMPA was conjugated to hydroxyl PAMAM dendrimers (D-2PMPA) C_LIO_LID-2PMPA targeted activated glia in culture and displayed anti-inflammatory activity C_LIO_LIWhen dosed systemically to EAE mice, D-2PMPA inhibited CD11b+ cell GCPII activity C_LIO_LIWhen dosed systemically to EAE mice, D-2PMPA improved cognitive function C_LI

neuroscience↗