ferumoxytol / Apoptosis Cancer Research Results

Fer, ferumoxytol: Click to Expand ⟱
Features:
Ferumoxytol is an intravenous iron replacement product composed of superparamagnetic iron oxide nanoparticles coated with a carbohydrate shell. It was primarily developed to treat iron deficiency anemia, particularly in patients with chronic kidney disease (CKD). The nanoparticle formulation offers both therapeutic iron supplementation and a potential role as a magnetic resonance imaging (MRI) contrast agent because of its unique magnetic properties.

Because iron is essential for cell proliferation, there has been some concern about the theoretical risk of providing additional iron to environments where tumor cells might use it for growth. Nevertheless, the clinical significance of this in the context of ferumoxytol administration remains controversial and is not clearly established by current evidence.

There has been some research combining Ferumoxytol with high dose Vitamin C. Some laboratory studies have examined whether the combination of ferumoxytol and vitamin C can enhance anticancer effects. For instance, exposure of cancer cell lines or tumor models to this combination has been evaluated to see if there is an increase in ROS-mediated cytotoxicity compared to using either agent alone.

Ferumoxytol — an intravenously administered, carbohydrate-coated superparamagnetic iron oxide nanoparticle used as an iron-replacement drug. It consists of a non-stoichiometric magnetite core surrounded by a polyglucose sorbitol carboxymethylether coating, with an overall colloidal particle size of approximately 17–31 nm. The principal US brand is Feraheme, with additional ferumoxytol products now approved. Clinically, ferumoxytol is used to treat iron-deficiency anemia in adults with chronic kidney disease or intolerance or inadequate response to oral iron. Its strong magnetic susceptibility also permits off-label blood-pool, vascular, inflammatory and tumor-associated macrophage MRI, although it is not FDA-approved as an MRI contrast agent. Experimental anticancer activity is distinct from its approved hematologic use and remains investigational.

Primary mechanisms (ranked):

  1. Macrophage uptake and tumor-associated macrophage repolarization toward a pro-inflammatory, tumor-inhibitory M1-like phenotype in responsive preclinical tumor models.
  2. Iron-dependent Fenton chemistry and ROS generation after nanoparticle degradation, producing oxidative injury, mitochondrial dysfunction and cancer-cell death, particularly when combined with pharmacologic ascorbate.
  3. Enhancement of oxidative stress-mediated radiosensitization and chemosensitization when combined experimentally with high-dose intravenous ascorbate, radiation and temozolomide.
  4. Ferroptosis-related lipid peroxidation and iron-dependent membrane injury reported for iron oxide nanoparticle systems; direct attribution to clinically dosed ferumoxytol remains model-dependent.
  5. Preferential phagocytic accumulation in macrophages and reticuloendothelial tissues, enabling MRI detection of tumor-associated macrophages, inflammation and vascular compartments.
  6. Systemic iron delivery through macrophage processing of the nanoparticle coating and incorporation of released iron into ferritin, transferrin and hemoglobin.

Bioavailability / PK relevance: Ferumoxytol must be administered intravenously and has no meaningful oral bioavailability. The nanoparticle initially remains largely within the vascular compartment and is subsequently cleared primarily by macrophages of the reticuloendothelial system. Its apparent plasma half-life is approximately 15 hours at therapeutic doses, while intracellular iron persists much longer after macrophage uptake. The standard labeled regimen is 510 mg elemental iron followed by a second 510 mg infusion 3–8 days later. Tumor delivery depends on vascular permeability, perfusion, macrophage abundance and phagocytic uptake; heterogeneous intratumoral accumulation limits extrapolation from cell culture or highly macrophage-rich animal tumors.

In-vitro vs systemic exposure relevance: Free iron concentrations and direct nanoparticle-to-cell ratios used in many mechanistic studies do not reproduce the protein corona, vascular compartmentalization, macrophage sequestration and regulated iron handling occurring in patients. Direct cancer-cell cytotoxicity often requires high local nanoparticle exposure, prolonged incubation or an added pro-oxidant such as pharmacologic ascorbate. Clinically achievable ferumoxytol exposure is sufficient for iron replacement and prolonged MRI effects, but autonomous anticancer activity at approved anemia doses has not been established.

Clinical evidence status: Approved intravenous treatment for iron-deficiency anemia; off-label human MRI experience is substantial but does not constitute an approved imaging indication. Anticancer evidence is predominantly cellular and animal-model based. A first-in-human phase I glioblastoma study is evaluating ferumoxytol plus pharmacologic ascorbate with radiation and temozolomide, primarily for safety, tolerability and dose determination. There is presently no randomized evidence demonstrating improved cancer survival, and ferumoxytol should not be classified as an established anticancer drug or standard radiosensitizer.

Ferumoxytol Mechanistic Profile

Rank Pathway / Axis Cancer Cells Normal Cells TSF Primary Effect Notes / Interpretation
1 Tumor-associated macrophage polarization Indirect ↓ survival and growth ↑ macrophage inflammatory activation (context-dependent) G ↑ M1-like macrophage phenotype and antitumor innate immunity Best-supported ferumoxytol-specific anticancer mechanism, but demonstrated principally in murine tumor models. Response depends on macrophage abundance and tumor microenvironment.
2 Iron-dependent Fenton chemistry ↑ hydroxyl-radical stress and cytotoxicity ↑ oxidative burden if antioxidant capacity is exceeded R/G Conversion of peroxide into highly reactive oxygen species Requires intracellular nanoparticle degradation and available peroxide. Strongly enhanced by pharmacologic ascorbate or other pro-oxidant conditions.
3 Pharmacologic ascorbate interaction ↑ H₂O₂-mediated killing ↔ or modest injury under controlled exposure R Ferumoxytol-derived iron accelerates ascorbate-driven oxidative chemistry Investigational combination. Selectivity is proposed to arise from differences in peroxide metabolism and redox buffering, not from tumor-exclusive nanoparticle uptake.
4 Radiosensitization ↑ radiation-associated oxidative damage (requires external trigger) Potential ↑ normal-tissue oxidative injury R/G Amplification of radiation-induced ROS and macromolecular damage Being tested with pharmacologic ascorbate, radiation and temozolomide in glioblastoma. Ferumoxytol-alone radiosensitization is not clinically established.
5 Chemosensitization ↑ temozolomide-associated cytotoxicity (context-dependent) Potential ↑ treatment toxicity G Oxidative augmentation of DNA-damaging therapy Evidence is primarily combination-based and cannot be separated cleanly from the effects of pharmacologic ascorbate and radiation.
6 Mitochondrial ROS and dysfunction ↑ ROS, ↓ membrane potential and ↑ apoptosis ↔ at regulated iron exposure; ↑ injury with overload R/G Oxidative impairment of mitochondrial function Often secondary to iron release and Fenton chemistry rather than a direct nanoparticle receptor-mediated effect.
7 Ferroptosis and lipid peroxidation ↑ lipid ROS and ferroptotic susceptibility (model-dependent) ↑ susceptibility during iron overload or depleted antioxidant defenses G Iron-dependent oxidative membrane damage Well described for iron oxide nanoparticle platforms, but ferumoxytol-specific evidence is less mature than the macrophage-polarization mechanism.
8 NRF2 antioxidant response ↑ adaptive NRF2 signaling or ↓ cytotoxicity (context-dependent) ↑ antioxidant defense G Compensatory response to nanoparticle-induced oxidative stress Secondary mechanism. NRF2 activation may protect cells and reduce oxidative treatment efficacy rather than function as the principal therapeutic action.
9 Macrophage and reticuloendothelial uptake ↑ tumor-associated macrophage labeling ↑ hepatic, splenic and marrow macrophage uptake G Phagocytic sequestration and gradual iron processing Central to iron delivery and off-label MRI. Uptake does not itself prove antitumor activity.
10 Iron availability and erythropoiesis Potential ↑ iron availability (context-dependent) ↑ transferrin iron, ferritin and hemoglobin synthesis G Correction of iron-deficiency anemia Established clinical mechanism. Theoretical concern that iron could support tumor metabolism has not established a clinically meaningful tumor-promoting effect from appropriately indicated ferumoxytol therapy.
11 Magnetic resonance signal modulation ↓ T2 and T2-star signal in nanoparticle-rich regions ↓ signal in blood pool and reticuloendothelial tissues R/G Prolonged susceptibility-based MRI contrast Useful for vascular and macrophage imaging but off-label. Ferumoxytol can alter MRI findings for weeks to months and may obscure or mimic pathology.
12 Clinical Translation Constraint ↔ uncertain therapeutic exposure Risk of hypersensitivity, hypotension, iron overload and extravasation staining R/G Limits oncology deployment outside controlled trials Anticancer effects are unproven in randomized trials. Administration requires infusion over at least 15 minutes, immediate availability of anaphylaxis treatment and observation for at least 30 minutes. Tumor uptake is heterogeneous, and approved anemia dosing cannot be assumed to reproduce experimental intratumoral concentrations.

P: 0–30 min    R: 30 min–3 hr    G: >3 hr
Apoptosis, Apoptosis: Click to Expand ⟱
Source:
Type: type of cell death
Situation in which a cell actively pursues a course toward death upon receiving certain stimuli.
Cancer is one of the scenarios where too little apoptosis occurs, resulting in malignant cells that will not die.
Scientific Papers found: Click to Expand⟱
6891- Fer,    Iron oxide nanoparticles inhibit tumor growth by ferroptosis in diffuse large B-cell lymphoma
- vitro+vivo, lymphoma, NA
TumCG↓, Ferroptosis↑, i-Iron↑, lipid-P↑, GPx4↓, ROS↑, Fenton↑, TfR1/CD71↝, FPN↝, LIP↑, TumCP↓, Apoptosis↑, TumCG↓,

Showing Research Papers: 1 to 1 of 1

* indicates research on normal cells as opposed to diseased cells
Total Research Paper Matches: 1

Pathway results for Effect on Cancer / Diseased Cells:


NA, unassigned(tgid=0) ⓘ

FPN↝, 1,   LIP↑, 1,  

Redox & Oxidative Stress(tgid=1) ⓘ

Fenton↑, 1,   Ferroptosis↑, 1,   GPx4↓, 1,   i-Iron↑, 1,   lipid-P↑, 1,   ROS↑, 1,  

Metal & Cofactor Biology(tgid=2) ⓘ

TfR1/CD71↝, 1,  

Cell Death(tgid=5) ⓘ

Apoptosis↑, 1,   Ferroptosis↑, 1,  

Proliferation, Differentiation & Cell State(tgid=12) ⓘ

TumCG↓, 2,  

Migration(tgid=13) ⓘ

TumCP↓, 1,  
Total Targets: 13

Pathway results for Effect on Normal Cells:


Total Targets: 0

Scientific Paper Hit Count for: Apoptosis, Apoptosis
Query results interpretion may depend on "conditions" listed in the research papers.
Such Conditions may include : 
  -low or high Dose
  -format for product, such as nano of lipid formations
  -different cell line effects
  -synergies with other products 
  -if effect was for normal or cancerous cells

Filter Conditions: Pro/AntiFlg:%  IllCat:%  CanType:%  Cells:%  prod#:285  Target#:14  State#:%  Dir#:%
  wNotes=0  sortOrder:rid,rpid

 

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