Afsana Sheikh1, Prashant Kesharwani1(), Waleed H. Almalki2, Salem Salman Almujri3, Linxin Dai4, Zhe-Sheng Chen5, Amirhossein Sahebkar6,7, Fei Gao4()
Understanding the Novel Approach of Nanoferroptosis for Cancer Therapy
Afsana Sheikh1, Prashant Kesharwani1(), Waleed H. Almalki2, Salem Salman Almujri3, Linxin Dai4, Zhe-Sheng Chen5, Amirhossein Sahebkar6,7, Fei Gao4()
1 Department of Pharmaceutics, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi, 110062, India 2 Department of Pharmacology and Toxicology, Faculty of Pharmacy, Umm Al-Qura University, Makkah, Saudi Arabia 3 Department of Pharmacology, College of Pharmacy, King Khalid University, 61421, Asir-Abha, Saudi Arabia 4 State Key Laboratory of Southwestern Chinese Medicine Resources, Pharmacy School, Chengdu University of Traditional Chinese Medicine, Chengdu, 611130, People's Republic of China 5 Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, New York, 11439, USA 6 Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran 7 Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
As a new form of regulated cell death, ferroptosis has unraveled the unsolicited theory of intrinsic apoptosis resistance by cancer cells. The molecular mechanism of ferroptosis depends on the induction of oxidative stress through excessive reactive oxygen species accumulation and glutathione depletion to damage the structural integrity of cells. Due to their high loading and structural tunability, nanocarriers can escort the delivery of ferro-therapeutics to the desired site through enhanced permeation or retention effect or by active targeting. This review shed light on the necessity of iron in cancer cell growth and the fascinating features of ferroptosis in regulating the cell cycle and metastasis. Additionally, we discussed the effect of ferroptosis-mediated therapy using nanoplatforms and their chemical basis in overcoming the barriers to cancer therapy.
It is a programmed cell death (PCD) wherein both the nuclear and cellular size decrease, leading to the fragmentation of nuclear bodies while maintaining an unchanged response to the mitochondria
Ferroptosis
A newly discovered regulated form of cell death that damages mitochondrial Crista and ruptures the nucleus and mitochondrial membrane
Necroptosis
This kind of PCD causes rupture of cell membrane, random DNA degradation, swelling of cell and its deformation and deformation of organelles
Cuproptosis
Aggregation of lipoylated mitochondrial proteins
Table 1
Inducers of ferroptosis
Function
References
Doxorubicin
HO-1
[251]
RSL3
GPX4 inhibition
[252]
Hemin
Iron accumulation
[253]
Sulfasalazine
Inhibition of System Xc−
[254]
Altretamine
GPX4 inhibition
[255]
Glutamate
Inhibition of System Xc− that affect cellular transport of cysteine
[256]
FINs
ROS generation
[10]
Bromelain
ROS generation in KRAS mutation
[257]
All-trans retinoic acid (ATRA)
ROS generation
[258]
Lapatinib
Improve oxidative stress inside the cells
[259]
Artesunate
Induces programmed cell death through ROS generation
[260]
Ferumoxytol
Lipid peroxidation
[261]
Cotylenin A
ROS generator
[262]
Table 2
Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Type of nanocarrier system
Chemotherapeutics
Genes
Cancer type
In vitro
In vivo
Inference
References
MOF
Doxorubicin
-
Breast cancer
4T1 cells
Balb/c mice
Doxorubicin-induced ferroptosis causing immunogenic cell death (ICD)
[251]
Gold mesoporousMOF
-
-
Breast cancer
4T1 cells
Balb/c mice
Cu and Fe ion bridged using disulfide bond induces ferroptosis by depleting GSH, finally inhibiting GPX-4 level
[137]
MOF
Doxorubicin
-
Breast cancer
4T1 and MCF-7
Mice (name not mentioned)
The drug-loaded nanoparticle showed great potency and clinical translation by targeting CD44 over-expressed cells
[141]
Fe(III)- porphyrin-MOF
Oxaliplatin
-
-
Breast cancer
4T1 cells
The therapy increased the level of H2O2 and (IFN-γ), which in turn caused ferroptosis of cells
[145]
Fe-MOF
-
-
Breast cancer
4T1 cells
Aptamer PD-L1-attached glucose oxidase and PEG-modified iron-based MOF were an innovative strategy to disrupt iron homeostasis and hinder intracellular redox
[21]
RBC membrane camouflaged MOF
Doxorubicin
-
Breast cancer
MCF-7
Balb/c nude mice
Results illustrated that self-assembled RBC membrane camouflaged MOF could amplify the oxidative stress of ROS, reduce glutathione potentiating remarkable anticancer effects
[146]
MOF
Doxorubicin
-
Breast cancer
4T1 cells
Balb/c mice
The nanoplatform downregulated GPX4 to induce ferroptosis
[251]
Nanophoto-sensitizer
-
-
Human melanoma cancer
A375
Nu/Nu female mice
A photodynamic therapy-based nanosheets of graphitic carbon nitride functionalized with mitochondria-targeting iridium (III) polypyridine complexes caused hypoxic environment resulting in cell death
[225]
Theranostic nanoparticle composed of iron ions, cinnamaldehyde prodrug and amphiphilic polymer skeletal (FCS/GCS)
-
-
Breast cancer
4T1 cells
Balb/c mice
The preparation with the help of CA induces Fenton reaction, generated ·OH and accelerated lipid peroxides (LPO) accumulation and accordingly augments ferroptosis
[229]
Bonsai-inspired AIE nanohybrid photosensitizer
-
-
Colon cancer
MC38 cells
Balb/c
The Bonsa-inspired nanopreparation in presence of white light irradiation produced hydroxyl radical and depleted GSH to induce ferroptosis in cancer cells
[240]
Cell membrane decorated iron-siRNA nanohybrid
-
Anti- SLC7A11 siRNA
Human oral squamous cell carcinoma
CAL-27
Male Balb/c
The nanohybrid system elevated the ROS level to show synergic anti-cancer effect in vivo
[96]
Magnetic lipid nanoparticle
-
siDECR1
Castration-resistant prostate cancer
C4-2B or C4-2BEnz cells
Nude mice (name not mentioned)
The biomimetic nanoparticles were stable, safe and effective in showing remarked inhibition of distant organ metastasis
[218]
Graphene oxide-PEG-PEI nanoparticle
Sorafenib
PD-L1 siRNA
Hepatocellular carcinoma
MHCC97H cells
C57BL/6 mice
The developed preparation reduced the expression of GPX4 in the intrahepatic tumor regions in immunocompetent mice
[219]
Liposome
Artemisinin
-
Lung carcinoma
LLC cells
Balb/c nude mice
The remarkable autophagy-mediated ferroptosis-involved cancer-therapeutic efficacy is suggested by therapeutic outcomes both in vitro and in vivo which is further confirmed by transcriptome sequencing
[160]
Nanostructured lipid carrier
Doxorubicin, ferrocene
-
Breast cancer
4T1 cells
Balb/c mice
TGF-β receptor inhibitor along with ferrocene and doxorubicin-loaded NLC inhibited mammary cancer metastasis by extracellular as well as intracellular hybrid mechanism
[164]
Liposomes
-
-
Breast cancer
4T1 cells
Balb/c mice
An amalgamation of sonosensitizing agent (PpIX) and ferumoxytol in liposomes induced apoptosis and ferroptosis overcoming the tumor resistance
[215]
Iron oxide nanoparticles
Paclitaxel
-
Glioblastoma
U251 and HMC3 cells
Balb/c-nu mice
PTX-IONP reduced the ability of cells to invade and migrate, elevated ROS, iron ions and lipid peroxidation, enhanced the expression of the autophagy-related proteins LC3II, and Beclin1 and suppressed the expression of the p62 and GPX4
[173]
Nanozyme
Cisplatin
-
Ovarian cancer
SKOV3/DDP cells
BALB/cJGpt-Foxn1nu/Gpt mice
The formulation was able to induce both apoptosis and ferroptosis with the help of ultrasound treatment for cisplatin-resistant cancer cells
[193]
Nanozyme
-
-
Triple-negative breast cancer
MDA-MB-231 cells
Balb/c nude mice
The imaging-based nanosystem used SPIO and Avastin to induce tumor starvation and ferroptosis
[263]
Nanozyme
-
-
Breast cancer
4T1 and MCF-7 cells
Balb/c mice
Tumor ablation was accomplished with Fenton reaction-independent ferroptosis driven by photothermal nanozyme
[197]
Nanozyme
Gemcitabine
-
Pancreatic cancer
PANC02
Balb/c mice
GEM and MnFe2O4 can synergistically improve anti-cancer profile via ferroptosis and GEM-mediated chemotherapy
[198]
Human serum albumin nanoparticle (HAS-NP)
Pt (IV)
-
Ovarian cancer
SKOV3
Mice (name not mentioned)
The prodrug of platinum in HAS nanoparticles was effective for ovarian cancer cell resistance to platinum
[241]
Iron-doped calcium carbonate nanoparticles
Pt(IV)
-
Breast cancer
4T1 and CT26 cells
Balb/c
Iron-doped platinum-SA-based CaCO3 showed development of ROS and lipid peroxidation to mediate cancer cell death
[242]
Zeolite imidazolate framework (Zif-8)
-
-
Head and neck squamous cell carcinoma
HN6
Male Balb/c
DHA and SNP enveloped nanoreactor system prompted Fe2+ and NO release to initiate ferroptosis and apoptosis synergistically
[247]
Hypoxia-responsive nanoelicitor
Mitoxantrone
-
Colorectal cancer
CT26 cells
Balb/c nude mice
The simultaneous co-stimulating effects of CA and MIT resulted in an elevated antiproliferative and anti-cancer immunity, which in turn aborted the system Xc− to GPX4 pathway and increased the iron-initiated tumor cell destruction
[248]
Table 3
Fig. 7
Fig. 8
Fig. 9
Fig. 10
Fig. 11
Fig. 12
Fig. 13
Fig. 14
Fig. 15
Fig. 16
Fig. 17
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