The Applications Of Functionalized Biomaterials To Induce Ferroptosis For Cancer Therapy

Apoptosis dysregulation is one of the important mechanisms responsible for cancer resistance,which necessitates the exploration of oncological treatments to activate nonapoptotic cell death.Ferroptosis has been recently described as a new form of regulated cell death that is closely related to the metabolism of amino acids,lipids,and iron.It main regulated by the proteins of GPX4,FSP1 and DHODH,but is independent of classic initiating signals in apoptosis(e.g.,caspase3/7,Bcl-2,etc.).Recently studies indicated that cancer cells may be more susceptible to ferroptotic inducers treatment.Herein,we speculated that induction of ferroptosis in cancer cells could overcome cancer resistances.In this study,to overcome cancer resistances by triggering ferroptosis,we developed a combination treatment of hyperoxia and X-rays for lipid peroxidation,as well as a new ferroptotic inducer of liposome-OOH to target lysosome to perturb the metabolism of ferrous ion.We also made the following findings:1)Construction of photosynthetic microcapsules(PMCs)for controllable and long-lasting oxygen supply.An evolved strain(e-S.7942)was acquired by stepwise changing the culture temperature from 25 ℃ to 37℃ and media components of RPMI 1640(0-90%).After that,the PMCs were prepared by encapsulating e-S.7942 and photoluminescent upconversion nanoparticles(UCNPs)in alginate microcapsules.The densities of e-S.7942 and UCNPs encapsulated in PMCs were elaborately examined to acquire an optimized formula of 1 × 106 e-S.7942 and 0.7 μg UCNPs for efficient photosynthesis.The construted PMCs were able to improve the dissolved oxygen from 1.6 mg/L to 7.3 mg/L for creating hyperoxia biocontexts and ameliorating the hypoxic status in 90%cells.2)Combined treatment of PMCs and X-rays to trigger lipid peroxidation and induce ferroptosis for overcoming drug-resistant malignant melanoma.The PMCs treatment could increase the oxygen levels from 10.9 mmHg to 33.1 mmHg in tumor site.The combination treatment of PMCs and X-rays could produce ·OH,which further induced lipid peroxidation for accumulating lipid peroxides and targeting ferroptosis in cells.Consequently,the intrinsic and acquired resistance in melanoma could be overcome by the combined treatment,which further inhibited tumor metastases and improved the survival rate of melanoma-bearing mice.3)The peroxidation of liposomes(liposome-OOH)induced ferroptosis for treating refractory cancers.First,three liposome-OOHs were designed by rational engineering to induce ferroptosis.A comparative study on three functionalized phospholipids indicated that phosphatidylcholine(PC,18:2)peroxides-based liposomes(liposome-OOH)could induce ferroptosis in over 11 cell lines.Liposome-OOH could target lysosomes and perturb the metabolism of ferrous ions,which further evoked lipid peroxidation,reduced GSH levels,prevented GPX4 expression and induced ferroptosis in drug-resistant cancers.4)The liposome-OOH improved the survival rates of tumor-bearing mice.The antitumor effects of liposome-OOH were intravenous injected and examined in an orthotopic DOX-resistant breast tumor model.The animal results indicated that liposome-OOH inhibited tumor growth and lung metastases,prolonged survival time from 38 days to at least 60 days and made 90%tumor-bearing mice survival time longer than 60 days.To summarize,this study has the following conclusions:ⅰ)PMCs could create hyperoxia biocontexts to improve the hypoxic tumor microenvironment;ⅱ)the combination treatment of PMCs and X-rays could overcome malignant melanoma by inducing lipid peroxidation and targeting ferroptosis;and ⅲ)liposome-OOH could treat refractory cancers by targeting cellular lysosomes,perturbing ferrous ion metabolism and inducing ferroptosis.This study has the following implications:ⅰ)the oxygen supply by the photosynthesis of PMCs provides a new strategy for ameliorating the hypoxic tumor microenvironment;ⅱ)the combination treatment of PMCs and X-rays develops a new therapeutic regimen for overcoming cancer resistance;and ⅲ)liposome-OOH,as a new ferroptotic inducer,provides a new therapeutic agent for treating refractory cancers.