Efficient Cancer Therapy Research Articles

Ultrathin 2D Pd/Cu Single-Atom MOF Nanozyme to Synergistically Overcome Chemoresistance for Multienzyme Catalytic Cancer Therapy.

Single-atom nanozymes (SAzymes) have obtained increasing interest to mimic natural enzymes for efficient cancer therapy, while challenged by chemoresistance from cellular redox homeostasis and the interface of reductive species in tumor microenvironment (TME). Herein, a dual single-atomic ultrathin 2D metal organic framework (MOF) nanosheet of multienzyme (Pd/Cu SAzyme@Dzy) is prepared to synergistically overcome chemoresistance for multienzyme enhanced cancer catalytic therapy. The Pd SAzyme exhibits peroxidase (POD)-like catalytic activity for overcoming chemoresistance via disturbing cellular redox balance. This is further enhanced by cascade generation of more ∙OH via Cu+ -catalyzed POD-like reactions, initiated by in situ-reduction of Cu2+ into Cu+ upon GSH depletion. This process can also avoid the consumption of ∙OH by endogenous reductive GSH in TME, ensuring the adequate amount of ∙OH for highly efficient therapy. Besides, the DNAzyme is also delivered for gene therapy of silencing cancer-cell-targeting VEGFR2 protein to further enhance the therapy. Based on both experiments and theoretical calculations, the synergetic multienzyme-based cancer therapy is examined and the enhancement by the cascade tumor antichemoresistance is revealed.

MitoQ combats tumor cell progression in Ehrlich ascites carcinoma mice: A crosstalk between mitochondrial oxidative status, mitophagy, and NF-κB signaling

Despite the clinical advances in cancer treatment, the high mortality rate is still a great challenge, requiring much effort to find new and efficient cancer therapies. AimsThe present evidence investigated the potential antiproliferative impact of the mitochondrial-targeted antioxidant, Mitoquinol (MitoQ), on a mouse model of Ehrlich ascites carcinoma (EAC). Main methodsMice-bearing tumors were administered two doses of MitoQ (0.3 mg & 0.5 mg/kg; i.p daily) or doxorubicin (2 mg/kg; i.p daily) for 20 days. Key findingsEAC mice revealed exacerbated mitochondrial reactive oxygen species (mtROS) and impaired mitochondrial membrane potential (△Ψm). Dysfunctional mitophagy was observed in EAC mice, along with boosting aerobic glycolysis. In addition, tumor cells exhibited higher proliferation rates, thereby stimulating cell cycle, invasion, and angiogenesis biomarkers together with suppressing proapoptotic proteins, events that might be correlated with activation of NF-κB signaling. The administration of MitoQ combated tumor cell survival and dissemination in EAC mice as evidenced by reducing tumor volumes and weights and increasing the number of necrotic areas in histopathological assessment. MitoQ also repressed tumor cell cycle, invasion, and angiogenesis via preventing cyclin D1 mRNA, MMP-1, and CD34 levels as well as VEGF protein expression. These observations were associated with the abrogation of mtROS overproduction and enhancement of the mitophagy proteins, PINK1/Parkin levels, followed by inhibition of NADH dehydrogenase. Notably, NF-κB signaling was modulated. SignificanceThis study suggests that MitoQ combated tumor cell survival and progression in EAC mice by maintaining mtROS and restoring mitophagy, thereby attenuation of NF-κB activation.

Hybrid organosilica nanoagent with Fenton-like reaction activity and glutathione depletion for augmented chemo/chemodynamic therapy

Development of efficient and specialized anti-cancer agent is highly desirable for both basic and clinical research. Herein, a multifunctional organosilica nanoagent (MOCL-DOX) loaded with copper ion, arginine, and doxorubicin was designed and prepared. Copper ion (Cu2+) and arginine (LA) were doped into the S-S bond-containing degradable organosilica nanocarrier as functional components. S-S bonds were broken under excessive glutathione (GSH) conditions when the nanoagent reached the tumor sites. Simultaneously Cu2+ was released, reduced by GSH to Cu+, and Cu+ selectively converted hydrogen peroxide (H2O2) to hydroxyl radical (•OH) by Fenton-like reaction which caused extensive cellular oxidation and even apoptosis. Tumor cell viability and growth were inhibited to a great extent by the combination of CDT and chemotherapy with minimal normal cells toxicity. Thus, the MOCL-DOX nanoagent demonstrates as a novel paradigm for the fabrication of Fenton's nanoagent for efficient cancer therapy with minimal side effects.

In Vivo Aggregation of Clearable Bimetallic Nanoparticles with Interlocked Surface Motifs for Cancer Therapeutics Amplification.

Although renal-clearable luminescent metal nanoparticles (NPs) have been widely developed, their application to efficient cancer therapy is still limited due to low reactive oxygen species (ROS) production. Here, a novel system of clearable mercaptosuccinic acid (MSA) coated Au-Ag bimetallic NPs is designed to enhance ROS production. The results show that the strong COO-Ag coordination bonds between the carboxylic acid groups of MSA and Ag atoms on the Au-Ag bimetallic NPs could construct high-rigidity interlocked surface motifs to restrict the intrananoparticle motions for enhanced ROS generation. Moreover, bimetallic NPs exhibit pH-responsive self-assembly capability under the acidic environment inside lysosomes of cancer cells at both in vitro and in vivo, restricting the internanoparticle motions to further boost ROS production. The well-designed bimetallic NPs show high tumor targeting efficiency, fast elimination from the body through rapid liver biotransformation, and extensive destruction to cancer cells, resulting in good security and prominent therapeutic performance.

Design and Synthesis of BODIPY-Hetero[5]helicenes as Heavy-Atom-Free Triplet Photosensitizers for Photodynamic Therapy of Cancer.

Designing heavy-atom-free triplet photosensitizers (PSs) is a challenge for the efficient photodynamic therapy (PDT) of cancer. Helicenes are twisted polycyclic aromatic hydrocarbons (PAHs) with an efficient intersystem crossing (ISC) that is proportional to their twisting angle. But their difficult syntheses and weak absorption profile in the visible spectral region restrict their use as heavy-atom-free triplet PSs for PDT. On the other hand, boron-containing PAHs, BODIPYs are highly recognized for their outstanding optical properties. However, planar BODIPY dyes has low ISC and thus they are not very effective as PDT agents. We have designed and synthesized fused compounds containing both BODIPY and hetero[5]helicene structures to develop red-shifted chromophores with efficient ISC. One of the pyrrole units of the BODIPY core was also replaced by a thiazole unit to further enhance the triplet conversion. All the fused compounds have helical structure, and their twisting angles are also increased by substitutions at the boron centre. The helical structures of the BODIPY-hetero[5]helicenes were confirmed by X-ray crystallography and DFT structure optimization. The designed BODIPY-hetero[5]helicenes showed superior optical properties and high ISC with respect to [5]helicene. Interestingly their ISC efficiencies increase proportionally with their twisting angles. This is the first report on the relationship between the twisting angle and the ISC efficiency in twisted BODIPY-based compounds. Theoretical calculations showed that energy gap of the S1 and T1 states decreases in BODIPY-hetero[5]helicene as compared to planar BODIPY. This enhances the ISC rate in BODIPY-hetero[5]helicene, which is responsible for their high generation of singlet oxygen. Finally, their potential applications as PDT agents were investigated, and one BODIPY-hetero[5]helicene showed efficient cancer cell killing upon photo-exposure. This new design strategy will be very useful for the future development of heavy-atom-free PDT agents.

The mirrored cationic peptide as miRNA vehicle for efficient lung cancer therapy.

Gene therapy has emerged as a potential approach for lung cancer therapy. However, the application of gene therapy is still limited by their properties, such as low specificity to the cancer cells, negatively charged groups, short systemic circulation time, and rapid degradation by nucleases. The progression of lung adenocarcinoma (LUAD) can be promoted through the methylation process of miR-148a-3p promoter, as confirmed by our previous research. In the current study, we are the first to design a mirrored Arg-Gly-Asp (RGD)-modified cationic peptide (RD24) as a microRNA (miRNA) vehicle, which enabled to pack the miRNA (miR-148a-3p) efficiently and generate RD24/miR-148a-3p nanoparticles (RPRIN) by self-assembling. RPRIN exhibited a high transfection efficiency in lung cancer cells via the conjugation between RGD and integrins on the surface of lung cancer cells. Furthermore, RD24 showed matrix metallopeptidase 2 (MMP2) responsiveness, which improved lung cancer cell inhibition induced by the miRNA intracellularly. In addition, RPRIN exhibits several advantages, such as prolonged circulation duration, reduced toxicity, and immune escape. Experiments conducted both in vitro and in vivo revealed that RPRIN effectively suppressed the growth and progression of lung cancer. Thus, the mirrored RGD-modified cationic peptide showed great potential in transducing miRNA for lung cancer therapy.

Amplifying oxidation stress and T-cell activation by bioactive layered double hydroxide sonosensitizers for enhanced cancer immunotherapy

Sonodynamic therapy (SDT) is a potential non-invasive therapeutic to overcome the limitation of depth and to enhance immunotherapy by converting “cold” to “hot” tumors. However, the intervention effect of SDT-induced hot tumors may not be sufficient to effectively enhance the effect of immunotherapy due to the intricate tumor microenvironment (TME). Herein, a multifunctional and potent sonosensitizer based on layered double hydroxides (LDHs) with a suitable bandgap and diverse immunological effects (activation of T cells and enhancement infiltration of T cells) was designed to facilitate high-performance SDT combined with immunotherapy. Briefly, Ca2+ was introduced into MgFe-LDH to construct MgCaFe-LDH to achieve excellent SDT performance, outstanding modulated TME ability, and a tremendous prognosis effect. The better SDT efficiency was attributed to the optimized electron structure and bandgap with increasing Ca2+ introduction. The regulation of the intricate TME by improving the hypoxic microenvironment and decreasing the concentration of glutathione (GSH) with reducibility to enhance oxidation stress further boosted the SDT effect. In addition, bioactive MgCaFe-LDH exhibited an excellent immunological function, resulting from Mg2+ and Ca2+ ions synergistically activating CD8+ and CD4+ T cells and enhancing the infiltration of T cells into tumor tissues. Moreover, the combined therapy with SDT and αCTLA-4 also displayed a suppressive effect on the bilateral tumor model. Our work highlights novel bioactive LDH sonosensitizers that integrate TME regulation, SDT, and immunological effects for efficient cancer therapy.

Codelivery of Que and BCL-2 siRNA with Lipid-Copolymer Hybrid Nanocomplexes for Efficient Tumor Regression.

The efficacy of chemotherapy is often reduced due to the chemotherapy resistance of tumor cells, which is usually caused by abnormal gene overexpression. Herein, multifunctional nanocomplexes (Que/siBCL2@BioMICs) were developed to deliver quercetin (Que) and BCL-2 siRNA (siBCL2) to synergistically inhibit tumor growth. The nanocomplexes were composed of an amphiphilic triblock copolymer of poly(ethylene glycol) methyl ether methacrylate-poly[2-(dimethylamino) ethyl acrylate]-polycaprolactone (PEGMA-PDMAEA-PCL) and 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-poly(ethylene glycol)-biotin (DSPE-PEG-biotin). Que was encapsulated into the cores through hydrophobic interactions, while negatively charged siBCL2 was loaded through electrostatic interactions. The nanocomplexes could effectively facilitate cellular uptake via biotin-mediated active targeting and cytosolic release of cargos by the "proton sponge effect" of PDMAEA. Que/siBCL2@BioMICs achieved enhanced cytotoxicity and anti-metastasis activity due to a synergistic effect of Que and siBCL2 in vitro. More importantly, superior anti-tumor efficacy was observed in orthotopic 4T1 tumor-bearing mice with reduced primary tumor burden and lung metastatic nodules, while no obvious side effects to major organs were observed. In conclusion, the biotin-targeted nanocomplexes with chemotherapeutic and nucleotide agent entrapment provide a promising strategy for efficient triple-negative breast cancer (TNBC) therapy.

Redox Homeostasis Disruptors Based on Metal-Phenolic Network Nanoparticles for Chemo/Chemodynamic Synergistic Tumor Therapy through Activating Apoptosis and Cuproptosis.

The combination of chemo/chemodynamic therapy is a promising strategy for improving antitumor efficacy. Herein, metal-phenolic network nanoparticles (NPs) self-assembled from copper ions and gallic acid (Cu-GA) are developed to evoke apoptosis and cuproptosis for synergistic chemo/chemodynamic therapy. The Cu-GA NPs are biodegraded in response to the highly expressed glutathione (GSH) in tumor cells, resulting in the simultaneous release of Cu+ and GA. The intracellular GSH content is dramatically reduced by the released GA, rendering the tumor cells incapable of scavenging reactive oxygen species (ROS) and more susceptible to cuproptosis. Meanwhile, ROS levels within the tumor cells are significantly increased by the Fenton-like reaction of released Cu+ , which disrupts redox homeostasis and achieves apoptosis-related chemodynamic therapy. Moreover, massive accumulation of Cu+ in the tumor cells further induces aggregation of lipoylated dihydrolipoamide S-acetyltransferase and downregulation of iron-sulfur cluster protein, activating cuproptosis to enhance the antitumor efficacy of Cu-GA NPs. The experiments in vivo further demonstrate that Cu-GA NPs exhibited the excellent biosafety and superior antitumor capacity, which can efficiently inhibit the growth of tumors due to the activation by the tumor specific GSH and hydrogen peroxide. TheseCu-based metal-phenolic network NPs provide a potential strategy to build up efficient and safe cancer therapy.

Nanoscale Multivariate Metal–Organic Frameworks Amplify Oxidative Stress for Efficient Photodynamic Therapy of Cancer

Nanoscale Multivariate Metal–Organic Frameworks Amplify Oxidative Stress for Efficient Photodynamic Therapy of Cancer

CO2-Responsive drug delivery system created by supramolecular design and assembly for safer, more effective cancer therapy

We developed a carbon dioxide (CO2)-responsive supramolecular drug carrier system through a combination of hydrophobic CO2-sensitive imidazole-containing rhodamine 6G (I–R6G) as an efficient anticancer agent and hydrophilic ureido-cytosine (UrCy) end-capped polyethylene glycol (UrCy-PEG) as a self-assembled nanocarrier that could potentially enhance the safety and efficiency of cancer treatment. Owing to the self-complementary quadruple hydrogen bonding interactions between the UrCy moieties at the polymer chain ends, UrCy-PEG can spontaneously self-assemble into spherical-like nanoobjects in water that can effectively encapsulate hydrophobic I–R6G and form co-assembled nanoparticles with tunable sizes (depending on the I–R6G loading content). These nanoparticles display several notable physical features, including high structural stability in normal physiological aqueous media or red blood cell-containing media, unique CO2-responsiveness, and controlled CO2-sensitive I–R6G release. In vitro cytotoxicity assays clearly indicated I–R6G-loaded nanoparticles exerted selective cytotoxicity towards cancer cells, but had no adverse effects on normal cells. I–R6G-loaded nanoparticles exerted significantly higher levels of cytotoxicity at lower doses in CO2-treated cell culture media compared to I–R6G-loaded nanoparticles in pristine media. More importantly, cellular assays demonstrated that—in comparison to I–R6G-loaded nanoparticles in pristine media—CO2-treated culture media accelerated macropinocytic internalization of I–R6G-loaded nanoparticles into cancer cells, and subsequently led to more rapid induction of apoptosis in cancer cells and massive programmed cell death. Thus, this newly created system may act as a potential route to manipulate the drug delivery and release performance of self-assembled nanobjects for efficient cancer therapy.

Functionalized europium-doped hollow mesoporous silica nanospheres as a cell imaging and drug delivery agents

In an effort to enhance the antitumor efficacy of breast cancer treatment, the chemotherapeutic agent Paclitaxel (PTX) was encapsulated within hyaluronic acid (HA) modified hollow mesoporous silica (HMSNs). In vitro drug release assays showed that the resulting formulation, Eu-HMSNs-HA-PTX, exhibited enzyme-responsive drug release. In addition, cell cytotoxicity and hemolysis assays demonstrated the favorable biocompatibility of both Eu-HMSNs and Eu-HMSNs-HA. Notably, compared to Eu-HMSNs alone, Eu-HMSNs-HA showed enhanced accumulation within CD44-expressing cancer cells (MDA-MB-231). As anticipated, apoptosis experiments indicated that Eu-HMSNs-HA-PTX displayed significantly greater cytotoxicity toward MDA-MB-231 cells than non-targeted Eu-HMSNs-PTX and free PTX. In conclusion, Eu-HMSNs-HA-PTX demonstrated excellent anticancer effects and holds promise as a potent candidate for the efficient therapy of breast cancer.

Medicinal Characteristics of Withania somnifera L. in Colorectal Cancer Management.

Research into tumorigenic pathways can aid in the development of more efficient cancer therapies and provide insight into the physiological regulatory mechanisms employed by rapidly proliferating cancer cells. Due to the severe side effects of cancer chemotherapeutic medications, plant chemicals and their analogues are now explored more frequently for the treatment and prevention of colorectal cancer (CRC), opening the stage for new phytotherapeutic strategies that are considered effective and safe substitutes. Our study aimed to evaluate the medicinal properties of Withania somnifera L. and its safety applications in CRC management. Important databases were rigorously searched for relevant literature, and only 82 full-text publications matched the inclusion requirements from a massive collection of 10,002 titles and abstracts. W. somnifera L. contains a high concentration of active plant-based compounds. The pharmacological activity of the plant from our study has been demonstrated to exert antiproliferation, upregulation of apoptosis, decrease in oxidative stress, downregulation of cyclooxygenase-2 (COX-2), induction of targeted cytotoxic effects on cancerous cells, and exertion of both antiangiogenesis and antimigratory effects. We advise further research before recommending W. somnifera L. for clinical use to identify the optimal concentrations required to elicit beneficial effects in CRC management in humans, singly or in combination.

Synergistic therapeutic effect of nanomotors triggered by Near-infrared light and acidic conditions of tumor

Due to the complexity of tumors, multimodal therapy for them has always been of concern to researchers. How to design a multifunctional drug nanoplatform with cascade effect and capable of responding to specific stimuli in the tumor microenvironment is the key to achieve efficient multimodal synergistic therapy of cancer. Here, we prepare a kind of GNRs@SiO2@PDA-CuO2-l-Arg (GSPRs-CL) nanomotors for systematic treatment of tumor. First, under near-infrared (NIR) irradiation, GSPRs-CL can generate heat and exhibit excellent photothermal therapy effect. Then under acidic conditions, CuO2 can be decomposed to release Cu2+ and generate H2O2, which not only complemented the limited endogenous H2O2 in cells, but also further triggered Fenton-like reaction, converting H2O2 into •OH to kill cancer cells, thereby achieving chemodynamic therapy. Furthermore, both endogenous and exogenous H2O2 can release nitric oxide (NO) in response to the occurrence of l-Arg of nanomotors to enhance gas therapy. In addition, as a dual-mode drive, NIR laser and NO can promote the penetration ability of nanomotors at tumor sites. The experimental results in vivo show that the drug nanoplatform had good biosafety and significant tumor killing effect triggered by NIR light and acidic conditions of tumor. It provide a promising strategy for the development of advanced drug nanoplatform for cancer therapy.

Tumor microenvironment-initiated lipid redox cycling for efficient triple-negative breast cancer therapy

The use of overwhelming reactive oxygen species (ROS) attack has shown great potential for treating aggressive malignancies; however, targeting this process for further applications is greatly hindered by inefficiency and low selectivity. Here, a novel strategy for ROS explosion induced by tumor microenvironment-initiated lipid redox cycling was proposed, which was developed by using soybean phosphatidylcholine (SPC) to encapsulate lactate oxidase (LOX) and sorafenib (SRF) self-assembled nanoparticles (NPs), named LOX/SRF@Lip. SPC is not only the delivery carrier but an unsaturated lipid supplement for ROS explosion. And LOX catalyzes excessive intratumoral lactate to promote the accumulation of large amounts of H2O2. Then, H2O2 reacts with excessive endogenous iron ions to generate amounts of hydroxyl radical for the initiation of SPC peroxidation. Once started, the reaction will proceed via propagation to form new lipid peroxides (LPO), resulting to devastating LPO explosion and widespread oxidative damage in tumor cells. Furthermore, SRF makes contribution to mass LPO accumulation by inhibiting LPO elimination. Compared to normal tissue, tumor tissue has higher levels of lactate and iron ions. Therefore, LOX/SRF@Lip shows low toxicity in normal tissues, but generates efficient inhibition on tumor proliferation and metastasis, enabling excellent and safe tumor-specific therapy. This work offers new ideas on how to magnify anticancer effect of ROS through rational nanosystem design and tumor-specific microenvironment utilization.

Protein-based nanocarriers for efficient Etoposide delivery and cancer therapy

Protein-based nanocarriers for efficient Etoposide delivery and cancer therapy

Development of multifunctional polymeric nanoparticles co-loaded with ZnPc and Fe2+ ions for synergetic PDT/CDT therapy

Recently photodynamic therapy (PDT)-based combinational therapeutic approaches have been extensively studied to circumvent the hurdle of tissue hypoxia in solid tumors. In this paper, we reported a facile way to prepare multifunctional nanoparticles (NPs) for synergetic PDT/chemodynamic therapy (CDT). Specifically, photosensitizer ZnPc was firstly loaded inside polymeric NPs by a reprecipitation method, followed by surface coating of Fe2+ ions-chelated polydopamine (PDA) shell, which was polymerized via photo-generated 1O2 from the ZnPc-loaded NPs. The resulting ZnPc@PDA-Fe2+ could not only generate 1O2 upon 660-nm photo-irradiation but also produce OH when exposed to H2O2 through the Fenton reaction. Taking advantage of the ZnPc and Fe2+ co-loaded NPs, in vitro combination therapy was performed on Hela cells. As a result, a higher therapeutic effect was achieved compared to single-modality PDT, corresponding to an improved cell inhibitory rate from 59% to 80%. These results demonstrate that our facilely prepared NPs are promising PDT/CDT nanoagents for efficient cancer therapy.

PEGylated magnetic nanographene oxide for targeted delivery of arsenic trioxide and sec-o-glucosylhamaudol in tumor treatment with improved dual-drugs synergistic effect

Arsenic trioxide (ATO) is a promising chemotherapeutic agent, but its clinical application is limited due to its poor pharmacokinetics and dose-limited toxicity. Moreover, the combination of ATO and sec-o-glucosylhamaudol (SOG) can improve the therapeutic effect of hepatoma. In this study, PEGylated magnetic nanographene oxide (PEG@MGO) was used as magnetic carriers to enhance the targeting ability of the drug delivery system. ATO and SOG are loaded on the surface of PEG@MGO nanoparticles through electrostatic interactions. This biocompatible nanocomposite shows magnetic susceptibility, pH sensitivity, and high loading capacity of the drugs. The in vitro cytotoxicity study of human hepatoma cell line (HepG2) cells showed more significant cytotoxicity and obvious synergistic effect between ATO and SOG compared with that of single drug-loaded nanoparticles via MTT assay. In vitro cellular uptake was observed by Prussian blue staining and fluorescently labeling. The results demonstrated a high cellular internalization rate of PEG@MGO. The ATO and SOG co-loaded nanodrug significantly inhibits the growth of tumors in vivo, which might be due to the oxidative stress and proapoptotic effect. This type of multidrug nanocomposite offers a promising alternative for cancer therapy.Graphical A pH-sensitive polyethylene glycol-modified magnetic graphene oxide loaded with ATO and SOG (PEG@MGO@ATO + SOG) was prepared for the magnetically targeted and efficient synergistic-chemo cancer therapy, which exhibited high specificity and good biocompatibility.

Core-Shell Nanostructured Drug Delivery Platform Based on Biocompatible Metal-Organic Framework-Ligated Polyethyleneimine for Targeted Hepatocellular Carcinoma Therapy.

Multifunctional nanosized metal-organic frameworks (NMOFs) have advanced rapidly over the past decade to develop drug delivery systems (DDSs). These material systems still lack precise and selective cellular targeting, as well as the fast release of the quantity of drugs that are simply adsorbed within and on the external surface of nanocarriers, which hinders their application in the drug delivery. Herein, we designed a biocompatible Zr-based NMOF with an engineered core and the hepatic tumor-targeting ligand, glycyrrhetinic acid grafted to polyethyleneimine (PEI) as the shell. The improved core-shell serves as a superior nanoplatform for efficient controlled and active delivery of the anticancer drug doxorubicin (DOX) against hepatic cancer cells (HepG2 cells). In addition to their high loading capacity of 23%, the developed nanostructure DOX@NMOF-PEI-GA showed an acidic pH-stimulated response and extended the drug release time to 9 days as well as enhanced the selectivity toward the tumor cells. Interestingly, the DOX-free nanostructures showed a minimal toxic effect on both normal human skin fibroblast (HSF) and hepatic cancer cell line (HepG2), but the DOX-loaded nanostructures exhibited a superior killing effect toward the hepatic tumor, thus opening the way for the active drug delivery and achieving efficient cancer therapy applications.

Exploiting Cancer Vulnerabilities by Blocking of the DHODH and GPX4 Pathways: A Multifunctional Bodipy/PROTAC Nanoplatform for the Efficient Synergistic Ferroptosis Therapy.

Ferroptosis is a form of programmed cell death and plays an important role in many diseases. Dihydroorotate dehydrogenase (DHODH) and glutathione peroxidase 4 (GPX4) play major roles in cell resistance to ferroptosis. Therefore, inactivation of these proteins provides an excellent opportunity for efficient ferroptosis-based synergistic cancer therapy. In this study, a multifunctional nanoagent (BPNpro ) containing a GPX4 targeting boron dipyrromethene (Bodipy) probe (BP) and a DHODH targeting proteolysis targeting chimera (PROTAC) is reported. BPNpro is prepared using a nanoprecipitation method in the presence of a thermoresponsive liposome, where BP is encapsulated inside and the cathepsin B (CatB)-cleavable PROTAC peptide (DPCP) is modified on the outer surface. In the presence of near-infrared (NIR) photoirradiation, BPNpro is melted and BP is released in tumor cells. Subsequently, BP inhibits the activity of GPX4 by covalently bonding with the selenocysteine at the enzyme active site. In addition, DPCP achieves sustained degradation of DHODH upon activation by CatB overexpressed in the tumor. The synergistic deactivation of GPX4 and DHODH induces extensive ferroptosis and subsequent cell death. In vivo and in vitro studies clearly show that the proposed ferroptosis therapy provides excellent antitumor effect.