Polydopamine-based coordination nanocomplex for T1/T2 dual mode magnetic resonance imaging-guided chemo-photothermal synergistic therapy.
Chen Yan,Ai Kelong,Liu Jianhua,Ren Xiaoyan,Jiang Chunhuan,Lu Lehui
Despite the progress in the design and synthesis of theranostic agents, limitations on efficiency and safety offer significant room for improvement in these agents. Inspired by the natural binding ability of polydopamine nanospheres (PDAs) with iron ion, a simple and versatile synthesis strategy is developed to prepare biodegradable coordination polymer (CP) encapsulated PDAs nanocomplex (PDAs@CPx, x = 3, 6, 9). We found that the PDAs@CP3 can serve as a T1/T2 dual mode contrast agent (DMCA) for magnetic resonance imaging (MRI), which possesses high longitudinal (r1 = 7.524 mM(-1) s(-1)) and transverse (r2 = 45.92 mM(-1) s(-1)) relaxivities. In this system, benefitting from the high photothermal conversion efficiency derived from PDAs, DOX loaded PDAs@CP3 nanocomplex is able to not only destroy the tumor directly by heat, but also stimulate the chemotherapy by enabling NIR-responsive on demand delivery of DOX. To the best of our knowledge, this is the first example exploring the potential of PDAs@CPx nanocomplex for T1/T2 dual mode MRI-guided chemo-photothermal synergistic therapy. This work extends the currently available theranostic agents, and opens up new avenues to rationally design the high-performance T1/T2 DMCA.
Mild photothermal therapy/photodynamic therapy/chemotherapy of breast cancer by Lyp-1 modified Docetaxel/IR820 Co-loaded micelles.
Li WenTing,Peng JinRong,Tan LiWei,Wu Jing,Shi Kun,Qu Ying,Wei XiaWei,Qian ZhiYong
Patients suffering from cancer have benefited from combination therapy. Nanocarriers are the ideal candidates for combination therapy. In this study, we constructed docetaxel (DTX) loaded micellar nanomedicines co-loaded with near infrared (NIR) dye-IR820 for photothermal therapy (PTT)/photodynamic therapy (PDT)/chemotherapy of breast cancer. Lyp-1, a tumor homing peptide, was introduced into the nanosystems to construct the active targeting nanomedicine. In order to deliver IR820 to the tumor site and overcome its short lifetime in vivo, a PEI derivative-PCL-g-PEI was introduced. IR820 with negative charge was formed stable static interaction with the amine groups, meanwhile, the absorption of IR820 in the NIR region was weakened. It indicated that the nanosystem constructed in this study may provide an alternative candidate for mild PTT. By the evaluation of the photothermal conversion in vivo, we can confirm that IR820 has been successfully delivered and effectively accumulated in the tumor site. Furthermore, the tumor cells targeting and anticancer performances of this nanosystem have been studied in vitro and in vivo. The results demonstrated Lyp-1 modification has enhanced the tumor targeting delivery of DTX and IR820. By combining PTT and PDT, DTX nanomedicine efficiently inhibited the growth and metastasis of breast cancer in mice. This nanosystem is a promising candidate for combination therapy of breast cancer.
Emerging Strategies of Cancer Therapy Based on Ferroptosis.
Shen Zheyu,Song Jibin,Yung Bryant C,Zhou Zijian,Wu Aiguo,Chen Xiaoyuan
Advanced materials (Deerfield Beach, Fla.)
Ferroptosis, a new form of regulated cell death that is iron- and reactive oxygen species dependent, has attracted much attention in the research communities of biochemistry, oncology, and especially material sciences. Since the first demonstration in 2012, a series of strategies have been developed to induce ferroptosis of cancer cells, including the use of nanomaterials, clinical drugs, experimental compounds, and genes. A plethora of research work has outlined the blueprint of ferroptosis as a new option for cancer therapy. However, the published ferroptosis-related reviews have mainly focused on the mechanisms and pathways of ferroptosis, which motivated this contribution to bridge the gap between biological significance and material design. Therefore, it is timely to summarize the previous efforts on the emerging strategies for inducing ferroptosis and shed light on future directions for using such a tool to fight against cancer. Here, the current strategies of cancer therapy based on ferroptosis will be elaborated, the design considerations and the advantages and limitations are highlighted, and finally a future perspective on this emerging field is given.
Cellular Uptake Behaviors of Rigidity-Tunable Dendrimers.
Liu Hui,Wang Jingjing,Li Wenchao,Hu Jie,Wang Min,Kang Yuejun
Understanding of the interaction between cells and nanoparticles (NPs) is critical. Despite numerous attempts to understand the effect of several parameters of NPs on their cellular uptake behaviors, such as size, shape, surface chemistry, etc., limited information is available regarding NP rigidity. Herein, we investigate the effect of rigidity on cellular uptake behaviors of NPs, using generation 5 poly(amidoamine) dendrimer as a model. By harnessing the abundant inner cavity, their rigidity could be effectively regulated by forming size-tunable gold NPs. The NPs thus formed were well characterized and displayed similar hydrodynamic size, surface potential, fluorescence intensity, and distinct rigidity (owing to differences in the size of the Au core). Flow cytometry analysis revealed a positive correlation between NP rigidity and cellular uptake of NPs. Confocal microscopic evaluation revealed that the entrapped gold NPs may affect the intracellular localization of the internalized dendrimers. The present findings can potentially guide the preparation of suitable NPs for biomedical applications.
Development of Multifunctional Polydopamine Nanoparticles As a Theranostic Nanoplatform against Cancer Cells.
Wang Jingjing,Guo Yuan,Hu Jie,Li Wenchao,Kang Yuejun,Cao Yang,Liu Hui
Langmuir : the ACS journal of surfaces and colloids
Although demanding, the development of multifunctional theranostic nanoplatforms is attracting considerable worldwide interest. Herein, a theranostic nanoplatform with multifunctions based on polydopamine (PDA) nanoparticles (NPs) was developed, owning dual-imaging and dual-therapy functions for cancer theranostic applications. PDA NPs were generated using a facile polymerization method under alkaline conditions, followed by poly(ethylene glycol) (PEG) modification. Then, the obtained NPs were loaded with IR820 and Fe ions to produce the final PEGylated PDA/IR820/Fe (PPIF) NPs. The PPIF NPs thus generated displayed increasingly brighter photoacoustic and magnetic resonance signals with increasing NP concentration and were demonstrated to be cytocompatible and effectively taken up and internalized into HeLa cells. Under near-infrared light irradiation, PPIF NPs can produce heat and reactive oxygen species for photothermal/photodynamic combined cancer therapy. In this study, the versatility of PDA NPs was demonstrated to be promising as a multifunctional nanoplatform for potential cancer theranostic applications.
Multifunctional nanoplatform for photoacoustic imaging-guided combined therapy enhanced by CO induced ferroptosis.
Yao Xianxian,Yang Peng,Jin Zhaokui,Jiang Qin,Guo Ranran,Xie Ruihong,He Qianjun,Yang Wuli
A multifunctional CO/thermo/chemotherapy nanoplatform is here reported, which is composed of mesoporous carbon nanoparticles (MCN) as near infrared (NIR)-responsive drug carrier, doxorubicin (DOX) as chemotherapeutic drug and triiron dodecacarbonyl (FeCO) as thermosensitive CO prodrug. The nanoplatform could absorb near-infrared (NIR) light and convert it into ample heat to trigger CO release and could also release DOX in the acidic tumor microenvironment. More importantly, the generated CO molecules successfully increase cancer cell sensitivity to chemotherapeutics by the ferroptosis pathway. Subsequently, under the guidance of photoacoustic imaging, the FeCO-DOX@MCN nanoplatform demonstrates high treatment efficacies in vitro and in vivo by combination of chemotherapy, photothermal therapy and gas therapy. This multifunctional platform with excellent antitumor efficacy has great potential in precision cancer therapy.
Coordinatively Unsaturated Fe Based Activatable Probes for Enhanced MRI and Therapy of Tumors.
Zhang Peisen,Hou Yi,Zeng Jianfeng,Li Yingying,Wang Zihua,Zhu Ran,Ma Tiancong,Gao Mingyuan
Angewandte Chemie (International ed. in English)
Exogenous Fe can be used for cancer magnetic resonance (MR) imaging and potentially for cancer treatment by a ferroptosis pathway or photothermal ablation. To achieve this, effective and accurate delivery of Fe to cancerous sites is critical, requiring a balance of release kinetics of Fe in tumorous and normal tissues. A nanoprobe is described consisting of upconversion luminescence (UCL) nanoparticles as a core and a coordinatively unsaturated Fe -containing Fe /gallic acid complex as a shell. Owing to the introduction of an unsaturated coordination structure, Fe in the nanoprobe can be released only in the tumor microenvironment in response to the lightly acidic pH. The multiple UCLs are used for quantitatively visualizing the release of Fe in vivo, whilst the release resultant serves as a photothermal agent. This nanoprobe exhibited ligand-free tumor targeting ability, activatable MR imaging performance, and efficacious therapeutic effects against tumors in vivo.
Selective Single Molecule Nanopore Sensing of microRNA Using PNA Functionalized Magnetic Core-Shell FeO-Au Nanoparticles.
Wang Hao,Tang Haoran,Yang Cheng,Li Yongxin
Solid-state nanopores have been employed as useful tools for single molecule analysis due to their advantages of easy fabrication and controllable diameter, but selectivity is always a big concern for complicated samples. In this work, functionalized magnetic core-shell FeO-Au nanoparticles, which acted as a molecular carrier, were introduced into nanopore electrochemical system for microRNA sensing in complicated samples with high sensitivity, selectivity and signal-to-noise ratio (SNR). This strategy is based on the specific affinity between neutral peptide nucleic acids (PNA)-modified FeO-Au nanoparticles and negative miRNA, and the formation of negative FeO-Au-PNA-miRNA complex, which can pass through the nanopore by application of a positive potential and eliminate neutral FeO-Au-PNA complex. To detect miRNA in complicated samples, a magnet has been used to separate FeO-Au-PNA-miRNA complex with good selectivity. We think this is a facile and effective method for the detection of different targets at single molecular level, including nucleic acids, proteins, and other small molecules, which will open up a new approach in the nanopore sensing field.
Intracellular cascade activated nanosystem for improving ER+ breast cancer therapy through attacking GSH-mediated metabolic vulnerability.
Xiong Hui,Wang Cheng,Wang Zihan,Jiang Zhijie,Zhou Jianping,Yao Jing
Journal of controlled release : official journal of the Controlled Release Society
Estrogen receptor-positive (ER+) breast carcinoma therapy faces the challenges of estrogen receptors heterogeneity and endocrine therapy resistance. Selectively attacking glutathione (GSH) biosynthesis which is the metabolic vulnerability of ER+ breast carcinoma could bypass conventional treatment limitations through blocking oxidative stress disorders-driven tumor cell proliferation. Herein, we developed drug-organics-inorganics self-assembled nanosystem (DFTA) with doxorubicin (DOX) as chemotherapeutic agent, ferric chloride (FeCl) as ferroptosis inducer and tannic acid (TA) as activator of superoxide dismutase (SOD)-like reaction in intracellular cascade for the combined therapy in ER+ breast carcinoma. DFTA displayed a particle size of 106.4 ± 0.7 nm with flat irregular nanonetwork-like shape and predominant photothermal effect produced in the assembly process. The drug release from DFTA could be triggered by photothermal excitation efficiently. ELISA analysis showed that DFTA + laser group significantly reduced intracellular GSH level through reactive oxygen species (ROS)-produced intracellular oxidative stress cascade amplification and photothermal therapy (PT)-mediated ROS production. Furthermore, in vivo antitumor efficiency evaluation showed that the tumor inhibition ratio of DFTA + laser was as high as 93.38 % even though the dosage of iron and DOX reduced by about 9 times and 1.5 times respectively. In summary, our study established a high-efficiency nanosystem based on triple combination therapy of chemotherapy, ferroptosis and PT, which might be a promising nanosystem for effective ER+ breast carcinoma therapy.
Integration of cascade delivery and tumor hypoxia modulating capacities in core-releasable satellite nanovehicles to enhance tumor chemotherapy.
Wang Jingjing,Wang Xingyue,Lu Shi-Yu,Hu Jie,Zhang Wei,Xu Luen,Gu Dachong,Yang Wenting,Tang Wei,Liu Fujuan,Cao Yang,Liu Hui
Drug nanovehicles owning tumor microenvironment responsive and modulating capacities are highly demanding for effective tumor chemotherapy but still lack of exploration. Here, a kind of core-releasable satellite nanovehicles was rational constructed, which is composed of polydopamine (PDA) cores as photothermal agents and the carrier for small satellite nanoparticles (NPs) and drugs, G5Au NPs as the drug-loading satellites for deep tumor drug delivery and as catalase-like agents for relieving tumor hypoxia, doxorubicin (DOX) as the model chemotherapeutic drug loaded by both PDA and G5Au NPs, and polyethylene glycol (PEG) shells to improve biosafety. The developed drug-loaded nanovehicles (denoted as PDA-G5Au-PEG@DOX) can release G5Au satellites and DOX in stimuli-responsive manners. Thorough drug delivery in solid tumor can be realized via transporting DOX to the near-by area of and remote area from blood vessels by PDA and G5Au, respectively. Monitored by photoacoustic imaging and near-infrared fluorescence imaging, these PDA-G5Au-PEG@DOX NPs could accumulate in 4T1 tumor effectively. Under this guidance, significant tumor growth suppression could be achieved by the treatment of PDA-G5Au-PEG@DOX NPs plus laser without detectable side effects during the treatment period. The developed drug-loaded core-satellite nanovehicles with tumor microenvironment responsive/modulating capacities are of great potential in precise tumor treatments.
Tumor microenvironment responsive FePt/MoS nanocomposites with chemotherapy and photothermal therapy for enhancing cancer immunotherapy.
Zhang Dongsheng,Cui Ping,Dai Zhichao,Yang Baochan,Yao Xiuxiu,Liu Qingyun,Hu Zunfu,Zheng Xiuwen
The metastasis and recurrence of tumors are the main reasons for cancer death. In this work, a promising therapy for tumor treatment that can eliminate primary tumors and prevent tumor relapses is introduced by combining chemotherapy, photothermal therapy (PTT) and immunotherapy. Multifunctional FePt/MoS-FA nanocomposites (FPMF NCs) were obtained via anchoring FePt nanoparticles and folic acid (FA) on MoS nanosheets. As an efficient ferroptosis agent, FePt nanoparticles could catalyze the Fenton reaction to produce the reactive oxygen species (ROS). Through the highly effective photothermal conversion of MoS nanosheets, the primary tumor cells could be ablated by photothermal therapy (PTT). Moreover, the metastatic tumors were eliminated effectively with the help of oligodeoxynucleotides containing cytosine-guanine (CpG ODNs) combined with systemic checkpoint blockade therapy using an anti-CTLA4 antibody. Even more intriguingly, a strong immunological memory effect was obtained by this synergistic therapy. Taking all these results into consideration, we anticipate that the photo-chemo-immunotherapy strategies show great promise toward the development of a multifunctional platform for anticancer therapeutic applications.
The effect of metal ions on endogenous melanin nanoparticles used as magnetic resonance imaging contrast agents.
Chen Anqi,Sun Jinghua,Liu Shijie,Li Liping,Peng Xiaoyang,Ma Lixin,Zhang Ruiping
Melanin nanoparticles are of great importance in biomedicine. They have excellent affinity for metallic cations, especially paramagnetic ions, which has sparked interest in their application in the development of magnetic resonance imaging (MRI) contrast agents. In this work, we prepared ultrasmall water-soluble melanin nanoparticles, and investigated the binding properties of melanin toward different metal cations (Gd, Mn, Fe and Cu), and compared their physicochemical properties and the MRI contrast enhancement ability in various metal chelated forms (MNP-PEG-M) in vitro and in vivo. We show that the saturation binding numbers of Gd, Mn, Fe and Cu per MNP-PEG were 49, 59, 69 and 62, respectively. MNP-PEG-Gd, MNP-PEG-Mn, MNP-PEG-Fe and MNP-PEG-Cu exhibited the maximum r relaxivities at the loading mass ratios of Gd : MNP = 1 : 1, Mn : MNP = 0.5 : 1, Fe : MNP = 0.1 : 1 and Cu : MNP = 0.1 : 1, corresponding to 49, 57, 54 and 51 chelated metals per MNP-PEG, respectively. The maximal per metal ion r relaxivity values were 61.9, 48.7, 11.1 and 9.7 mM s for MNP-PEG-Gd, MNP-PEG-Mn, MNP-PEG-Fe and MNP-PEG-Cu at 1.5 T, respectively. MNP-PEG-Gd and MNP-PEG-Fe presented larger sizes (6.9 nm and 5.8 nm) than MNP-PEG-Mn and MNP-PEG-Cu (3.4 nm and 3.7 nm), all featuring excellent solubility, high stability and ultrasmall size. A significant in vivo MRI signal enhancement in tissues was observed for all MNP-PEG-M after intravenous injection in mice, and these nanoparticles were excreted through renal and hepatobiliary pathways. In agreement with their r relaxivity values, MNP-PEG-Gd and MNP-PEG-Mn showed a significantly greater in vivo tissue maximum enhancement than MNP-PEG-Fe and MNP-PEG-Cu. This study could yield valuable insight into the development of a new class of MRI contrast agents.
Manganese Oxide Nanomaterials: Synthesis, Properties, and Theranostic Applications.
Ding Binbin,Zheng Pan,Ma Ping'an,Lin Jun
Advanced materials (Deerfield Beach, Fla.)
Despite the comprehensive applications in bioimaging, biosensing, drug/gene delivery, and tumor therapy of manganese oxide nanomaterials (MONs including MnO , MnO, Mn O , Mn O , and MnO ) and their derivatives, a review article focusing on MON-based nanoplatforms has not been reported yet. Herein, the representative progresses of MONs on synthesis, heterogene, properties, surface modification, toxicity, imaging, biodetection, and therapy are mainly introduced. First, five kinds of primary synthetic methods of MONs are presented, including thermal decomposition method, exfoliation strategy, permanganates reduction method, adsorption-oxidation method, and hydro/solvothermal. Second, the preparations of hollow MONs and MON-based composite materials are summarized specially. Then, the chemical properties, surface modification, and toxicity of MONs are discussed. Next, the diagnostic applications including imaging and sensing are outlined. Finally, some representative rational designs of MONs in photodynamic therapy, photothermal therapy, chemodynamic therapy, sonodynamic therapy, radiotherapy, magnetic hyperthermia, chemotherapy, gene therapy, starvation therapy, ferroptosis, immunotherapy, and various combination therapy are highlighted.
One-pot synthesis of water-soluble and biocompatible superparamagnetic gadolinium-doped iron oxide nanoclusters.
Xiang Huijing,Dong Pingli,Pi Lei,Wang Zhijie,Zhang Tingting,Zhang Siyang,Lu Chichong,Pan Yao,Yuan Huanxiang,Liang Haiyan
Journal of materials chemistry. B
The synthesis of superparamagnetic nanoclusters is critical for ultra-sensitive magnetic resonance imaging (MRI). Herein, we describe the synthesis of water-soluble, biocompatible and superparamagnetic gadolinium-doped iron oxide nanoclusters (GdIO NCs) via a one-pot reaction by thermal decomposition of ferric oleate and gadolinium oleate precursors with α,ω-dicarboxyl poly(ethylene glycol) as a surfactant. The resulting water-dispersible GdIO NCs possess good stability and monodispersity with narrow size distribution, and exhibit superparamagnetic behaviors. We also explored the effect of gadolinium doping amounts on the magnetic properties and longitudinal (r1) and transverse relaxivity (r2) of the nanoclusters. In addition, the GdIO NCs can be functionalized with fluorescein isothiocyanate (FITC) while maintaining their magnetic properties and biocompatibility. The GdIO NCs and FITC conjugated NCs were preliminarily evaluated as MRI and fluorescent probes. The results show that the GdIO NCs provide an important nano-platform for theranostics with non-invasive MRI and optical monitoring capabilities.
Mesoporous polydopamine carrying sorafenib and SPIO nanoparticles for MRI-guided ferroptosis cancer therapy.
Guan Qingqing,Guo Ruomi,Huang Shihui,Zhang Fan,Liu Jie,Wang Zhiyong,Yang Xi,Shuai Xintao,Cao Zhong
Journal of controlled release : official journal of the Controlled Release Society
Iron-based nanomaterials as the main ferroptosis-inducing platforms are more promising because iron itself is a key component in the Fenton reaction to produce ROS. However, the Fe dose needs to be very high in order to induce ferroptosis-based cancer treatment using the SPIO NPs. Therefore, it is still of great challenge to enhance the efficacy of ferroptosis-based cancer therapy by associating the iron-based nanomaterials with other components and therapeutic modalities. In this study, sorafenib (SRF) and ultrasmall SPIO nanoparticles were loaded into the mesopores and onto the surface of MPDA NPs to form SRF@MPDA-SPIO nanoparticles. SPIO loading endowed the system with iron-supply for ferroptosis and made the system MRI-visible. Meanwhile, SRF was able to induce ferroptosis in cancer cells with lower Fe dose. Furthermore, the heat generated by MPDA NPs upon laser irradiation offered a moderate PTT to boost the ferroptosis effect. The SRF@MPDA-SPIO exhibited biocompatibility highly desirable for in vivo application and superior anticancer therapy via the combination of ferroptosis and photothermal therapy.
Chromatographic determination of sulfasalazine and its active metabolites: greenness assessment and application to spiked human plasma.
Abdelrahman Maha M,Habib Neven M,Emam Aml A,Mahmoud Hamada M,Abdelwhab Nada S
Biomedical chromatography : BMC
Green TLC-densitometric and RP-HPLC methods were developed and validated for the determination of the active prodrug sulfasalazine (SZ), its active metabolite mesalazine (MZ) and the major active metabolite of mesalazine, N-acetyl-5-aminosalicylic acid (AS). In the developed TLC-densitometric method, chromatographic separation was carried out on TLC silica gel plates 60 F using a developing system consisting of ethyl acetate-methanol-ammonia solution 33% (8:2.5:0.3, by volume) and then scanning the separated bands at 215 nm using hydrochlorothiazide as an internal standard with linearity ranges of 0.4-3, 0.4-2.4 and 0.3-2 for SZ, MZ and AS, respectively. The developed RP-HPLC method depended on chromatographic separation using a C column with a solvent mixture of methanol-aqueous acetic acid solution (pH 5) as a mobile phase with gradient elution mode and UV scanning at 243 nm using pyrazinamide as internal standard with linearity ranges of 5-50, 5-40, and 3-20 for SZ, MZ and AS, respectively. US Food and Drug Administration guidelines were followed during validation of the methods. The greenness of the developed methods was estimated using the greenness profile and the Eco-Scale approach. Both methods passed the four quadrants of the greenness profile and had Eco-Scale score ˃75, thus they were considered to be green according to these approaches.
PEGylated Bilirubin-coated Iron Oxide Nanoparticles as a Biosensor for Magnetic Relaxation Switching-based ROS Detection in Whole Blood.
Lee Dong Yun,Kang Sukmo,Lee Yonghyun,Kim Jin Yong,Yoo Dohyun,Jung Wonsik,Lee Soyoung,Jeong Yong Yeon,Lee Kwangyeol,Jon Sangyong
: Magnetic relaxation switching (MRSw) induced by target-triggered aggregation or dissociation of superparamagnetic iron oxide nanoparticles (SPIONs) have been utilized for detection of diverse biomarkers. However, an MRSw-based biosensor for reactive oxygen species (ROS) has never been documented. : To this end, we constructed a biosensor for ROS detection based on PEGylated bilirubin (PEG-BR)-coated SPIONs (PEG-BR@SPIONs) that were prepared by simple sonication via ligand exchange. In addition, near infra-red (NIR) fluorescent dye was loaded onto PEG-BR@SPIONs as a secondary option for fluorescence-based ROS detection. Resul: PEG-BR@SPIONs showed high colloidal stability under physiological conditions, but upon exposure to the model ROS, NaOCl, , they aggregated, causing a decrease in signal intensity in T2-weighted MR images. Furthermore, ROS-responsive PEG-BR@SPIONs were taken up by lipopolysaccharide (LPS)-activated macrophages to a much greater extent than ROS-unresponsive control nanoparticles (PEG-DSPE@SPIONs). In a sepsis-mimetic clinical setting, PEG-BR@SPIONs were able to directly detect the concentrations of ROS in whole blood samples through a clear change in T2 MR signals and a 'turn-on' signal of fluorescence. : These findings suggest that PEG-BR@SPIONs have the potential as a new type of dual mode (MRSw-based and fluorescence-based) biosensors for ROS detection and could be used to diagnose many diseases associated with ROS overproduction.
Enhanced Ferroptosis by Oxygen-Boosted Phototherapy Based on a 2-in-1 Nanoplatform of Ferrous Hemoglobin for Tumor Synergistic Therapy.
Xu Tian,Ma Yuying,Yuan Qinling,Hu Huixin,Hu Xinkai,Qian Zhiyu,Rolle Janiqua Kyiesha,Gu Yueqing,Li Siwen
Photodynamic therapy (PDT) combined with oxygenating strategies is widely employed in cancer treatment; however, oxygen-boosted PDT has failed to achieve an ideal effect due to the complexity, heterogeneity, and irreversible hypoxic environment generated by tumor tissues. With the emergence of Fe-dependent ferroptosis boasting reactive oxygen species (ROS) cytotoxicity as well, such a chemodynamic approach to cancer therapy has drawn extensive attention. In this study, hemoglobin (Hb) is connected with the photosensitizer chlorin e6 (Ce6) to construct a 2-in-1 nanoplatform (SRF@Hb-Ce6) with Sorafenib (SRF, ferroptosis promotor) loaded, combining oxygen-boosted PDT and potent ferroptosis. Benefiting from the intrinsic presence of Fe capable of binding oxygen, hemoglobin concurrently furnishes oxygen for oxygen-dependent PDT and Fe for Fe-dependent ferroptosis. Furthermore, amphiphilic MMP2-responsive peptide is incorporated into the skeleton of the nanoplatform to ensure drug-release specificity for safety improvement. Correlative measurements demonstrate the potentiation of PDT and ferroptosis with SRF@Hb-Ce6. More importantly, PDT strengthens ferroptosis by recruiting immune cells to secrete IFN-γ, which can sensitize the tumor to ferroptosis in our findings. The therapeutic effect of synergistic treatment with SRF@Hb-Ce6 and was proven significant, revealing the promising prospects of combined PDT and ferroptosis therapy with the 2-in-1 nanoplatform.
Semiconducting Polycomplex Nanoparticles for Photothermal Ferrotherapy of Cancer.
He Shasha,Jiang Yuyan,Li Jingchao,Pu Kanyi
Angewandte Chemie (International ed. in English)
This study reports the development of iron-chelated semiconducting polycomplex nanoparticles (SPFeN) for photoacoustic (PA) imaging-guided photothermal ferrotherapy of cancer. The hybrid polymeric nanoagent comprises a ferroptosis initiator (Fe ) and an amphiphilic semiconducting polycomplex (SP ) serving as both the photothermal nanotransducer and iron ion chelator. By virtue of poly(ethylene glycol) (PEG) grafting and its small size, SPFeN accumulates in the tumor of living mice after systemic administration, which can be monitored by PA imaging. In the acidic tumor microenvironment, SPFeN generates hydroxyl radicals, leading to ferroptosis; meanwhile, under NIR laser irradiation, it generates localized heat to not only accelerate the Fenton reaction but also implement photothermal therapy. Such a combined photothermal ferrotherapeutic effect of SPFeN leads to minimized dosage of iron compared to previous studies and effectively inhibits the tumor growth in living mice, which is not possible for the controls.
Platelet Membrane-Camouflaged Magnetic Nanoparticles for Ferroptosis-Enhanced Cancer Immunotherapy.
Jiang Qin,Wang Kuang,Zhang Xingyu,Ouyang Boshu,Liu Haixia,Pang Zhiqing,Yang Wuli
Small (Weinheim an der Bergstrasse, Germany)
Although cancer immunotherapy has emerged as a tremendously promising cancer therapy method, it remains effective only for several cancers. Photoimmunotherapy (e.g., photodynamic/photothermal therapy) could synergistically enhance the immune response of immunotherapy. However, excessively generated immunogenicity will cause serious inflammatory response syndrome. Herein, biomimetic magnetic nanoparticles, Fe O -SAS @ PLT, are reported as a novel approach to sensitize effective ferroptosis and generate mild immunogenicity, enhancing the response rate of non-inflamed tumors for cancer immunotherapy. Fe O -SAS@PLT are built from sulfasalazine (SAS)-loaded mesoporous magnetic nanoparticles (Fe O ) and platelet (PLT) membrane camouflage and triggered a ferroptotic cell death via inhibiting the glutamate-cystine antiporter system X pathway. Fe O -SAS @ PLT-mediated ferroptosis significantly improves the efficacy of programmed cell death 1 immune checkpoint blockade therapy and achieves a continuous tumor elimination in a mouse model of 4T1 metastatic tumors. Proteomics studies reveal that Fe O -SAS @ PLT-mediated ferroptosis could not only induce tumor-specific immune response but also efficiently repolarize macrophages from immunosuppressive M2 phenotype to antitumor M1 phenotype. Therefore, the concomitant of Fe O -SAS @ PLT-mediated ferroptosis with immunotherapy are expected to provide great potential in the clinical treatment of tumor metastasis.
Enzyme-Triggered Disassembly of Perylene Monoimide-based Nanoclusters for Activatable and Deep Photodynamic Therapy.
Cai Yang,Ni Dongqi,Cheng Wenyu,Ji Chendong,Wang Yaling,Müllen Klaus,Su Zhiqiang,Liu Ying,Chen Chunying,Yin Meizhen
Angewandte Chemie (International ed. in English)
Photodynamic therapy (PDT) exhibits great potential for cancer therapy, but still suffers from nonspecific photosensitivity and poor penetration of photosensitizer. Herein, a smart perylene monoimide-based nanocluster capable of enzyme-triggered disassembly is reported as an activatable and deeply penetrable photosensitizer. A novel carboxylesterase (CE)-responsive tetrachloroperylene monoimide (P1) was synthesized and assembled with folate-decorated albumins into a nanocluster (FHP) with a diameter of circa 100 nm. Once P1 is hydrolyzed by the tumor-specific CE, FHP disassembles into ultrasmall nanoparticles (ca. 10 nm), facilitating the deep tumor penetration of FHP. Furthermore, such enzyme-triggered disassembly of FHP leads to enhanced fluorescence intensity (ca. 8-fold) and elevated singlet oxygen generation ability (ca. 4-fold), enabling in situ near-infrared fluorescence imaging and promoted PDT. FHP permits remarkable tumor inhibition in vivo with minimal side effects through imaging-guided, activatable, and deep PDT. This work confirms that this cascaded multifunctional control through enzyme-triggered molecular disassembly is an effective strategy for precise cancer theranostics.
A novel theranostic nano-platform (PB@FePt-HA-g-PEG) for tumor chemodynamic-photothermal co-therapy and triple-modal imaging (MR/CT/PI) diagnosis.
Hu Zunfu,Wang Shan,Dai Zhichao,Zhang Hongxiu,Zheng Xiuwen
Journal of materials chemistry. B
The construction of multi-functional oncotherapy nano-platforms combining diagnosis and therapy remains a tough challenge. Prussian blue nano-cubes with optimized particle size were applied as photothermal agents and loaded with FePt NPs, effective ferroptosis agents, on the surface via an in situ reduction strategy. To attain the goal of precise medicine, hyaluronic acid was wrapped around the surface of the nanocomposites (PB@FePt NCs) for highly specific recognition of tumor cells. Finally, we successfully designed and fabricated a nano-agent (PB@FePt-HA-g-PEG NCs) to serve as a versatile nano-platform with both highly specific targeting ability for chemodynamic-photothermal co-therapy and triple-modal imaging (magnetic resonance/computed tomography/photothermal imaging) capability. Via intravenous injection, the as-constructed oncotherapy nano-platform could effectively ablate 4T1 tumor xenografts with excellent biocompatibility for chemodynamic-photothermal co-therapy. In this study we conducted a reasonable exploration to design multi-functional oncotherapy nano-platforms combining multiplexed imaging diagnosis and high therapeutic performance, which provides an innovative paradigm for precision cancer treatment.
Phagocyte-membrane-coated and laser-responsive nanoparticles control primary and metastatic cancer by inducing anti-tumor immunity.
Hu Chuan,Lei Ting,Wang Yazhen,Cao Jun,Yang Xiaotong,Qin Lin,Liu Rui,Zhou Yang,Tong Fan,Umeshappa Channakeshava Sokke,Gao Huile
To achieve safe and effective antitumor immunity, we constructed the M1-macrophage-membrane-coated nanoparticles [(C/I)BP@B-A(D)&M1m] having laser-responsive, size-changeable, on-demand drug release and prolonged circulation retention properties. (C/I)BP@B-A(D)&M1m delayed clearance by the phagocytic system and homed to tumor efficiently. Upon 650 nm laser irradiation, the hydrophobic core of the PEGylated bilirubin nanoparticles (BP) got disrupted, releasing small-sized deep-penetrating B-A(D) particles, photosensitive chlorin e6 (C), and tolerance-inducing indoleamine 2,3-dioxygenase inhibitor, indoximode (I). Treatment-induced immunogenic cell death and antitumor immunity, suppressing primary tumor growth in both 4T1 and B16F10 models without causing any adverse effects. Most importantly, it inhibited primary tumor recurrence as well as metastasis. Thus, this study provides a promising combinatorial strategy to trigger antitumor immunity in malignancies.
The influence of iron oxidation state on quantitative MRI parameters in post mortem human brain.
Birkl Christoph,Birkl-Toeglhofer Anna Maria,Kames Christian,Goessler Walter,Haybaeck Johannes,Fazekas Franz,Ropele Stefan,Rauscher Alexander
A variety of Magnetic Resonance Imaging (MRI) techniques are known to be sensitive to brain iron content. In principle, iron sensitive MRI techniques are based on local magnetic field variations caused by iron particles in tissue. The purpose of this study was to investigate the sensitivity of MR relaxation and magnetization transfer parameters to changes in iron oxidation state compared to changes in iron concentration. Therefore, quantitative MRI parameters including R, R, R∗, quantitative susceptibility maps (QSM) and magnetization transfer ratio (MTR) of post mortem human brain tissue were acquired prior and after chemical iron reduction to change the iron oxidation state and chemical iron extraction to decrease the total iron concentration. All assessed parameters were shown to be sensitive to changes in iron concentration whereas only R, R∗ and QSM were also sensitive to changes in iron oxidation state. Mass spectrometry confirmed that iron accumulated in the extraction solution but not in the reduction solution. R∗ and QSM are often used as markers for iron content. Changes in these parameters do not necessarily reflect variations in iron content but may also be a result of changes in the iron's oxygenation state from ferric towards more ferrous iron or vice versa.
Trastuzumab conjugated porphyrin-superparamagnetic iron oxide nanoparticle: A potential PTT-MRI bimodal agent for herceptin positive breast cancer.
Khaniabadi Pegah Moradi,Shahbazi-Gahrouei Daryoush,Aziz Azlan Abdul,Dheyab Mohammed Ali,Khaniabadi Bita Moradi,Mehrdel Baharak,Jameel Mahmood Subhi
Photodiagnosis and photodynamic therapy
BACKGROUND:Theranostic agents can combine photosensitizers and contrast agents into a single unit for photothermal therapy (PTT) and magnetic resonance imaging (MRI). The possibility of treating and diagnosing malignant cancers without any ionizing radiation could become an option. This study investigates the theranostic potential of FeO nanoparticles (IONs) for the diagnosis and treatment of cancer by developing a single integrated nanoprobe. METHODS:Oleylamin-coated IONs (ION-Ol) were synthesized and surface of the IONs was modified using protoporphyrin (PP) and trastuzumab (TZ) to develop the TZ-conjugated SPION-porphyrin [ION-PP-TZ]. The structure, morphology, size, and cytotoxicity of all samples were investigated using Fourier-transform infrared spectroscopy (FT-IR), Transmission electron microscopy (TEM), X-ray powder diffraction (XRD), WST-1 assay, respectively. In addition to MRI and in vitro laser irradiation (808 nm, 200 mW) to determine the r values and photothermal ablation. RESULTS:The sizes of monodispersed nanoparticles were measured in rang 5.74-7.17 nm. No cytotoxicity was observed after incubating MCF 7 cells under various Fe concentrations of nanoparticles and theranostic agents. The transverse relaxation time of the protoporphyrin conjugated to IONs (52.32 mMs) exceeded that of ION-Ol and TZ-conjugated ION-PP. In addition, the in vitro photothermal ablation of ION-PP-TZ revealed a 74 % MCF 7 cell reduction after 10 min of at the highest Fe concentration (1.00 mg Fe/mL). CONCLUSIONS:In summary, the water-soluble ION-PP-TZ is a promising bimodal agent for the diagnosis and treatment of human epidermal growth factor receptor 2-positive breast cancer cells using a T MRI contrast agent and photothermal therapy.
Identification of a Profile of Neutrophil-Derived Granule Proteins in the Surface of Gold Nanoparticles after Their Interaction with Human Breast Cancer Sera.
Chantada-Vázquez María Del Pilar,García-Vence María,Vázquez-Estévez Sergio,Bravo Susana B,Núñez Cristina
Nanomaterials (Basel, Switzerland)
It is well known that the interaction of a nanomaterial with a biological fluid leads to the formation of a protein corona (PC) surrounding the nanomaterial. Using standard blood analyses, alterations in protein patterns are difficult to detect. PC acts as a "nano-concentrator" of serum proteins with affinity for nanoparticles' surface. Consequently, characterization of PC could allow detection of otherwise undetectable changes in protein concentration at an early stage of a disease, such as breast cancer (BC). Here, we employed gold nanoparticles (AuNPs: 10.02 ± 0.91 nm) as an enrichment platform to analyze the human serum proteome of BC patients (n = 42) and healthy controls (n = 42). Importantly, the analysis of the PC formed around AuNPs after their interaction with serum samples of BC patients showed a profile of proteins that could differentiate breast cancer patients from healthy controls. These proteins developed a significant role in the immune and/or innate immune system, some of them being neutrophil-derived granule proteins. The analysis of the PC also revealed serum proteome alterations at the subtype level.
Stimuli-Responsive Small-on-Large Nanoradiosensitizer for Enhanced Tumor Penetration and Radiotherapy Sensitization.
Fu Wenhui,Zhang Xiao,Mei Linqiang,Zhou Ruyi,Yin Wenyan,Wang Qiang,Gu Zhanjun,Zhao Yuliang
Development of an efficient nanoradiosensitization system that enhances the radiation doses in cancer cells to sensitize radiotherapy (RT) while sparing normal tissues is highly desirable. Here, we construct a tumor microenvironment (TME)-responsive disassembled small-on-large molybdenum disulfide/hafnium dioxide (MoS/HfO) dextran (M/H-D) nanoradiosensitizer. The M/H-D can degrade and release the HfO nanoparticles (NPs) in TME to enhance tumor penetration of the HfO NPs upon near-infrared (NIR) exposure, which can solve the bottleneck of insufficient internalization of the HfO NPs. Simultaneously, the NIR photothermal therapy increased peroxidase-like catalytic efficiency of the M/H-D nanoradiosensitizer in TME, which selectively catalyzed intratumorally overexpressed HO into highly oxidized hydroxyl radicals (·OH). The heat induced by PTT also relieved the intratumoral hypoxia to sensitize RT. Consequently, this TME-responsive precise nanoradiosensitization achieved improved irradiation effectiveness, potent oxygenation in tumor, and efficient suppression to tumor, which can be real-time monitored by computed tomography and photoacoustic imaging.
Vacancies on 2D transition metal dichalcogenides elicit ferroptotic cell death.
Xu Shujuan,Zheng Huizhen,Ma Ronglin,Wu Di,Pan Yanxia,Yin Chunyang,Gao Meng,Wang Weili,Li Wei,Liu Sijin,Chai Zhifang,Li Ruibin
Sustainable developments of nanotechnology necessitate the exploration of structure-activity relationships (SARs) at nano-bio interfaces. While ferroptosis may contribute in the developments of some severe diseases (e.g., Parkinson's disease, stroke and tumors), the cellular pathways and nano-SARs are rarely explored in diseases elicited by nano-sized ferroptosis inducers. Here we find that WS and MoS nanosheets induce an iron-dependent cell death, ferroptosis in epithelial (BEAS-2B) and macrophage (THP-1) cells, evidenced by the suppression of glutathione peroxidase 4 (GPX4), oxygen radical generation and lipid peroxidation. Notably, nano-SAR analysis of 20 transition metal dichalcogenides (TMDs) disclosures the decisive role of surface vacancy in ferroptosis. We therefore develop methanol and sulfide passivation as safe design approaches for TMD nanosheets. These findings are validated in animal lungs by oropharyngeal aspiration of TMD nanosheets. Overall, our study highlights the key cellular events as well as nano-SARs in TMD-induced ferroptosis, which may facilitate the safe design of nanoproducts.
Redox Responsive Metal Organic Framework Nanoparticles Induces Ferroptosis for Cancer Therapy.
He Haozhe,Du Lihua,Guo Huanling,An Yongcheng,Lu Liejing,Chen Yali,Wang Yong,Zhong Huihai,Shen Jun,Wu Jun,Shuai Xintao
Small (Weinheim an der Bergstrasse, Germany)
Ferroptosis is attracting significant attention due to its effectiveness in tumor treatment. The efficiency to produce toxic lipid peroxides (LPOs) at the tumor site plays a key role in ferroptosis. A hybrid PFP@Fe/Cu-SS metal organic framework (MOF) is synthesized and shown to increase intratumoral LPO content through redox reactions generating ·OH. In addition, glutathione (GSH) depletion through disulfide-thiol exchange leads to the inactivation of glutathione peroxide 4 (GPX4), which results in a further increase in LPO content. This MOF exhibits high inhibitory effect on the growth of xenografted Huh-7 tumors in mice. The coadministration of a ferroptosis inhibitor reduces the antitumor effect of the MOF, leading to a restoration of GPX4 activity and an increase in tumor growth. Moreover, the construction of Cu into mesoporous PFP@Fe/Cu-SS not only allows the MOF to be used as a contrast agent for T -weighted magnetic resonance imaging, but also renders its photothermal conversion capacity. Thus, near-infrared irradiation is able to induce photothermal therapy and transform the encapsulated liquid perfluoropentane into microbubbles for ultrasound imaging.
Hyperthermia can alter tumor physiology and improve chemo- and radio-therapy efficacy.
Dunne Michael,Regenold Maximilian,Allen Christine
Advanced drug delivery reviews
Hyperthermia has demonstrated clinical success in improving the efficacy of both chemo- and radio-therapy in solid tumors. Pre-clinical and clinical research studies have demonstrated that targeted hyperthermia can increase tumor blood flow and increase the perfused fraction of the tumor in a temperature and time dependent manner. Changes in tumor blood circulation can produce significant physiological changes including enhanced vascular permeability, increased oxygenation, decreased interstitial fluid pressure, and reestablishment of normal physiological pH conditions. These alterations in tumor physiology can positively impact both small molecule and nanomedicine chemotherapy accumulation and distribution within the tumor, as well as the fraction of the tumor susceptible to radiation therapy. Hyperthermia can trigger drug release from thermosensitive formulations and further improve the accumulation, distribution, and efficacy of chemotherapy.
Localized Fe(II)-Induced Cytotoxic Reactive Oxygen Species Generating Nanosystem for Enhanced Anticancer Therapy.
Ding Yuxue,Wan Jiaxun,Zhang Zihao,Wang Fang,Guo Jia,Wang Changchun
ACS applied materials & interfaces
The anticancer therapy on the basis of reactive oxygen species (ROS)-mediated cellular apoptosis has achieved great progress. However, this kind of theraputic strategy still faces some challenges such as light, photosensitizer and oxygen (O) dependence. In this article, a ROS-mediated anticancer therapy independent of light, photosensitizer and oxygen was established based on a Fe-induced ROS-generating nanosystem. First, artemisinin (ART) was loaded in porous magnetic supraparticles (MSP) by a nanodeposition method. Then, the poly(aspartic acid)-based polymer, which consisted of dopamine, indocyanine green, and polyethylene glycol side chain, was coated onto the surface of ART-loaded MSP. When the nanoparticles entered into cancer cells, a reaction of Fe-mediated cleavage of the endoperoxide bridge contained in ART occurred and subsequent a large amount of ROS was generated. Moreover, a NIR light was used to effectively increase the local temperature of tumor in virtue of the superior photothermal effects of MSP, which enabled us to accelerate the ROS generation and achieved an enhanced ROS yield. The newly developed nanodrug system displayed a high level of intracellular ROS generation, leading to the desired killing efficacy against malignant cells and solid tumor. This smart nanosystem holds great potential to overcome the existing barrier in PDT and opens a promising avenue for anticancer therapy.
Supramolecular Nanodiscs Self-Assembled from Non-Ionic Heptamethine Cyanine for Imaging-Guided Cancer Photothermal Therapy.
Mu Xueluer,Lu Yingxi,Wu Fapu,Wei Yuhan,Ma Huihui,Zhao Yingjie,Sun Jing,Liu Shaofeng,Zhou Xianfeng,Li Zhibo
Advanced materials (Deerfield Beach, Fla.)
Supramolecular nanomedicines, which use supramolecular design to improve the precision and effectiveness of pharmaceutical practice and optimize pharmacokinetic profiles, have gathered momentum to battle cancer and other incurable diseases, for which traditional small-molecular and macromolecular drugs are less effective. However, the lack of clinical approval of supramolecular assembly-based medicine underscores the challenges facing this field. A 2D nanodisc-based supramolecular structure is formed by a non-ionic heptamethine cyanine (Cy7) dye, which generates fluorescence self-quenching but unique photothermal and photoacoustic properties. These Cy7-based supramolecular nanodiscs exhibit passive tumor-targeting properties to not only visualize the tumor by near-infrared fluorescence imaging and photoacoustic tomography but also induce photothermal tumor ablation under irradiation. Due to the nature of organic small molecule, they induce undetectable acute toxicity in mice and can be eliminated by the liver without extrahepatic metabolism. These findings suggest that the self-assembling cyanine discs represent a new paradigm in drug delivery as single-component supramolecular nanomedicines that are self-delivering and self-formulating, and provide a platform technology for synergistic clinical cancer imaging and therapy.
Berberine associated photodynamic therapy promotes autophagy and apoptosis via ROS generation in renal carcinoma cells.
Lopes Tairine Zara,de Moraes Fabio Rogério,Tedesco Antonio Claudio,Arni Raghuvir Krishnaswamy,Rahal Paula,Calmon Marilia Freitas
Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie
Renal cell carcinoma (RCC) consists of the most lethal common urological cancer and the clinical practice has shown that resistant RCC to commons therapies is extremely high. Berberine is an isoquinoline alkaloid, presents in different kinds of plants and it has long been used in Chinese medicine. It has several properties, such as antioxidant, anti-inflammatory, anti-diabetic, anti-microbial and anti-cancer. Moreover, berberine has photosensitive characteristics and its association with photodynamic therapy (PDT) is effective against tumor cells. This study aimed to evaluate the effects of berberine associated with PDT in renal carcinoma cell lines. The cellular viability assay showed increased cytotoxicity in concentration and time-dependent manner. Berberine presented efficient internalization in all cell lines analyzed. In addition, after treatment with berberine associated with PDT, it was observed a high phototoxicity effect with less than 20 % of viable cells. In this study we observed that the increase of reactive oxygen species (ROS) levels was accompanied by an increase of autophagy levels and apoptosis by caspase 3 activity, suggesting cell death by both mechanisms. Additionally, three target genes of anti-cancer drugs were differentially expressed in 786-O cells, being that Vascular Endothelial Growth Factor-D (FIGF) and Human Telomerase Reverse Transcriptase (TERT) gene presented low expression and Polo Like Kinase 3 (PLK3) presented overexpression after treatment with berberine associated with PDT. In this study, the proposed treatment triggered metabolites changes related to cell proliferation, tumorigenesis and angiogenesis. Thus, it was possible to suggest that berberine has promising potential as a photosensitizing agent in a photodynamic therapy, because it induced significant anticancer effects on renal carcinoma cells.
Hybrid Nanospheres to Overcome Hypoxia and Intrinsic Oxidative Resistance for Enhanced Photodynamic Therapy.
Shi Leilei,Hu Fang,Duan Yukun,Wu Wenbo,Dong Jinqiao,Meng Xiangjun,Zhu Xinyuan,Liu Bin
Photodynamic therapy (PDT) has been a well-accepted clinical treatment for malignant tumors owing to its noninvasiveness and high spatiotemporal selectivity. However, the efficiency of PDT is still severely hindered by an inherent aggregation-caused quenching (ACQ) effect of traditional photosensitizers (PSs), the presence of B-cell lymphoma 2 (Bcl-2), an antiapoptosis protein in cells, and hypoxia in the tumor microenvironment. To address these issues, hybrid nanospheres containing Fe, aggregation-induced emission (AIE) PS, and Bcl-2 inhibitor of sabutoclax were constructed coordination-driven self-assembly in aqueous media. Once the hybrid nanospheres are taken up by tumor cells, intracellular O concentration is observed to increase Fenton reaction driven by Fe, whereas intracellular PDT resistance of the AIE PS was mitigated by sabutoclax. The design of the multifunctional hybrid nanospheres demonstrates a prospective nanoplatform for image-guided enhanced PDT of tumors.
Fe-Doped Polyoxometalate as Acid-Aggregated Nanoplatform for NIR-II Photothermal-Enhanced Chemodynamic Therapy.
Shi Yunhao,Zhang Jiaojiao,Huang Han,Cao Changyu,Yin Jiajia,Xu Wenjing,Wang Wenjun,Song Xuejiao,Zhang Yewei,Dong Xiaochen
Advanced healthcare materials
The combination of reactive oxygen species-involved chemodynamic therapy (CDT) and photothermal therapy (PTT) holds great promise in enhancing anticancer effects. Herein, a multifunctional Fe-doped polyoxometalate (Fe-POM) cluster is fabricated via a simple method. The Fe-POM can not only be utilized as PTT agents to generate a hyperthermia effect for cancer cell killing under near-infrared (NIR) II laser (1060 nm) irradiation, but also can be used as CDT agents to convert endogenous less-reactive H O into harmful ·OH and simultaneously deplete glutathione for an amplified CDT effect. Notably, the hyperthermia induced by PTT can further enhance the CDT effect, achieving a synergistic PTT/CDT effect. Owing to the self-assembling properties at lowered pH values, the Fe-POM exhibits high tumor accumulation as revealed by photoacoustic imaging. More importantly, Fe-POM enables effective destruction of tumors without inducing noticeable damage to normal tissues under 1060 nm laser irradiation. The work presents a new type of multifunctional agent with high PTT/CDT efficacy, providing promising methods for PTT-enhanced CDT in a NIR-II biowindow.
Self-assembling prodrug nanotherapeutics for synergistic tumor targeted drug delivery.
Wang Zhiren,Chen Jiawei,Little Nicholas,Lu Jianqin
Self-assembling prodrugs represents a robust and effective nanotherapeutic approach for delivering poorly soluble anticancer drugs. With numerous intrinsic advantages, self-assembling prodrugs possess the maximum drug loading capacity, controlled drug release kinetics, prolonged blood circulation, and preferential tumor accumulation based on the enhanced permeability and retention (EPR) effect. These prodrug conjugates allow for efficient self-assembly into nanodrugs with the potential of encapsulating other therapeutic agents that have different molecular targets, enabling simultaneous temporal-spatial release of drugs for synergistic antitumor efficacy with reduced systemic side effects. The aim of this review is to summarize the recent progress of self-assembling prodrug cancer nanotherapeutics that are made through conjugating therapeutically active agents to Polyethylene glycol, Vitamin E, or drugs with different physicochemical properties via rational design, for synergistic tumor targeted drug delivery. STATEMENT OF SIGNIFICANCE: All current FDA-approved nanomedicines use inert biomaterials as drug delivery carriers. These biomaterials lack any therapeutic potential, contributing not only to the cost, but may also elicit severe unfavorable adverse effects. Despite the reduction in toxicity associated with the payload, these nanotherapeutics have been met with limited clinical success, likely due to the monotherapy regimen. The self-assembling prodrug (SAP) has been emerging as a powerful platform for enhancing efficacy through co-delivering other therapeutic modalities with distinct molecular targets. Herein, we opportunely present a comprehensive review article summarizing three unique approaches of making SAP for synergistic drug delivery: pegylation, vitamin E-derivatization, and drug-drug conjugation. These SAPs may inevitably pave the way for developing more efficacious, clinically translatable, combination cancer nanotherapies.
Supramolecular Self-Assembled Nanostructures for Cancer Immunotherapy.
Huang Zichao,Song Wantong,Chen Xuesi
Frontiers in chemistry
Functional materials and nanostructures have been widely used for enhancing the therapeutic potency and safety of current cancer immunotherapy. While profound nanostructures have been developed to participate in the development of cancer immunotherapy, the construction of intricate nanostructures with easy fabrication and functionalization properties to satisfy the diversified requirements in cancer immunotherapy are highly required. Hierarchical self-assembly using supramolecular interactions to manufacture organized architectures at multiple length scales represents an interesting and promising avenue for sophisticated nanostructure construction. In this mini-review, we will outline the recent progress made in the development of supramolecular self-assembled nanostructures for cancer immunotherapy, with special focus on the supramolecular interactions including supramolecular peptide assembly, supramolecular DNA assembly, lipid hydrophobic assembly, host-guest assembly, and biomolecular recognition assembly.
Intriguing H-Aggregates of Heptamethine Cyanine for Imaging-Guided Photothermal Cancer Therapy.
Wu Fapu,Lu Yingxi,Mu Xueluer,Chen Zhitai,Liu Shengsen,Zhou Xianfeng,Liu Shaofeng,Li Zhibo
ACS applied materials & interfaces
Organic small-molecule-based photothermal agents such as cyanine dyes have received increasing attention in developing novel cancer therapies with potential clinical utility but suffer from poor stability, low photothermal efficiency, and limited accumulation at tumor sites in molecular forms. Self-assembly of small-molecule dyes into supramolecular assemblies may address these concerns by controlling the molecular organization of dye monomers to form structures of a higher order. Among them, H-aggregates of dyes favor face-to-face contacts with strongly overlapping areas, which always have a negative connotation to exhibit low or no fluorescence in most cases but may emanate energy in nonradiative forms such as heat for photothermal cancer therapy applications. Here, the synergistic self-assembly of cyanine dyes into H-aggregates is developed as a new supramolecular strategy to fabricate small-molecule-based photothermal nanomaterials. Compared to the free cyanine dyes, the H-aggregates assembled from pyrene or tetraphenylethene (TPE) conjugating cyanine exhibit the expected absorption spectral blue shift and fluorescence self-quenching but unique photothermal properties. Remarkably, the obtained H-aggregates are saucer-shaped nanoparticles that exhibit passive tumor-targeting properties to induce imaging-guided photothermal tumor ablation under irradiation. This supramolecular strategy presented herein may open up new opportunities for constructing next-generation small-molecule-based self-assembly nanomaterials for PTT cancer therapy in clinics.
Synergistic Anticancer Therapy by Ovalbumin Encapsulation-Enabled Tandem Reactive Oxygen Species Generation.
Jiang Shuai,Xiao Ming,Sun Wen,Crespy Daniel,Mailänder Volker,Peng Xiaojun,Fan Jiangli,Landfester Katharina
Angewandte Chemie (International ed. in English)
The anticancer efficacy of photodynamic therapy (PDT) is limited due to the hypoxic features of solid tumors. We report synergistic PDT/chemotherapy with integrated tandem Fenton reactions mediated by ovalbumin encapsulation for improved in vivo anticancer therapy via an enhanced reactive oxygen species (ROS) generation mechanism. O produced by the PDT is converted to H O by superoxide dismutase, followed by the transformation of H O to the highly toxic OH via Fenton reactions by Fe originating from the dissolution of co-loaded Fe O nanoparticles. The PDT process further facilitates the endosomal/lysosomal escape of the active agents and enhances their intracellular delivery to the nucleus-even for drug-resistant cells. Cisplatin generates O in the presence of nicotinamide adenine dinucleotide phosphate oxidase and thereby improves the treatment efficiency by serving as an additional O source for production of OH radicals. Improved anticancer efficiency is achieved under both hypoxic and normoxic conditions.
Smart Magnetic and Fluorogenic Photosensitizer Nanoassemblies Enable Redox-Driven Disassembly for Photodynamic Therapy.
An Ruibing,Cheng Xiaoyang,Wei Shixuan,Hu Yuxuan,Sun Yidan,Huang Zheng,Chen Hong-Yuan,Ye Deju
Angewandte Chemie (International ed. in English)
Stimuli-responsive smart photosensitizer (PS) nanoassemblies that allow enhanced delivery and controlled release of PSs are promising for imaging-guided photodynamic therapy (PDT) of tumors. However, the lack of high-sensitivity and spatial-resolution signals and fast washout of released PSs from tumor tissues have impeded PDT efficacy in vivo. Herein, we report tumor targeting, redox-responsive magnetic and fluorogenic PS nanoassemblies (NP-RGD) synthesized via self-assembly of a cRGD- and disulfide-containing fluorogenic and paramagnetic small molecule (1-RGD) for fluorescence/magnetic resonance bimodal imaging-guided tumor PDT. NP-RGD show high r relaxivity but quenched fluorescence and PDT activity; disulfide reduction by glutathione (GSH) promotes efficient disassembly into a small-molecule probe (2-RGD) and an organic PS (PPa-SH), which could further bind with intracellular albumin, allowing prolonged retention and cascade activation of fluorescence and PDT to ablate tumors.
Clinical development and potential of photothermal and photodynamic therapies for cancer.
Li Xingshu,Lovell Jonathan F,Yoon Juyoung,Chen Xiaoyuan
Nature reviews. Clinical oncology
Light-activated, photosensitizer-based therapies have been established as safe modalities of tumour ablation for numerous cancer indications. Two main approaches are available: photodynamic therapy, which results in localized chemical damage in the target lesions, and photothermal therapy, which results in localized thermal damage. Whereas the administration of photosensitizers is a key component of photodynamic therapy, exogenous photothermal contrast agents are not required for photothermal therapy but can enhance the efficiency and efficacy of treatment. Over the past decades, great strides have been made in the development of phototherapeutic drugs and devices as cancer treatments, but key challenges have restricted their widespread clinical use outside of certain dermatological indications. Improvements in the tumour specificity of photosensitizers, achieved through targeting or localized activation, could provide better outcomes with fewer adverse effects, as could combinations with chemotherapies or immunotherapies. In this Review, we provide an overview of the current clinical progress of phototherapies for cancer and discuss the emerging preclinical bioengineering approaches that have the potential to overcome challenges in this area and thus improve the efficiency and utility of such treatments.
A Multi-action Pt Conjugate with Oleate and Cinnamate Ligands Targets Human Epithelial Growth Factor Receptor HER2 in Aggressive Breast Cancer Cells.
Kostrhunova Hana,Zajac Juraj,Markova Lenka,Brabec Viktor,Kasparkova Jana
Angewandte Chemie (International ed. in English)
HER2-positive breast cancer is an aggressive subtype that typically responds poorly to standard chemotherapy. To design an anticancer drug selective for HER2-expressing breast cancer, a Pt prodrug with axial oleate and cinnamate ligands was synthesized. We demonstrate its superior antiproliferative activity in monolayer and 3D spheroid models; the antiproliferative efficiency increases gradually with increasing expression of HER2. The results also suggest that the released Pt compound inhibits the proliferation of cancer cells by a DNA-damage-mediated mechanism. Simultaneously, the released oleic and cinnamic acid can effectively inhibit HER2 expression. To our knowledge, this is the first platinum-based complex inhibiting HER2 expression that does not contain protein or peptide. Moreover, this Pt prodrug is capable of overcoming the resistance of cancer stem cells (CSCs), inducing death in both CSCs and differentiated cancer cells. Thus, the results substantiate our design strategy and demonstrate the potential of this approach for the development of new, therapeutically relevant compounds.
Enhanced cancer therapy by hypoxia-responsive copper metal-organic frameworks nanosystem.
Zhang Kai,Meng Xiangdan,Yang Zhou,Dong Haifeng,Zhang Xueji
Tumor hypoxia-responsive size-switchable nanosystems for precise delivery of drug into deep tumor show great prospects for killing cancer cells with high specificity and minimal invasiveness. However, the development of versatile nanosystems is still a challenge. Herein, for the first time, we report a novel hypoxia-responsive copper metal-organic framework nanoparticles (Cu-MOF NPs) for chemodynamic therapy and sonodynamic therapy (CDT/SDT). The large size Cu-MOF NPs show good stability under normal oxygen partial pressure and enhance tumor accumulation, and it quickly degraded and released Cu and Ce6 when exposed to the hypoxic tumor microenvironment (TME), significantly reinforced the intratumoral penetration. The internalized Cu reacts with local GSH to deplete GSH and reduce Cu to Cu, which subsequently reacts with endogenous HO to produce cytotoxic hydroxyl radicals (•OH) through Fenton-like reaction for CDT. The released Ce6 further mediated SDT under US irradiation. The synergistic SDT/CDT efficacy was significantly enhanced owing to the GSH depletion, realizing selective and effective MCF-7 killing with minimal invasiveness. This work presents a novel hypoxia-responsive MOF nanosystem with intrinsic CDT properties, mainly, the MOF nanosystem is flexible to the integration with other therapy approaches. It provides a general strategy to design a hypoxia-responsive MOF nano theranostic platform.