Cancer is one of the deadliest diseases worldwide. Recent statistics have shown that metastases and tumor relapse are the leading causes of cancer‐associated deaths. While traditional treatments are ...able to efficiently remove the primary tumor, secondary tumors remain poorly accessible. Capitalizing on this there is an urgent need for novel treatment modalities. Among the most promising approaches, increasing research interest has been devoted to immunogenic cell death inducing agents that are able to trigger localized cell death of the cancer cells as well as induce an immune response inside the whole organism. Preliminary studies have shown that immunogenic cell death inducing compounds could be able to overcome metastatic and relapsing tumors. Herein, the application of metal complexes as immunogenic cell death inducing compounds is systematically reviewed.
Metastases and tumor relapse are the leading causes of cancer‐associated deaths. Among other approaches, much research interest has been devoted to immunogenic cell death inducing agents that are able to trigger localized cell death of the cancer cells as well as induce an immune response inside the whole organism. Herein, the application of metal complexes as immunogenic cell death triggering compounds is systematically reviewed.
Despite the success of small interfering RNA (siRNA) in clinical settings and its potential value in human immunodeficiency virus (HIV) therapy, the rapid clearance and absence of precise delivery to ...target cells still hinder the therapeutic effect of siRNA. Herein, a new system, which can escape immune recognition, has HIV‐1 neutralizing capacity, and the ability to deliver siRNA specifically into HIV‐1‐infected cells, is constructed by functionalizing siRNA delivery lipid nanoparticles with the lymphocyte membrane and 12p1. The constructed system is shown to escape uptake by the mononuclear phagocyte system. The constructed system exhibits strong binding ability with gp120, thus displaying distinguished neutralizing breadth and potency. The constructed system neutralizes all tested HIV‐1 pseudotyped viruses with a geometric mean 80% inhibitory concentration (IC80) of 29.75 µg mL−1 and inhibits X4‐tropic HIV‐1 with an IC80 of 64.20 µg mL−1, and R5‐tropic HIV‐1 with an IC80 of 16.39 µg mL−1. The new system also specifically delivers siRNA into the cytoplasm of HIV‐1‐infected cells and exhibits evident gene silencing of tat and rev. Therefore, this new system can neutralize HIV‐1 and deliver siRNA selectively into HIV‐1‐infected cells and may be a promising therapeutic candidate for the precise therapy of HIV.
Lymphocyte membrane‐ and 12p1‐dual‐functionalized nanoparticles are constructed for free HIV‐1 trapping and precise siRNA delivery into HIV‐1‐infected cells. This new system exhibits strong binding ability with gp120, distinguished neutralizing potency against HIV‐1, and evident gene silencing of tat and rev in HIV‐1‐infected cells. Therefore, the constructed system can neutralize HIV‐1 and deliver siRNA selectively into the cytoplasm of HIV‐1‐infected cells.
A polymeric prodrug of cisplatin was constructed from MPEG-b-PCL-b-PLL and a cisplatin(IV) complex containing two COOH groups on its axial positions. The latter also plays a role of cross-linker for ...the micelle formed. As a result, the polymeric prodrug showed enhanced stability in blood circulation, more accumulation in cancer site, lower systematic toxicity, and comparable cytotoxicity to cisplatin.
A polymeric cisplatin(IV) prodrug in the form of cross-linked micelles (M(Pt(IV)) was prepared by first constructing MPEG-b-PCL-b-PLL micelles and then attaching a cisplatin(IV) complex with two axial succinic moieties to the lysine residues of the carrier polymer in aqueous medium. The micelles obtained were characterized by TEM, DLS, and zeta potential measurement. Their in vitro release experiments were carried out at pH 7.4 and 5.0 or in the presence of 5mM sodium ascorbate (NaAsc). Results showed that the micelles were sensitive to both acidic hydrolysis and mild reducing agents; in the presence of 5mM NaAsc, cisplatin(II) was directly released and the released cisplatin(II) could chelate with nucleobases; the micelles displayed comparable cytotoxicities to cisplatin; and the micelles were much more efficiently internalized by the cells than cisplatin(II) and cisplatin(IV) counterparts. Moreover, in vivo study showed accumulation of more Pt species in the tumor site and lower systematic toxicity compared to free cisplatin(II) and cisplatin(IV). This polymeric prodrug of cisplatin is expected to be used more for future study and applications.
Advanced staged high‐grade serous ovarian cancer (HGSOC) is the leading cause of gynecological cancer death in the developed world, with 5‐year survival rates of only 25–30% due to late‐stage ...diagnosis and the shortcomings of platinum‐based therapies. A Phase I clinical trial of a combination of free cisplatin and poly(ADP‐ribose) polymerase inhibitors (PARPis) showed therapeutic benefit for HGSOC. In this study, we address the challenge of resistance to platinum‐based therapy by developing a targeted delivery approach. Novel electrostatic layer‐by‐layer (LbL) liposomal nanoparticles (NPs) with a terminal hyaluronic acid layer that facilitates CD44 receptor targeting are designed for selective targeting of HGSOC cells; the liposomes can be formulated to contain both cisplatin and the PARPi drug within the liposomal core and bilayer. The therapeutic effectiveness of LbL NP‐encapsulated cisplatin and PARPi alone and in combination was compared with the corresponding free drugs in luciferase and CD44‐expressing OVCAR8 orthotopic xenografts in female nude mice. The NPs exhibited prolonged blood circulation half‐life, mechanistic staged drug release and targeted codelivery of the therapeutic agents to HGSOC cells. Moreover, compared to the free drugs, the NPs resulted in significantly reduced tumor metastasis, extended survival, and moderated systemic toxicity.
Diffuse alveolar damage (DAD) triggers neutrophilic inflammation in damaged tissues of the lung, but little is known about the distinct roles of tissue structural cells in modulating the recruitment ...of neutrophils to damaged areas. Here, by combining single‐cell and spatial transcriptomics, and using quantitative assays, we systematically analyze inflammatory cell states in a mouse model of DAD‐induced neutrophilic inflammation after aerosolized intratracheal inoculation with ricin toxin. We show that homeostatic resident fibroblasts switch to a hyper‐inflammatory state, and the subsequent occurrence of a CXCL1‐CXCR2 chemokine axis between activated fibroblasts (AFib) as the signal sender and neutrophils as the signal receiver triggers further neutrophil recruitment. We also identify an anatomically localized inflamed niche (characterized by a close‐knit spatial intercellular contact between recruited neutrophils and AFib) in peribronchial regions that facilitate the pulmonary inflammation outbreak. Our findings identify an intricate interplay between hyper‐inflammatory fibroblasts and neutrophils and provide an overarching profile of dynamically changing inflammatory microenvironments during DAD progression.
Diffuse alveolar damage (DAD) triggers intense neutrophilic airway inflammation. This work demonstrates that proinflammatory activated fibroblasts (AFib) are induced in a mouse model of DAD. Neutrophil infiltration into the airway crucially depends on their cross‐talk with AFib via the soluble CXCL1‐CXCR2 chemokine axis.
Display omitted
Electrospinning provides a versatile technique for the preparation of matrices with micro/nanoscopic fibers. The non-woven polymer materials produced by electrospinning have an ...extremely high surface-to-volume ratio, a complex porous structure with excellent pore-interconnectivity, and diverse fibrous morphologies. These remarkable features impart a wide range of desirable properties to electrospun matrices for meeting the requirements of advanced biomedical applications, such as pharmaceutical repositories, tissue engineering scaffolds, wound healing, sensors, reinforcement, sound absorption, and filtration. This review presents a comprehensive overview of the recent progress and potential developments of electrospun polymer matrices and their application as biomaterials.
To explore the pharmacogenomic markers that affect the platinum-based chemotherapy response in non-small-cell lung carcinoma (NSCLC), we performed a two-cohort of genome-wide association studies ...(GWAS), including 34 for WES-based and 433 for microarray-based analyses, as well as two independent validation cohorts. After integrating the results of two studies, the genetic variations related to the platinum-based chemotherapy response were further determined by fine-mapping in 838 samples, and their potential functional impact were investigated by eQTL analysis and in vitro cell experiments. We found that a total of 68 variations were significant at P < 1 × 10−3 in cohort 1 discovery stage, of which 3 SNPs were verified in 262 independent samples. A total of 541 SNPs were significant at P < 1 × 10−4 in cohort 2 discovery stage, of which 8 SNPs were verified in 347 independent samples. Comparing the validated SNPs in two GWAS, ADCY1 gene was verified in both independent studies. The results of fine-mapping showed that the G allele carriers of ADCY1 rs2280496 and C allele carriers of rs189178649 were more likely to be resistant to platinum-based chemotherapy. In conclusion, our study found that rs2280496 and rs189178649 in ADCY1 gene were associated the sensitivity of platinum-based chemotherapy in NSCLC patients.
This study found that rs2280496 and rs189178649 in ADCY1 gene were associated the sensitivity of platinum-based chemotherapy in NSCLC patients. Display omitted
Tumor immunotherapy has emerged as one of the most promising clinical techniques to treat cancer tumors. Despite its clinical application, the cancerous immunosuppressive microenvironment limits the ...therapeutic efficiency of the treatment. To generate a stronger immunogenic therapeutic effect, herein, a platinum complex for chemotherapy and a BODIPY photosensitizer for photodynamic therapy are encapsulated into multimodal type II immunogenic cell death (ICD) induce nanoparticles. As the platinum complex and the photosensitizer are able to induce type II ICD, an exceptionally strong immune response is observed in triple‐negative breast cancer cells. While remaining stable and therefore poorly cytotoxic in the dark, the nanomaterial is found to quickly dissociate upon exposure to near‐infrared light, causing a multimodal mechanism of action in cancer cells as well as multicellular tumor spheroids through combined chemotherapy, photodynamic therapy, and immunotherapy. The nanoparticles are found to nearly fully eradicate a triple‐negative breast cancer tumor and therefore to strongly enhance the survival of tumor‐bearing mice models using low drug and light doses.
Low immunogenicity is a decisive factor for ineffective cancer immunotherapy. To generate a stronger immunogenic effect, herein, a polymeric photosensitizer with BODIPY backbones is designed to deliver a cationic platinum complex (Pt‐NHC) as nanoparticles that can induce a type II immunogenic cell death (ICD) effect. The nanoparticles can be disintegrated upon NIR light irradiation, resulting in a combined chemotherapy, photodynamic therapy, and immunotherapy.
Photothermal therapy holds great promise for cancer treatment due to its effective tumor ablation and minimal invasiveness. Herein a new class of biodegradable photothermal agents with effective ...adsorption in both near‐infrared‐I (NIR‐I) and NIR‐II windows is reported for deep tumor therapy. As demonstrated in a deep‐seated ovarian cancer model, photothermal therapy using 1064 nm irradiation effectively inhibits tumor progression and prolongs survival spans. This work provides a new design of photothermal agents toward a more effective therapy of tumors.
A biodegradable photothermal agent is developed by inserting cleavable disulfide moieties into a conjugative polymer, which affords biodegradability and excellent adsorption in both the near‐infrared (NIR)‐I and NIR‐II windows, effectively inhibits tumor progression, and extends survival spans in a deep‐seated ovarian cancer mouse model.
The development of Pt
prodrugs which are selectively reduced within cancerous cells into their Pt
therapeutically active species has received increasing attention within the last decade. Despite ...recent research progress, the majority of investigated compounds are excited using ultraviolet or blue light. As the light penetration depth is low at these wavelengths, the treatment of deep-seated or large tumors is limited. To overcome this limitation, herein, the example of Pt
-functionalized nanoparticles that could be excited within the NIR region at 808 nm is reported. The polymer backbone which can self-assemble into nanoparticles was functionalized with Pt
complexes for chemotherapy, photosensitizers for photodynamic immunotherapy, and nucleus/cancer-targeting peptides. Upon irradiation, the Pt
center is reduced to Pt
and the axially coordinated ligands are released, presenting a multimodal treatment. While selectively accumulating in tumorous tissue, the nanoparticles demonstrated the ability to eradicate a triple-negative breast cancer tumor inside a mouse model.
PDF
