Gene augmented nuclear-targeting sonodynamic therapy via Nrf2 pathway-based redox balance adjustment boosts peptide-based anti-PD-L1 therapy on colorectal cancer.
TL;DR: In this article, Nrf2-siRNA augmented nuclear-targeting sonodynamic therapy (SDT) could boost ICB therapy against colorectal cancer, which is known to be resistant to immune checkpoint blockade.
Abstract: Background
Colorectal cancer is known to be resistant to immune checkpoint blockade (ICB) therapy. Sonodynamic therapy (SDT) has been reported to improve the efficacy of immunotherapy by inducing immunogenic cell death (ICD) of cancer. However, the SDT efficacy is extremely limited by Nrf2-based natural redox balance regulation pathway in cancer cells in response to the increased contents of reactive oxygen species (ROS). Nuclear-targeting strategy has shown unique advantages in tumor therapy by directly destroying the DNA. Thus it can be seen that Nrf2-siRNA augmented nuclear-targeting SDT could boost ICB therapy against colorectal cancer.
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TL;DR: In this paper , the role of reactive oxygen species (ROS) in cancer cells, their mechanism of action in cancer cell death, and the challenges associated with ROS therapy were also discussed.
14 citations
TL;DR: Wang et al. as mentioned in this paper summarized the characteristics of the tumor immune microenvironment and the mechanisms of ICD, and the representative advances of SDT-based nanomedicines for cancer immunotherapy.
Abstract: Cancer immunotherapy effect can be greatly enhanced by other methods to induce immunogenic cell death (ICD), which has profoundly affected immunotherapy as a highly efficient paradigm. However, these treatments have significant limitations, either by causing damage of the immune system or limited to superficial tumors. Sonodynamic therapy (SDT) can induce ICD to promote immunotherapy without affecting the immune system because of its excellent spatiotemporal selectivity and low side effects. Nevertheless, SDT is still limited by low reactive oxygen species yield and the complex tumor microenvironment. Recently, some emerging SDT‐based nanomedicines have made numerous attractive and encouraging achievements in the field of cancer immunotherapy due to high immunotherapeutic efficiency. However, this cross‐cutting field of research is still far from being widely explored due to huge professional barriers. Herein, the characteristics of the tumor immune microenvironment and the mechanisms of ICD are firstly systematically summarized. Subsequently, the therapeutic mechanism of SDT is fully summarized, and the advantages and limitations of SDT are discussed. The representative advances of SDT‐based nanomedicines for cancer immunotherapy are further highlighted. Finally, the application prospects and challenges of SDT‐based immunotherapy in future clinical translation are discussed.
12 citations
TL;DR: This work establishes a cascade bioreactor of TiSX NSs with satisfactory H2S release ability and excellent ROS generation properties under US irradiation for programmed gas–sonodynamic cancer therapy.
Abstract: Gas‐mediated sonodynamic therapy (SDT) has the potential to become an effective strategy to improve the therapeutic outcome and survival rate of cancer patients. Herein, titanium sulfide nanosheets (TiSX NSs) are prepared as cascade bioreactors for sequential gas–sonodynamic cancer therapy. TiSX NSs themselves as hydrogen sulfide (H2S) donors can burst release H2S gas. Following H2S generation, TiSX NSs are gradually degraded to become S‐defective and partly oxidized into TiOX on their surface, which endows TiSX NSs with high sonodynamic properties under ultrasound (US) irradiation. In vitro and in vivo experiments show the excellent therapeutic effects of TiSX NSs. In detail, large amounts of H2S gas and reactive oxygen species (ROS) can simultaneously inhibit mitochondrial respiration and ATP synthesis, leading to cancer cell apoptosis. Of note, H2S gas also plays important roles in modulating and activating the immune system to effectively inhibit pulmonary metastasis. Finally, the metabolizable TiSX NSs are excreted out of the body without inducing any significant long‐term toxicity. Collectively, this work establishes a cascade bioreactor of TiSX NSs with satisfactory H2S release ability and excellent ROS generation properties under US irradiation for programmed gas–sonodynamic cancer therapy.
10 citations
TL;DR: In this paper , a cavitation assisted endoplasmic reticulum (ER) targeted sonodynamic nanodroplets (PMPS NDs, 329 nm) were used to enhance the effect of anti-PD-L1 immunotherapy effectively in orthotopic and distant pancreatic cancer.
Abstract: Sonodynamic therapy (SDT) induces immunogenic cell death (ICD) in tumors and promises to play an assistive role in immunotherapy in pancreatic cancer. However, the short half-life and limited diffusion distance of reactive oxygen species (ROS) impair ICD induction, especially in tumors with relatively poor blood perfusion and dense stroma.To address this problem, we fabricated cavitation-assisted endoplasmic reticulum (ER) targeted sonodynamic nanodroplets (PMPS NDs, 329 nm). The good sonodynamic effect and precise endoplasmic reticulum target effect was verified. After intravenous injection, the cRGD peptide modified nanodroplets initially aggregated around the tumor vascular endothelial cells. Stimulated by ultrasound, the liquid-to-gas bubbles began to oscillate and cavitate. This acoustic droplet evaporation strategy facilitated transport of the nanoparticle across the vessel, with deep penetration. This loosened the tumor stroma and facilitated accumulation and penetration of loaded sonosensitizer after 6 h. The modified sonosensitizer can selectively accumulate in the ER to generate a large amount of ROS in situ, inducing potent ER stress, amplified ICD and dendritic cell maturation in vitro and in vivo. Furthermore, the elevated antitumor effect of SDT plus anti-PD-L1 immunotherapy was verified using an orthotopic tumor model.This study reports a cavitation assisted ER targeted sonodynamic therapy that can enhance the effect of anti-PD-L1 immunotherapy effectively in orthotopic and distant pancreatic cancer.
9 citations
TL;DR: In this article , the interrelationship between programmed cell death and immunogenic cell death (ICD) is investigated using nanomedicines as examples, and the relationship between PCD and ICD and its application prospects in the development of new ICD nanomaterials are summarized.
Abstract: Programmed cell death (PCD, mainly including apoptosis, necrosis, ferroptosis, pyroptosis, and autophagy) and immunogenic cell death (ICD), as important cell death mechanisms, are widely reported in cancer therapy, and understanding the relationship between the two is significant for clinical tumor treatments. Considering that vast nanodrugs are developed to induce tumor PCD and ICD simultaneously, in this review, the interrelationship between PCD and ICD is described using nanomedicines as examples. First, an overview of PCD patterns and focus on the morphological differences and interconnections among them are provided. Then the interrelationship between apoptosis and ICD in terms of endoplasmic reticulum stress is described by introducing various cancer treatments and the recent developments of nanomedicines with inducible immunogenicity. Next, the crosstalk between non‐apoptotic (including necrosis, ferroptosis, pyroptosis, and autophagy) signaling pathways and ICD is introduced and their relationship through various nanomedicines as examples is further illustrated. Finally, the relationship between PCD and ICD and its application prospects in the development of new ICD nanomaterials are summarized. This review is believed to deepen the understanding of the relationship between PCD and ICD, extend the biomedical applications of various nanodrugs, and promote the progress of clinical tumor therapy.
5 citations
References
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TL;DR: A status report on the global burden of cancer worldwide using the GLOBOCAN 2018 estimates of cancer incidence and mortality produced by the International Agency for Research on Cancer, with a focus on geographic variability across 20 world regions.
Abstract: This article provides a status report on the global burden of cancer worldwide using the GLOBOCAN 2018 estimates of cancer incidence and mortality produced by the International Agency for Research on Cancer, with a focus on geographic variability across 20 world regions There will be an estimated 181 million new cancer cases (170 million excluding nonmelanoma skin cancer) and 96 million cancer deaths (95 million excluding nonmelanoma skin cancer) in 2018 In both sexes combined, lung cancer is the most commonly diagnosed cancer (116% of the total cases) and the leading cause of cancer death (184% of the total cancer deaths), closely followed by female breast cancer (116%), prostate cancer (71%), and colorectal cancer (61%) for incidence and colorectal cancer (92%), stomach cancer (82%), and liver cancer (82%) for mortality Lung cancer is the most frequent cancer and the leading cause of cancer death among males, followed by prostate and colorectal cancer (for incidence) and liver and stomach cancer (for mortality) Among females, breast cancer is the most commonly diagnosed cancer and the leading cause of cancer death, followed by colorectal and lung cancer (for incidence), and vice versa (for mortality); cervical cancer ranks fourth for both incidence and mortality The most frequently diagnosed cancer and the leading cause of cancer death, however, substantially vary across countries and within each country depending on the degree of economic development and associated social and life style factors It is noteworthy that high-quality cancer registry data, the basis for planning and implementing evidence-based cancer control programs, are not available in most low- and middle-income countries The Global Initiative for Cancer Registry Development is an international partnership that supports better estimation, as well as the collection and use of local data, to prioritize and evaluate national cancer control efforts CA: A Cancer Journal for Clinicians 2018;0:1-31 © 2018 American Cancer Society
58,675 citations
TL;DR: This work describes a standardized setup for reproducible, easy-handling culture, treatment and routine analysis of multicellular spheroids, the classical 3D culture system resembling many aspects of the pathophysiological situation in human tumor tissue and provides a list of human carcinoma cell lines that produce treatable sp Heroids under identical culture conditions.
Abstract: Although used in academic research for several decades, 3D culture models have long been regarded expensive, cumbersome and unnecessary in drug development processes. Technical advances, coupled with recent observations showing that gene expression in 3D is much closer to clinical expression profiles than those seen in 2D, have renewed attention and generated hope in the feasibility of maturing organotypic 3D systems to therapy test platforms with greater power to predict clinical efficacies. Here we describe a standardized setup for reproducible, easy-handling culture, treatment and routine analysis of multicellular spheroids, the classical 3D culture system resembling many aspects of the pathophysiological situation in human tumor tissue. We discuss essential conceptual and practical considerations for an adequate establishment and use of spheroid-based drug screening platforms and also provide a list of human carcinoma cell lines, partly on the basis of the NCI-DTP 60-cell line screen, that produce treatable spheroids under identical culture conditions. In contrast to many other settings with which to achieve similar results, the protocol is particularly useful to be integrated into standardized large-scale drug test routines as it requires a minimum number of defined spheroids and a limited amount of drug. The estimated time to run the complete screening protocol described herein--including spheroid initiation, drug treatment and determination of the analytical end points (spheroid integrity, and cell survival through the acid phosphatase assay)--is about 170 h. Monitoring of spheroid growth kinetics to determine growth delay and regrowth, respectively, after drug treatment requires long-term culturing (> or =14 d).
1,365 citations
TL;DR: The object of this review is the anticancer application of PDT, its advantages and possible modifications to potentiate its effects, and the use of nanoparticles enables achievement a targeted method which is focused on specific receptors, and, as a result, increases the selectivity of the photodynamic therapy.
995 citations
TL;DR: TAT peptide has been employed to conjugate onto mesoporous silica nanoparticles (MSNs-TAT) with high payload for nuclear-targeted drug delivery for the first time, and may provide an effective strategy for the design and development of cell-nuclear-targeting drug delivery.
Abstract: Most present nanodrug delivery systems have been developed to target cancer cells but rarely nuclei. However, nuclear-targeted drug delivery is expected to kill cancer cells more directly and efficiently. In this work, TAT peptide has been employed to conjugate onto mesoporous silica nanoparticles (MSNs-TAT) with high payload for nuclear-targeted drug delivery for the first time. Monodispersed MSNs-TAT of varied particle sizes have been synthesized to investigate the effects of particle size and TAT conjugation on the nuclear membrane penetrability of MSNs. MSNs-TAT with a diameter of 50 nm or smaller can efficiently target the nucleus and deliver the active anticancer drug doxorubicin (DOX) into the targeted nucleus, killing these cancer cells with much enhanced efficiencies. This study may provide an effective strategy for the design and development of cell-nuclear-targeted drug delivery.
849 citations
TL;DR: Clinical development of immune checkpoint inhibition in CRC leading to regulatory approvals for the treatment of dMMR–MSI-H CRC is reviewed and new advances in expanding the efficacy of immunotherapy to early-stage CRC and CRC that is mismatch-repair-proficient and has low microsatellite instability (pMMR- MSI-L) are focused on.
Abstract: Following initial successes in melanoma treatment, immunotherapy has rapidly become established as a major treatment modality for multiple types of solid cancers, including a subset of colorectal cancers (CRCs). Two programmed cell death 1 (PD1)-blocking antibodies, pembrolizumab and nivolumab, have shown efficacy in patients with metastatic CRC that is mismatch-repair-deficient and microsatellite instability-high (dMMR-MSI-H), and have been granted accelerated FDA approval. In contrast to most other treatments for metastatic cancer, immunotherapy achieves long-term durable remission in a subset of patients, highlighting the tremendous promise of immunotherapy in treating dMMR-MSI-H metastatic CRC. Here, we review the clinical development of immune checkpoint inhibition in CRC leading to regulatory approvals for the treatment of dMMR-MSI-H CRC. We focus on new advances in expanding the efficacy of immunotherapy to early-stage CRC and CRC that is mismatch-repair-proficient and has low microsatellite instability (pMMR-MSI-L) and discuss emerging approaches for targeting the immune microenvironment, which might complement immune checkpoint inhibition.
827 citations