Precise Depletion of Tumor Seed and Growing Soil with Shrinkable Nanocarrier for Potentiated Cancer Chemoimmunotherapy.
TL;DR: In this article, a nanocarrier of platinum(IV) prodrug and BLZ-945, BLZ@S-NP/Pt, was developed to differentially target tumor cells and tumor-associated macrophages (TAMs).
Abstract: Simultaneously targeting tumor cells and nonmalignant cells represent a more efficient strategy for replacing the traditional method of targeting only tumor cells, and co-delivery nanocarriers have inherent advantages to achieve this goal. However, differential delivery of multiple agents to various types of cell with different spatial distribution patterns remains a large challenge. Herein, we developed a nanocarrier of platinum(IV) prodrug and BLZ-945, BLZ@S-NP/Pt, to differentially target tumor cells and tumor-associated macrophages (TAMs). The BLZ@S-NP/Pt undergoes shrinkage to small platinum(IV) prodrug-conjugating nanoparticles under 660 nm light, resulting in deep tumor penetration to kill more cancer cells. Meanwhile, such shrinkage also enables the rapid release of BLZ-945 in the perivascular regions of tumor to preferentially deplete TAMs (enriched in perivascular regions). Therefore, BLZ@S-NP/Pt differentially and precisely delivers agents to TAMs and tumor cells located in different spatial distribution, respectively, eventually having synergistic anticancer effects in multiple tumor models.
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TL;DR: In this paper, the authors highlight the application, progress, and prospect of nanomedicine in the process of tumor immunoediting and also discuss several engineering methods to improve the efficiency of tumor treatment.
Abstract: Immunotherapy that harnesses the human immune system to fight cancer has received widespread attention and become a mainstream strategy for cancer treatment. Cancer immunotherapy not only eliminates primary tumors but also treats metastasis and recurrence, representing a major advantage over traditional cancer treatments. Recently with the development of nanotechnology, there exists much work applying nanomaterials to cancer immunotherapy on the basis of their excellent physiochemical properties, such as efficient tissue-specific delivery function, huge specific surface area, and controllable surface chemistry. Consequently, nanotechnology holds significant potential in improving the efficacy of cancer immunotherapy. Nanotechnology-based immunotherapy mainly manifests its inhibitory effect on tumors via two different approaches: one is to produce an effective anti-tumor immune response during tumorigenesis, and the other is to enhance tumor immune defense ability by modulating the immune suppression mechanism in the tumor microenvironment. With the success of tumor immunotherapy, understanding the interaction between the immune system and smart nanomedicine has provided vigorous vitality for the development of cancer treatment. This review highlights the application, progress, and prospect of nanomedicine in the process of tumor immunoediting and also discusses several engineering methods to improve the efficiency of tumor treatment.
62 citations
TL;DR: A tumor microenvironments‐adapted composite consisting of a thermosensitive hydrogel and a reactive oxygen species (ROS)‐responsive nanogel is developed for precisely sequential drug release to enhance molecularly targeted therapy and amplify immune activation.
Abstract: Various macro/microscopic biomaterials have been developed for controlled drug delivery in the combination therapy of malignancies. However, uncertain loading ratio, release sequence, and spatiotemporal distribution of drugs hinder their synergistic therapeutic effects and clinical applications. In this work, a tumor microenvironments‐adapted composite consisting of a thermosensitive hydrogel and a reactive oxygen species (ROS)‐responsive nanogel is developed for precisely sequential drug release to enhance molecularly targeted therapy and amplify immune activation. LY3200882 (LY), a selective transforming growth factor‐β (TGF‐β) inhibitor, is encapsulated in the ROS‐responsive nanogel and dispersed uniformly with regorafenib (REG) in a thermosensitive hydrogel (Gel/(REG+NG/LY)). After in situ administration, REG is preferentially released from the hydrogel to inhibit tumor growth and promote ROS generation, which triggers the subsequent on‐demand release of LY from the nanogel. LY contributes to preventing the epithelial–mesenchymal transition and immune escape of tumor cells induced by elevated TGF‐β. In subcutaneous and orthotopic colorectal tumor bearing mouse models, Gel/(REG+NG/LY) effectively inhibits tumor growth and liver metastases by increasing the tumor infiltration of CD8+ T cells, reducing the recruitment of tumor‐associated macrophages and myeloid‐derived suppressor cells, and promoting the polarization of macrophages from M2 to M1 type, indicating the significant potential in improving the prognosis of advanced cancer patients.
46 citations
TL;DR: Tumor-acidity responsive group poly(2-azepane ethyl methacrylate) with a rapid response rate and highly efficient bioorthogonal click chemistry is utilized to form large-sized aggregates in tumor tissue to enhance accumulation and retention and provides a general drug delivery strategy for enhanced tumor accumulation and penetration.
Abstract: Hypoxia, a common feature of most solid tumors, causes severe tumor resistance to chemotherapy and immunotherapy. Herein, a tumor-acidity and bioorthogonal chemistry-mediated on-site size transformation clustered nanosystem is designed to overcome hypoxic resistance and enhance chemoimmunotherapy. The nanosystem utilized the tumor-acidity responsive group poly(2-azepane ethyl methacrylate) with a rapid response rate and highly efficient bioorthogonal click chemistry to form large-sized aggregates in tumor tissue to enhance accumulation and retention. Subsequently, another tumor-acidity responsive group of the maleic acid amide with a slow response rate was cleaved allowing the aggregates to slowly dissociate into ultrasmall nanoparticles with better tumor penetration ability for the delivery of doxorubicin (DOX) and nitric oxide (NO) to a hypoxic tumor tissue. NO can reverse a hypoxia-induced DOX resistance and boost the antitumor immune response through a reprogrammed tumor immune microenvironment. This tumor-acidity and bioorthogonal chemistry-mediated on-site size transformation clustered nanosystem not only helps to counteract a hypoxia-induced chemoresistance and enhance antitumor immune responses but also provides a general drug delivery strategy for enhanced tumor accumulation and penetration.
29 citations
TL;DR: In this article , a bioorthogonal in situ assembly strategy for prolonged retention of nanomedicines within tumor areas to act as drug depots was presented, which remarkably improves the antimetastatic efficacy of extracellular-targeted drug batimastat, and also leads to the simultaneous enhanced retention and sustained release of multiple agents for combined cocktail chemoimmunotherapy to finally elicit a potent antitumor immune response.
Abstract: Developing precise nanomedicines to improve the transport of anticancer drugs into tumor tissue and to the final action site remains a critical challenge. Here, we present a bioorthogonal in situ assembly strategy for prolonged retention of nanomedicines within tumor areas to act as drug depots. After extravasating into the tumor site, the slightly acidic microenvironment induces the exposure of cysteine on the nanoparticle surface, which subsequently undergoes a bioorthogonal reaction with the 2-cyanobenzothiazole group of another neighboring nanoparticle, enabling the formation of micro-sized drug depots to enhance drug retention and enrichment. This in situ nanoparticle assembly strategy remarkably improves the antimetastatic efficacy of extracellular-targeted drug batimastat, and also leads to the simultaneous enhanced retention and sustained release of multiple agents for combined cocktail chemoimmunotherapy to finally elicit a potent antitumor immune response. Such in situ assembly of nanomedicines represents a generalizable strategy towards extracellular drug delivery and cocktail chemoimmunotherapy.
18 citations
TL;DR: In this paper, a novel strategy that combines photothermal therapy (PTT), tumor starvation and nitric oxide (NO) therapy based on functionalized black phosphorus nanosheets (BP) is developed.
15 citations
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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: The paradoxical roles of the tumor microenvironment during specific stages of cancer progression and metastasis are discussed, as well as recent therapeutic attempts to re-educate stromal cells within the TME to have anti-tumorigenic effects.
Abstract: Cancers develop in complex tissue environments, which they depend on for sustained growth, invasion and metastasis. Unlike tumor cells, stromal cell types within the tumor microenvironment (TME) are genetically stable and thus represent an attractive therapeutic target with reduced risk of resistance and tumor recurrence. However, specifically disrupting the pro-tumorigenic TME is a challenging undertaking, as the TME has diverse capacities to induce both beneficial and adverse consequences for tumorigenesis. Furthermore, many studies have shown that the microenvironment is capable of normalizing tumor cells, suggesting that re-education of stromal cells, rather than targeted ablation per se, may be an effective strategy for treating cancer. Here we discuss the paradoxical roles of the TME during specific stages of cancer progression and metastasis, as well as recent therapeutic attempts to re-educate stromal cells within the TME to have anti-tumorigenic effects.
5,396 citations
TL;DR: Novel engineering approaches are discussed that capitalize on the growing understanding of tumour biology and nano–bio interactions to develop more effective nanotherapeutics for cancer patients.
Abstract: The intrinsic limits of conventional cancer therapies prompted the development and application of various nanotechnologies for more effective and safer cancer treatment, herein referred to as cancer nanomedicine. Considerable technological success has been achieved in this field, but the main obstacles to nanomedicine becoming a new paradigm in cancer therapy stem from the complexities and heterogeneity of tumour biology, an incomplete understanding of nano-bio interactions and the challenges regarding chemistry, manufacturing and controls required for clinical translation and commercialization. This Review highlights the progress, challenges and opportunities in cancer nanomedicine and discusses novel engineering approaches that capitalize on our growing understanding of tumour biology and nano-bio interactions to develop more effective nanotherapeutics for cancer patients.
3,800 citations
TL;DR: Experimental data demonstrating the role of the microenvironment in metastasis is described, areas for future research are identified and possible new therapeutic avenues are suggested.
Abstract: Metastasis is a multistage process that requires cancer cells to escape from the primary tumour, survive in the circulation, seed at distant sites and grow. Each of these processes involves rate-limiting steps that are influenced by non-malignant cells of the tumour microenvironment. Many of these cells are derived from the bone marrow, particularly the myeloid lineage, and are recruited by cancer cells to enhance their survival, growth, invasion and dissemination. This Review describes experimental data demonstrating the role of the microenvironment in metastasis, identifies areas for future research and suggests possible new therapeutic avenues.
3,332 citations
TL;DR: How PEGylation can result in drugs that are often more effective and safer, and which show improved patient convenience and compliance are reviewed.
Abstract: Protein and peptide drugs hold great promise as therapeutic agents. However, many are degraded by proteolytic enzymes, can be rapidly cleared by the kidneys, generate neutralizing antibodies and have a short circulating half-life. Pegylation, the process by which polyethylene glycol chains are attached to protein and peptide drugs, can overcome these and other shortcomings. By increasing the molecular mass of proteins and peptides and shielding them from proteolytic enzymes, pegylation improves pharmacokinetics. This article will review how PEGylation can result in drugs that are often more effective and safer, and which show improved patient convenience and compliance.
3,142 citations