Tumor immunotherapy, especially immune checkpoint blockade (ICB), has revolutionized the cancer field. However, the limited response of tumors to immunotherapy is a major obstacle. Tumor immunogenic ...cell death (ICD) is a death mode of tumor cells that can promote tumor immunity. ICD can induce strong antitumor immune responses through the ectopic exposure of calreticulin on the plasma membrane surface and the release of the non-histone nuclear protein high-mobility group box 1 (HMGB1), ATP, and interferon (IFN), thus activating an adaptive immune response against dead cell-associated antigens and enhancing the therapeutic effect of tumor immunotherapy. Chemotherapy, radiotherapy, photothermal therapy, magneto-thermodynamics therapy, nanopulse stimulation, and oncolytic virus therapy can all induce a strong antitumor immune response by ICD. In addition, the application of nanotechnology can precisely target drug delivery and improve the efficacy of immunotherapy. Here we introduce the basic concepts and molecular mechanisms underlying the induction of ICD. Then, we summarize and discuss the progress in the application of nanotechnology in immunotherapy to promote ICD. Finally, we attempt to define the challenges and future directions in this area to extend the benefits of ICD to a broader patient population.
In this review, we introduced the basic concepts and molecular mechanisms underlying the induction of immunogenic cell death (ICD). Furthermore, we also summarized and discussed the progress in the application of nanotechnology in immunotherapy to promote tumor ICD.
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In this study, we designed a highly sensitive reactive oxygen species-responsive polymer PCP for encapsulating doxorubicin (DOX) and purpurin 18 (P18) simultaneously, realizing the synergistic ...treatment of photodynamic therapy and chemotherapy.
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Cyclodextrin (CD) has special spatial structure and well biological safety, so it has been widely used for constructing CD-based nanoplatforms. Through functionalization, cyclodextrin can form various stimulus-response nanoplatforms, such as pH, temperature, redox, light and magnetic fields. In this study, we designed a highly sensitive reactive oxygen species (ROS)-responsive polymer PCP which encapsulated doxorubicin (DOX) and purpurin 18 (P18) to achieve the synergy of photodynamic and chemotherapy. The high content of reactive oxygen species (ROS) in the tumor microenvironment (TME) triggers the cleavage of the borate bond of MPEG-CD-PHB (PCP), thereby promoting the release of drugs. When irradiated with near-infrared laser, the photosensitizer P18 released by polymer micelles can produce reactive oxygen species to promote cell apoptosis. Compared with monotherapy, a series of experiments confirmed that our micelles had enhanced anti-cancer activity. This work was beneficial to the design of ROS-responsive materials and provides an effective strategy for the application of collaborative anti-tumor therapy.
The absence of tumor antigens leads to a low response rate, which represents a major challenge in immune checkpoint blockade (ICB) therapy. Pyroptosis, which releases tumor antigens and ...damage‐associated molecular patterns (DAMPs) that induce antitumor immunity and boost ICB efficiency, potentially leads to injury when occurring in normal tissues. Therefore, a strategy and highly efficient agent to induce tumor‐specific pyroptosis but reduce pyroptosis in normal tissues is urgently required. Here, a smart tumor microenvironmental reactive oxygen species (ROS)/glutathione (GSH) dual‐responsive nano‐prodrug (denoted as MCPP) with high paclitaxel (PTX) and photosensitizer purpurin 18 (P18) loading is rationally designed. The ROS/GSH dual‐responsive system facilitates the nano‐prodrug response to high ROS/GSH in the tumor microenvironment and achieves optimal drug release in tumors. ROS generated by P18 after laser irradiation achieves controlled release and induces tumor cell pyroptosis with PTX by chemo‐photodynamic therapy. Pyroptotic tumor cells release DAMPs, thus initiating adaptive immunity, boosting ICB efficiency, achieving tumor regression, generating immunological memory, and preventing tumor recurrence. Mechanistically, chemo‐photodynamic therapy and control‐release PTX synergistically induce gasdermin E (GSDME)‐related pyroptosis. It is speculated that inspired chemo‐photodynamic therapy using the presented nano‐prodrug strategy can be a smart strategy to trigger pyroptosis and augment ICB efficiency.
A smart tumor microenvironmental reactive oxygen species/glutathione dual‐responsive nano‐prodrug (denoted as MCPP) with high paclitaxel and photosensitizer purpurin 18 loading is designed. Chemo‐photodynamic therapy using the presented nano‐prodrug strategy can be a smart strategy to trigger pyroptosis and augment the efficiency of immune checkpoint blockade therapy.
Despite the diversified therapeutic approaches for malignant tumors, chemotherapy remains the backbone of current cancer treatment. However, conventional chemotherapeutics was found to be associated ...with deficient recognition of tumor, low uptake efficiency, insolubility, short circulation, poor biocompatibility and low therapeutic outcomes. Herein, the active targeting redox-responsive mannosylated prodrug nanocolloids (HM NCs) were constructed for enhanced chemotherapy of colon cancer. HM NCs were prepared by the covalent cross-linking of 10-hydroxycamptothecin (HCPT) and mannose (MAN) via a redox-responsive cross-linker containing disulfide bonds, and modified with a moderate amount of polyethylene glycol (PEG). The large amount of mannose contained in HM NCs could actively target overexpressed mannose receptors on the surface of cancer cells and enhance cancer cell internalization through mannose receptor-mediated endocytosis. Owing to the combination of active targeting and the enhanced permeability and retention (EPR) passive targeting, HM NCs could effectively accumulate in tumors and high glutathione (GSH) in tumor microenvironment triggered cleavage of redox-responsive bonds and precise drug release. HM NCs exhibited superior antitumor activity both in vitro and in vivo and appreciably extended the mouse survival rate with good biocompatibility. The innovative HM NCs are expected to be conducive to overcoming the limitations of conventional chemotherapy for colon cancer and providing more choices for future clinical translation.
Despite the enhanced permeability and retention effect, the passive targeting can be interfered with by the complex biologic barriers in the body. In this study, an active targeting system (HM NCs) was constructed by covalent cross-linking of mannose and anticancer drug 10-hydroxycamptothecin via redox-responsive disulfide bonds for enhanced colon cancer chemotherapy. Mannosylation could promote hydrophilia and stability for prolonged blood circulation. Mannose could promote tumor recognition and cell internalization via mannose receptor-mediated endocytosis. High glutathione level could trigger the redox-responsive release of anticancer drugs and further induce cell apoptosis via DNA damage. The HM NCs exhibited superior antitumor activity both in vitro and in vivo and appreciably extended the mouse survival rate with good biocompatibility.
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Polymer systems can be designed into different structures and morphologies according to their physical and chemical performance requirements, and are considered as one of the most promising ...controlled delivery systems that can effectively improve the cancer therapeutic index. However, the majority of the polymer delivery systems are designed to be simple spherical nanostructures. To explore morphology/size-oriented delivery performance optimization, here, we synthesized three novel cylindrical polymer brushes (CPBs) by atom transfer radical polymerization (ATRP), which were cellulose-g-(CPT-b-OEGMA) (CCO) with different lengths (~86, ~40, and ~21 nm). The CPBs are composed of bio-degradable cellulose as the carrier, poly(ethylene glycol) methyl ether methacrylate (OEGMA) as hydrophily block, and glutathione (GSH)-responsive hydrophobic camptothecin (CPT) monomer as loaded anticancer drug. By controlling the chain length of the initiator, three kinds of polymeric prodrugs with different lengths (CCO-1, CCO-2, and CCO-3) could be self-organized into unimolecular micelles in water. We carried out comparative studies of three polymers, whose results verified that the shorter CPBs exhibited higher drug release efficiency, more cellular uptake, and enhanced tumor permeability, accompanied by shortened blood circulation time and lower tumor accumulation. As evidenced by in vivo experiments, the shorter CPBs exhibited higher anti-tumor efficiency, revealing that the size advantage has a higher priority than the anisotropic structure advantage. This provided vital information as to design an anisotropic polymer-based drug delivery system for cancer therapy.
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•Reduction-responsive cylindrical polymer brushes (CPBs) could reshape the tumor microenvironment to reinforce chemotherapy.•Three cellulose prodrugs-based CPBs with different lengths could form into unimolecular micelles in water.•Longer CPBs exhibited prolonged blood circulation time and higher tumor accumulation.•The CPBs showed an enhanced chemotherapy with real-time NIRF imaging.
Despite immunotherapy involving immune checkpoint inhibitors (ICIs) have revolutionized cancer therapy, the clinical efficacy is limited due to ICI resistance. Pyroptosis is a gasdermin-mediated ...programmed cell death that enhances responses to ICIs. However, nontargeted elicitation of pyroptosis may induce systemic side effects and toxicity. Therefore, we reasonably design and construct a tumor-specific prodrug that combines the heat shock protein 90 inhibitor tanespimycin (17-AAG) with the photosensitizer chlorin e6 (Ce6) to induce pyroptosis, by utilizing the high glutathione level in the tumor microenvironment. The released Ce6 and 17-AAG produce reactive oxygen species by laser triggering, which induces gasdermin E-mediated pyroptosis. Furthermore, 17-AAG reduces myeloid-derived suppressor cells and sensitizes tumors to anti-programmed death-1 (PD-1) therapy. Thus, our prodrug strategy achieves tumor-targeted pyroptosis to suppress tumor growth, thereby improving the response to anti-PD-1 therapy and extending the survival of 4T1 breast tumor-bearing mice. Consequently, this pyroptosis-based prodrug represents a novel strategy for enforcing immunogenic photodynamic therapy.
Although targeted therapy and immunotherapy are now shining in the treatment of some cancers, chemotherapy is still the cornerstone of drug treatment for many cancer patients. The emergence of ...chemotherapy prodrugs can improve the drug activity and reduce the side effects of chemotherapy. When used, the tumor microenvironment has characteristics different from normal tissues, and the existence of the microenvironment provided a more convenient way to design responsive nanodrugs. Herein, we designed a glutathione (GSH)-responsive prodrug nanogels for enhancing tumor chemotherapy. In the nanogels of HHNP, 10-hydroxycamptothecin (HCPT) played an essential role in killing cancer cells. HCPT was jointed with a cross-linker agent with disulfide bond and was further coated with polyethylene glycol, which not only prolonged the half-life of the drug, but also made HCPT accurate transport to the tumor fractions and achieved precise and controllable release. The proposal of HHNP effectively retained the biological activity of the drug, and introduced functions such as targeting, selective release and biodegradation, which greatly improved the medical efficiency of the drug and effectively reduced the toxic and side effects. This chemotherapeutic prodrug nanogel offers a new window for constructing efficient drug delivery platform.
In this work, we reported a microenvironment-responsive chemotherapeutic nanogels of 10-hydroxycamptothecin (HCPT) by a covalent crosslinking strategy for boosting the therapeutic treatment of cancer therapy. Display omitted
Early childhood caries (ECC) is a public healthcare concern that greatly reduces the quality of life of young children. As a leading factor of ECC, cariogenic biofilms are composed of ...acidogenic/aciduric pathogens and extracellular polysaccharides (EPSs), creating an acidic and protected microenvironment. Antimicrobial photodynamic therapy (aPDT) is a noninvasive, painless, and efficient therapeutic approach that is suitable for treating ECC. However, due to the hyperfine structure of cariogenic biofilms, most photosensitizers (PSs) could not access and penetrate deeply in biofilms, which dramatically hamper their efficiency in the clinic. Herein, bioresponsive nanoparticle loaded with chlorin e6 (MPP-Ce6) is developed, which largely increases the penetration depth (by over 75%) and retention (by over 100%) of PS in the biofilm compared with free Ce6. Furthermore, MPP-Ce6-mediated aPDT not only kills the bacteria in preformed biofilms but also inhibits multispecies biofilm formation. A rampant caries model is established to mimic ECC in vivo, where the population of cariogenic bacteria is decreased to 10% after MPP-Ce6-mediated aPDT. Importantly, the number and severity of carious lesions are efficiently reduced via Keyes’ scoring and micro-CT analysis. This simple but effective strategy can serve as a promising approach for daily oral hygiene in preventing ECC.
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•A pH-responsive nano-system is developed for biofilm-targeted drug delivery.•The nano-system could overcome biological barriers and penetrate deeply in biofilms.•This nano-system facilitates aPDT to kill bacteria in deep cariogenic biofilm.•This strategy prevents the progression of early childhood caries in a rat model.
The complex tumor microenvironment and non-targeting drugs limit the efficacy of clinical tumor therapy. For ensuring the accurate delivery and maximal effects of anticancer drugs, it is important to ...develop innovative drug delivery system based on nano-strategies.
In this study, an intracellular acidity-responsive polymeric metal organic framework nanoparticle (denoted as DIMP) has been constructed, which can co-deliver the chemotherapy agent of doxorubicin (DOX) and phototherapy agent of indocyanine green (ICG) for breast carcinoma theranostics. Specifically, DIMP possesses a suitable and stable nanometer size and can respond to the acidic microenvironment in cells, thus precisely delivering drugs into target tumor sites and igniting the biological reactions towards cell apoptosis. Following in vivo and in vitro results showed that DIMP could be effectively accumulated in tumor sites and induced powerful immunogenic cell death (ICD) effect.
The designed DIMP displayed its effectiveness in combined photo-chemotherapy with auxiliary of ICD effect under a multimodal imaging monitor. Thus, the present MOF-based strategy may offer a potential paradigm for designing drug-delivery system for image-guided synergistic tumor therapy.
Tumor cells show acidic conditions compared with normal cells, which further inspires scientist to build nanocarrier responsive to tumor microenvironment (TME) for enhancing tumor therapeutic ...efficacy. Here, we report a pH-sensitive and biocompatible polyprodrug based on dextran-doxorubicin (DOX) prodrug (DOXDT) for enhanced chemotherapy. High-density DOX component was covalently decorated on the nanocarrier and the drug molecules could be effectively released in the acidic tumor tissue/cells, improving chemotherapy efficacy. Specifically, a dextran-based copolymer was preliminarily prepared by one-step atom transfer radical polymerization (ATRP); then DOX was conjugated on the copolymer component via pH-responsive hydrazone bond. The structure of DOXDT can be well-controlled. The resulting DOXDT was able to further self-assemble into nanoscale micelles with a hydration diameter of about 32.4 nm, which presented excellent micellar stability. Compared to lipid-based drug delivery system, the DOXDT prodrug showed higher drug load capacity up to 23.6%. In addition, excellent stability and smaller size of the nanocarrier contributed to better tissue permeability and tumor suppressive effects in vivo. Hence, this amphipathic DOXDT prodrug is promising in the development of translational DOX formulations, which would be widely applied in cancer therapy.
Biocompatible polyprodrug based on dextran-doxorubicin (DOXDT) with high drug loading and pH-triggered release for enhanced chemotherapy. Display omitted
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