ABSTRACT
Cancer stem cells (CSCs), also known as tumor initiating cells or tumor repopulating cells, which comprise only a small fraction of tumor, have received tremendous attention during the past two decades, as they are considered as the ringleader for initiation and progression of tumors, therapy resistance, metastasis, and recurrence in the clinic. Hence, eradicating CSCs is critical for successful cancer treatment. To that end, various CSC-targeting therapeutic agents have been pursued. However, these CSC-specific drugs are ineffective toward bulk cancer cells. Furthermore, these anti-CSC drugs not only eradicate CSCs but also affect conventional stem cells in normal organs or tissues. By virtue of the enhanced permeability and retention (EPR) effect, nanomaterial drug delivery systems (NDDSs) passively accumulate in tumor tissues, thereby alleviating severe side effects toward normal viscera. NDDSs can be further functionalized with CSC-specific binding molecules to promote targeted drug delivery toward CSCs. Moreover, NDDSs have unique advantages in encapsulating CSC-specific drugs and cytotoxic agents, realizing synchronized killing of CSCs and bulk cancer cells both temporally and spatially. For these reasons, leveraging nanotherapeutic strategies to target CSCs has gained tremendous attention recently.Some ten years ago, we summarized five basic features of efficient nanotherapeutics (the five features principle), which consist of long circulation, tumor accumulation, deep penetration, cellular internalization, and drug release. Based on this design rationale, we constructed several NDDSs, including nanogels with adaptive hydrophobicity, CSC-derived microparticles with tailored softness, and tumor exosome sheathed porous silicon biomimetic nanoparticles, for targeted drug delivery to tumor. To our astonishment, these NDDSs that possess the five basic features achieve decent drug delivery efficiency toward not only bulk tumor cells but more importantly CSCs. Consequently, such nanotherapeutics as-designed based on the five features principle are potent in eradicating CSCs, even with only cytotoxic drugs, for instance, doxorubicin. Furthermore, commercialized nanomedicines, such as Doxil and Abraxane, can be endowed with these five basic features by hyperbaric oxygen therapy and therefore achieve outstanding drug delivery efficiency, potent CSC elimination, and efficient cancer therapy. These studies suggest that intractable CSCs can be tackled with a material-based approach, highlight the critical role of the five features principle in designing effective nanotherapeutics, and pinpoint the significance of drug delivery efficiency in eliminating CSCs and bulk cancer cells.
Subject(s)
Antineoplastic Agents , Nanoparticles , Neoplasms , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Drug Delivery Systems , Humans , Nanoparticles/chemistry , Neoplasms/pathology , Neoplastic Stem Cells/metabolism , Neoplastic Stem Cells/pathologyABSTRACT
Cancer stem cells (CSCs) have been blamed as the main culprit of tumor initiation, progression, metastasis, chemoresistance, and recurrence. However, few anti-CSCs agents have achieved clinical success so far. Here we report a novel derivative of lonidamine (LND), namely HYL001, which selectively and potently inhibits CSCs by targeting mitochondria, with 380-fold and 340-fold lower IC50 values against breast cancer stem cells (BCSCs) and hepatocellular carcinoma stem cells (HCSCs), respectively, compared to LND. Mechanistically, we reveal that HYL001 downregulates glutaminase (GLS) expression to block glutamine metabolism, blunt tricarboxylic acid cycle, and amplify mitochondrial oxidative stress, leading to apoptotic cell death. Therefore, HYL001 displays significant antitumor activity in vivo, both as a single agent and combined with paclitaxel. Furthermore, HYL001 represses CSCs of fresh tumor tissues derived from liver cancer patients. This study provides critical implications for CSCs biology and development of potent anti-CSCs drugs.
Subject(s)
Antineoplastic Agents , Liver Neoplasms , Humans , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Antineoplastic Agents/metabolism , Glutamine/metabolism , Liver Neoplasms/drug therapy , Liver Neoplasms/metabolism , Mitochondria/metabolism , Neoplastic Stem Cells , Cell Line, TumorABSTRACT
The systemic use of pharmaceutical drugs for cancer patients is a compromise between desirable therapy and side effects because of the intrinsic shortage of organ-specific pharmaceutical drug. Design and construction of pharmaceutical drug to achieve the organ-specific delivery is thus desperately desirable. We herein regulate perylene skeleton to effect organ-specificity and present an example of lung-specific distribution on the basis of bay-twisted PDIC-NC. We further demonstrate that PDIC-NC can target into mitochondria to act as cellular respiration inhibitor, inducing insufficient production of adenosine triphosphate, promoting endogenous H2 O2 and . OH burst, elevating calcium overload, efficiently triggering the synergistic apoptosis, autophagy and endoplasmic reticulum stress of lung cancer cells. The antitumor performance of PDIC-NC is verified on in vivo xenografted, metastasis and orthotopic lung cancer, presenting overwhelming evidences for potentially clinical application. This study contributes a proof-of-concept demonstration of twisted perylene to well attain lung-specific distribution, and meanwhile achieves intensive lung cancer chemotherapy.
Subject(s)
Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Perylene/chemistry , Perylene/pharmacology , Apoptosis/drug effects , Autophagy/drug effects , Cell Line, Tumor , Endoplasmic Reticulum Stress/drug effects , Humans , Structure-Activity RelationshipABSTRACT
The undesirable optical proximity effect (OPE) that appeared in the digital micro-mirrors device (DMD) based maskless lithography directly influences the final exposure pattern and decreases the lithography quality. In this manuscript, a convenient method of intensity modulation applied for the maskless lithography is proposed to optimize such an effect. According to the pulse width modulation based image recognition of DMD, we replaced the digital binary mask with a special digital grayscale mask to modulate the UV intensity distribution to be closer to the expectation in a way of point-by-point modification. The exposure result applying the grayscale mask has a better consistency with the design pattern than that for the case in which the original binary mask is used. The effectiveness of this method was analyzed by the image subtraction technique. Experimental data revealed that the matching rate between the exposure pattern and the mask pattern has been improved from 78% to 91%. Besides, more experiments have been conducted to verify the validity of this method for the optical proximity optimization and its potential in the high-fidelity DMD based maskless lithography.
ABSTRACT
Immune checkpoint inhibitors (ICIs) constitute a pivotal class of immunotherapeutic drugs in cancer treatment. However, their widespread clinical application has led to a notable surge in immune-related adverse events (irAEs), significantly affecting the efficacy and survival rates of patients undergoing ICI therapy. While conventional hematological and imaging tests are adept at detecting organ-specific toxicities, distinguishing adverse reactions from those induced by viruses, bacteria, or immune diseases remains a formidable challenge. Consequently, there exists an urgent imperative for reliable biomarkers capable of accurately predicting or diagnosing irAEs. Thus, a thorough review of existing studies on irAEs biomarkers is indispensable. Our review commences by providing a succinct overview of major irAEs, followed by a comprehensive summary of irAEs biomarkers across various dimensions. Furthermore, we delve into innovative methodologies such as machine learning, single-cell RNA sequencing, multiomics analysis, and gut microbiota profiling to identify novel, robust biomarkers that can facilitate precise irAEs diagnosis or prediction. Lastly, this review furnishes a concise exposition of irAEs mechanisms to augment understanding of irAEs prediction, diagnosis, and treatment strategies.
ABSTRACT
2,2',4,4'-Tetrabrominated biphenyl ether (BDE-47) is a polybrominated diphenyl ether (PBDE) homologue that is ubiquitous in biological samples and highly toxic to humans and other organisms. Prior research has confirmed that BDE-47 can induce oxidative damage in RAW264.7 cells, resulting in apoptosis and impaired immune function. The current study mainly focused on how Isoliquiritigenin (ISL) and Licochalcone B (LCB) might protect against BDE-47's immunotoxic effects on RAW264.7 cells. The results show that ISL and LCB could increase phagocytosis, increase the production of MHC-II, and decrease the production of inflammatory factors (TNF-α, IL-6, and IL-1ß) and co-stimulatory factors (CD40, CD80, and CD86), alleviating the immune function impairment caused by BDE-47. Secondly, both ISL and LCB could reduce the expressions of the proteins Bax and Caspase-3, promote the expression of the protein Bcl-2, and reduce the apoptotic rate, alleviating the apoptosis initiated by BDE-47. Additionally, ISL and LCB could increase the levels of antioxidant substances (SOD, CAT, and GSH) and decrease the production of reactive oxygen species (ROS), thereby counteracting the oxidative stress induced by BDE-47. Ultimately, ISL and LCB suppress the NF-κB pathway by down-regulating IKBKB and up-regulating IκB-Alpha in addition to activating the Nrf2 pathway and promoting the production of HO-1 and NQO1. To summarize, BDE-47 causes oxidative damage that can be mitigated by ISL and LCB through the activation of the Nrf2 pathway and inhibition of the NF-κB pathway, which in turn prevents immune function impairment and apoptosis. These findings enrich the current understanding of the toxicological molecular mechanism of BDE-47 and the detoxification mechanism of licorice.
ABSTRACT
Cuproptosis is a new kind of cell death that depends on delivering copper ions into mitochondria to trigger the aggradation of tricarboxylic acid (TCA) cycle proteins and has been observed in various cancer cells. However, whether cuproptosis occurs in cancer stem cells (CSCs) is unexplored thus far, and CSCs often reside in a hypoxic tumor microenvironment (TME) of triple negative breast cancers (TNBC), which suppresses the expression of the cuproptosis protein FDX1, thereby diminishing anticancer efficacy of cuproptosis. Herein, a ROS-responsive active targeting cuproptosis-based nanomedicine CuET@PHF is developed by stabilizing copper ionophores CuET nanocrystals with polydopamine and hydroxyethyl starch to eradicate CSCs. By taking advantage of the photothermal effects of CuET@PHF, tumor hypoxia is overcome via tumor mechanics normalization, thereby leading to enhanced cuproptosis and immunogenic cell death in 4T1 CSCs. As a result, the integration of CuET@PHF and mild photothermal therapy not only significantly suppresses tumor growth but also effectively inhibits tumor recurrence and distant metastasis by eliminating CSCs and augmenting antitumor immune responses. This study presents the first evidence of cuproptosis in CSCs, reveals that disrupting hypoxia augments cuproptosis cancer therapy, and establishes a paradigm for potent cancer therapy by simultaneously eliminating CSCs and boosting antitumor immunity.
ABSTRACT
Cancer stem cells (CSCs), enabled to self-renew, differentiate, and initiate the bulk tumor, are recognized as the culprit of treatment resistance, metastasis, and recurrence. Simultaneously eradicating CSCs and bulk cancer cells is crucial for successful cancer therapy. Herein, we reported that doxorubicin (Dox) and erastin co-loaded hydroxyethyl starch-polycaprolactone nanoparticles (DEPH NPs) eliminated CSCs and cancer cells by regulating redox status. We found that an excellently synergistic effect existed when Dox and erastin were co-delivered by DEPH NPs. Specifically, erastin could deplete intracellular glutathione (GSH), thereby inhibiting the efflux of intracellular Dox and boosting Dox-induced reactive oxygen species (ROS) to amplify redox imbalance and oxidative stress. The high ROS levels restrained CSCs self-renewal via downregulating Hedgehog pathways, promoted CSCs differentiation, and rendered differentiated cancer cells vulnerable to apoptosis. As such, DEPH NPs significantly eliminated not only cancer cells but more importantly CSCs, contributing to suppressed tumor growth, tumor-initiating capacity, and metastasis, in various tumor models of triple negative breast cancer. This study demonstrates that the combination of Dox and erastin is potent in elimination of both cancer cells and CSCs, and that DEPH NPs represent a promising treatment against CSCs-rich solid tumors.
Subject(s)
Nanoparticles , Neoplasms , Reactive Oxygen Species/metabolism , Cell Line, Tumor , Hedgehog Proteins , Doxorubicin , StarchABSTRACT
Tumor starvation induced by intratumor glucose depletion emerges as a promising strategy for anticancer therapy. However, its antitumor potencies are severely compromised by intrinsic tumor hypoxia, low delivery efficiencies, and undesired off-target toxicity. Herein, a multifunctional cascade bioreactor (HCG), based on the self-assembly of pH-responsive hydroxyethyl starch prodrugs, copper ions, and glucose oxidase (GOD), is engineered, empowered by hyperbaric oxygen (HBO) for efficient cooperative therapy against aggressive breast cancers. Once internalized by tumor cells, HCG undergoes disassembly and releases cargoes in response to acidic tumor microenvironment. Subsequently, HBO activates GOD-catalyzed oxidation of glucose to H2 O2 and gluconic acid by ameliorating tumor hypoxia, fueling copper-catalyzed â¢OH generation and pH-responsive drug release. Meanwhile, HBO degrades dense tumor extracellular matrix, promoting tumor accumulation and penetration of HCG. Moreover, along with the consumption of glucose and the redox reaction of copper ions, the antioxidant capacity of tumor cells is markedly reduced, collectively boosting oxidative stress. As a result, the combination of HCG and HBO can not only remarkably suppress the growth of orthotopic breast tumors but also restrain pulmonary metastases by inhibiting cancer stem cells. Considering the clinical accessibility of HBO, this combined strategy holds significant translational potentials for GOD-based therapies.
Subject(s)
Breast Neoplasms , Hyperbaric Oxygenation , Radiation-Sensitizing Agents , Humans , Female , Copper , Oxygen , Breast Neoplasms/therapy , Glucose Oxidase/pharmacology , Glucose/metabolism , Tumor MicroenvironmentABSTRACT
Rationale: Chemodynamic therapy (CDT) is an emerging tumor-specific therapeutic strategy. However, the anticancer activity of CDT is impeded by the insufficient Fenton catalytic efficiency and the high concentration of glutathione (GSH) in the tumor cells. Also, it is challenging to eliminate tumors with CDT alone. Thus, simple strategies aimed at constructing well-designed nanomedicines that can improve therapeutic efficiency of CDT and simultaneously incorporate extra therapeutic modes as helper are meaningful and highly required. Method: Tailored to specific features of tumor microenvironment (TME), in this study, we developed a biosafe, stable and TME-activated theranostic nanoplatform (P(HSD-Cu-DA)) for photoacoustic imaging (PAI) and self-amplified cooperative therapy. This intelligent nanoplatform was fabricated following a simple one-pot coordination and polymerization strategy by using dopamine and Cu2+ as precursors and redox-responsive hydroxyethyl starch prodrugs (HES-SS-DOX) as stabilizer. Results: Interestingly, the pre-doped Cu2+ in polydopamine (PDA) framework can endow P(HSD-Cu-DA) NPs with tumor-specific CDT ability and remarkably enhance NIR absorption of PDA. PAI and biodistribution tests proved such nanoplatform can effectively accumulate in tumor tissues. Following enrichment, massive amounts of toxic hydroxyl radicals (·OH, for CDT) and free DOX (for chemotherapy) were generated by the stimulation of TME, which was further boosted by local hyperthermia. Concomitantly, in the process of activating these therapeutic functions, GSH depletion triggered by disulfide bond (-SS-) breakage and Cu2+ reduction within tumor cells occurred, further amplifying intratumoral oxidative stress. Importantly, the framework structure dominated by bioinspired polydopamine and clinical-used HES guaranteed the long-term biosafety of in vivo treatment. As a result, the mutual promotion among different components yields a potent tumor suppression outcome and minimized systemic toxicity, with one dosage of drug administration and laser irradiation, respectively. Conclusion: This work provides novel insights into designing efficient and tumor-specific activatable nanotherapeutics with significant clinical translational potential for cancer therapy.
Subject(s)
Antineoplastic Agents/pharmacology , Hydroxyethyl Starch Derivatives/pharmacology , Indoles/pharmacology , Nanoparticles/therapeutic use , Polymers/pharmacology , Prodrugs/pharmacology , Theranostic Nanomedicine , Animals , Antineoplastic Agents/pharmacokinetics , Cell Line, Tumor , Copper/metabolism , Drug Screening Assays, Antitumor , Female , Humans , Indoles/pharmacokinetics , Mice , Mice, Inbred BALB C , Photoacoustic Techniques , Polymers/pharmacokinetics , Prodrugs/pharmacokineticsABSTRACT
Solar-driven interfacial evaporation is an ideal technology for seawater desalination, and the corresponding system is mainly composed of a solar evaporator and a condensing collector. The traditional scheme focuses on the evaporation efficiency of the evaporator. Still, it ignores the influence of condensing collection scheme on the overall efficiency, which is one of the obstacles to the practical use of solar seawater desalination. Here, we reported a new solar-driven interfacial evaporation seawater desalination system by studying the influence of the condensation architecture, i.e., vapor flow by a fan and an air pump, sidewall material, transparent cover shape and material, evaporation level, and transparent cover heating, on the apparent collection efficiency of the system. The apparent collection efficiency was up to over 90% after optimization. This study is expected to promote the practical application of solar evaporation desalination technology.
ABSTRACT
Chemotherapy is a conventional cancer treatment in clinical settings. Although numerous nano drug delivery systems have been developed, the chemotherapeutic effect is greatly limited by abnormal tumor mechanics in solid tumors. Tumor stiffening and accumulated solid stress compress blood vessels and inhibit drug delivery to tumor cells, becoming critical challenges for chemotherapy. By loading doxorubicin (DOX), tissue plasminogen activator (tPA), and fibrin targeting peptide CREKA (Cys-Arg-Glu-Lys-Ala) within pH responsive amphiphilic block polymers, pyridyldithio-hydroxyethyl starch-Schiff base-polylactic acid (PA-HES-pH-PLA), we report a smart nanomedicine, DOX@CREKA/tPA-HES-pH-PLA (DOX@CREKA/tPA-HP), which exhibits a potent antitumor efficacy. In triple-negative breast cancer (TNBC) 4T1 tumors, DOX@CREKA/tPA-HP precisely targeted and effectively decomposed fibrin matrix. By measuring Young's Modulus of tumor slices and quantifying tumor openings, we demonstrated that DOX@CREKA/tPA-HP remarkably reduced tumor stiffness and solid stress. Consequently, the alleviated tumor mechanics decompressed tumor blood vessels, promoted drug delivery, and led to amplified antitumor effect. Our work reveals that decomposing fibrin is a significant means for modulating tumor mechanics, and DOX@CREKA/tPA-HP is a promising smart nanomedicine for treating TNBC.
Subject(s)
Nanomedicine , Triple Negative Breast Neoplasms , Humans , Tissue Plasminogen Activator , Fibrin , Schiff Bases , Doxorubicin/pharmacology , Polyesters , Polymers , StarchABSTRACT
The application of photodynamic therapy (PDT) is limited by tumor hypoxia. To overcome hypoxia, catalase-like nanozymes are often used to catalyze endogenous H2O2 enriched in tumor tissues to O2. Nonetheless, the catalase activity may not be optimal at body temperature and the O2 supply may not meet the rapid O2 consumption of PDT. Herein, we provide a two-pronged strategy to alleviate tumor hypoxia based on hollow mesoporous Prussian blue nanoparticles (HMPB NPs). HMPB NPs can efficiently load the photosensitizer chlorin e6 (Ce6) and exhibit photothermal capability and temperature-dependent catalase activity. Under 808 nm laser irradiation, the photothermal effect of HMPB NPs elevated the catalase activity of HMPB NPs for O2 production. Furthermore, mild hyperthermia reduced cancer associated fibroblasts (CAFs) and induced extracellular matrix (ECM) degradation. The reduction of CAFs and the ECM decreased the solid stress of tumor tissues and normalized the tumor vasculature, which was beneficial for the external supplementation of O2 to tumors. Thereafter, under 606 nm laser irradiation, Ce6-mediated PDT generated excessive reactive oxygen species (ROS) that induced tumor cell apoptosis and achieved a high tumor inhibition rate of 92.2% in 4T1 breast tumors. Our work indicated that the alleviation of tumor hypoxia from both internal and external pathways significantly enhanced Ce6-mediated PDT against breast cancers.
Subject(s)
Hyperthermia, Induced , Nanoparticles , Photochemotherapy , Porphyrins , Humans , Catalase , Hydrogen Peroxide , Tumor Hypoxia , Cell Line, Tumor , Photosensitizing Agents/pharmacology , Photosensitizing Agents/therapeutic use , Porphyrins/pharmacologyABSTRACT
Photothermal therapy is promising for augmenting cancer therapeutic outcomes in cancer treatment. Diketopyrrolopyrrole (DPP)-conjugated polymer nanoparticles are in focus due to their dual photoacoustic imaging and photothermal therapy functions. Herein, the design and synthesis of three near-infrared absorbing conjugated polymers, named DPP-SO, DPP-SS and DPP-SSe, with heteroatom substitution of the thiophene moiety were developed for a photoacoustic imaging guided photothermal therapy. It was demonstrated that systematically changing only the heteroatom from O to S or Se could apparently adjust the absorption spectrum and energy gap of DPP-conjugated polymers to obtain the most suitable photothermal transduction agents (PTAs) for use in biomedicine. The characterization of photophysical properties proved that the photothermal conversion efficiency and absorption coefficient of DPP-SO nanoparticles under 808 nm irradiation was up to 79.3% and 66.51 L g-1 cm-1, respectively, which were much higher than those of DPP-SS and DPP-SSe nanoparticles. Remarkably, the IC50 value of DPP-SO for killing A549 cells was half that of DPP-SS and DPP-SSe nanoparticles. Further in vivo works demonstrated efficient photothermal therapeutic effects of DPP-SO nanoparticles with the guidance of photoacoustic imaging. Thus, this is an efficient method to regulate the photothermal performance of DPP-conjugated polymers by changing the heteroatom in the molecular skeleton.
Subject(s)
Antineoplastic Agents/pharmacology , Chalcogens/pharmacology , Ketones/pharmacology , Nanoparticles/chemistry , Photoacoustic Techniques , Photothermal Therapy , Polymers/pharmacology , Pyrroles/pharmacology , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Survival/drug effects , Chalcogens/chemistry , Drug Screening Assays, Antitumor , Humans , Ketones/chemistry , Mice , Mice, Nude , Neoplasms, Experimental/diagnostic imaging , Neoplasms, Experimental/drug therapy , Polymers/chemistry , Pyrroles/chemistryABSTRACT
BACKGROUND/OBJECTIVE: The relationship between postprandial glycaemic responses and cognitive performance, mood and satiety are inconsistent. The objective of this study is to compare the effects of different glycaemic responses, induced by beverages with different glycaemic index (GI) (sucrose and isomaltulose), and a non-glycaemic control (sucralose), on cognition, mood and satiety. SUBJECTS/METHODS: In this double-blinded, randomised crossover trial, healthy adults (n = 55) received sucrose (GI 65), isomaltulose (GI 32) and sucralose (non-caloric negative control) drinks on separate occasions. The Complex Figure test, the Word Recall test, Trail Making Test Part B and the Stroop test were administered 60 min after beverages ingestion. Mood and satiety were tested along with cognitive performance. RESULTS: Comparing between isomaltulose and sucrose, there were no significant differences in the mean (95% CI) for the following: Complex Figure: immediate recall -0.6 (-1.7, 0.5), delayed recall -0.8 (-1.9, 0.3); Word recall: immediate recall 0.2 (-0.7, 1.1), delayed recall 0.5 (-0.4, 1.4); Trail Making: completing time -2.4 (-7.5, 2.7) s; Stroop: time used for correct congruent responses -9 (-31, 14) ms and correct incongruent responses -18 (-42, 6) ms. No differences among beverages were found in the mood and satiety scores with exception that participants felt more energetic 60 min after isomaltulose ingestion (p = 0.028 for difference with sucrose) and hungrier 30 min after isomaltulose ingestion (p = 0.036 for difference with sucrose; p = 0.022 for difference with sucralose). CONCLUSION: Under these study conditions there is no convincing evidence for an effect of glycaemic response on cognitive performance, mood or satiety.
Subject(s)
Blood Glucose , Postprandial Period , Adult , Beverages , Cognition , Cross-Over Studies , Eating , HumansABSTRACT
Aberrant mechanical properties and immunosuppression are the two key factors that limit the antitumor efficacy of T cell immune checkpoint blockade inhibitors, e.g., programmed cell death-1 antibody (PD-1 Ab), against solid tumors in the clinic. This study leverages hyperbaric oxygen (HBO) for the first time to address these two issues and reports the PD-1-Ab-mediated immune responses against various stroma-rich solid malignancies. The results demonstrate that HBO promoted PD-1 Ab delivery and T cells infiltration into tumor parenchyma by depleting the extracellular matrix's main components, such as collagen and fibronectin. Furthermore, HBO disrupts hypoxia-mediated immunosuppression and helps PD-1 Ab trigger robust cytotoxic T lymphocytes and long-lasting immunological memory to inhibit tumor relapses. Such enhanced immune responses are effective in solid tumors from rodents and the cancer cells from hepatocellular carcinoma patients. The results illustrate that HBO bolsters antitumor efficacy of PD-1 Ab, and the HBO-PD-1 Ab combination is a promising stroma-rich solid tumors' treatment in the clinic.
Subject(s)
Hyperbaric Oxygenation/methods , Immunity/immunology , Liver Neoplasms/immunology , Liver Neoplasms/therapy , Programmed Cell Death 1 Receptor/immunology , T-Lymphocytes/immunology , Animals , Cell Line, Tumor , Disease Models, Animal , Mice , Mice, Inbred BALB CABSTRACT
Thionated perylenediimides (PDIs) can potentially generate thermal and reactive oxygen species and thus can be used as theranostic agents for photothermal/photodynamic therapy. Herein, thionated cis-/trans-isomer PDI-CS and PDI-TS were designed and prepared to investigate thionation engineering on therapeutic performance. The results revealed that the photodynamic performance is less associated with the positon of sulfur atoms. By contrast, trans-isomer PDI-TS showed a photothermal conversion efficiency of up to 58.4%, which was 40% higher than that of PDI-CS (â¼41.6%). An in vitro half-maximal inhibitory concentration of â¼7.78 µg mL-1 was achieved for PDI-TS, which was 1.7-fold smaller than that of PDI-CS, strongly reasserting the regioisomer-modulated phototheranostic performance. Notably, the strong π-π and CS interactions in PDI-TS nanoagents are essential factors attributed to their excellent photothermal performance, indicating that the optimization of non-bonding interactions is an ingenious way to improve phototheranostic performance. This work provides a facile means of creating thio-perylenediimides that possess excellent antitumor properties and a novel proof of concept to improve therapeutic performance through the optimization of non-bonding interactions.
Subject(s)
Antineoplastic Agents/pharmacology , Imides/pharmacology , Nanoparticles/chemistry , Perylene/analogs & derivatives , Photochemotherapy , Photothermal Therapy , Sulfhydryl Compounds/pharmacology , Theranostic Nanomedicine , A549 Cells , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Cell Proliferation/drug effects , Cell Survival/drug effects , Drug Screening Assays, Antitumor , Humans , Imides/chemical synthesis , Imides/chemistry , Mice , Mice, Inbred BALB C , Mice, Nude , Molecular Structure , Neoplasms, Experimental/drug therapy , Neoplasms, Experimental/metabolism , Neoplasms, Experimental/pathology , Optical Imaging , Particle Size , Perylene/chemical synthesis , Perylene/chemistry , Perylene/pharmacology , Reactive Oxygen Species/metabolism , Stereoisomerism , Sulfhydryl Compounds/chemical synthesis , Sulfhydryl Compounds/chemistry , Surface Properties , Tumor Cells, CulturedABSTRACT
Extensive recent progress has been made on the design and applications of organic photothermal agents for biomedical applications because of their excellent biocompatibility comparing with inorganic materials. One major hurdle for the further development and applications of organic photothermal agents is the rarity of high-performance materials in the second near-infrared (NIR-II) window, which allows deep tissue penetration and causes minimized side effects. Up till now, there have been few reported NIR-II-active photothermal agents and their photothermal conversion efficiencies are relatively low. Herein, optical absorption of π-conjugated small molecules from the first NIR window to the NIR-II window is precisely regulated by molecular surgery of substituting an individual atom. With this technique, the first demonstration of a conjugated oligomer (IR-SS) with an absorption peak beyond 1000 nm is presented, and its nanoparticle achieves a record-high photothermal conversion efficiency of 77% under 1064 nm excitation. The nanoparticles show a good photoacoustic response, photothermal therapeutic efficacy, and biocompatibility in vitro and in vivo. This work develops a strategy to boost the light-harvesting efficiency in the NIR-II window for cancer theranostics, offering an important step forward in advancing the design and application of NIR-II photothermal agents.
Subject(s)
Diagnosis , Drug Design , Infrared Rays/therapeutic use , Phototherapy/methods , Small Molecule Libraries/therapeutic use , Temperature , Optical Phenomena , Polymerization , Small Molecule Libraries/chemistryABSTRACT
We present the modulation of van der Waals interactions to further adjust supramolecular chirality by incorporation of S and Se into the bay region. These chalcogen atom-mediated supramolecular interactions were transferred to nanostructures and affected the gas responses of devices. This study will facilitate the development of smart materials with modulated handedness in materials science.
ABSTRACT
Development of high-performance photoactive agents with tumor-specific capability for effective nanotherapeutics has received much attention in the past decades. Herein, we report a nanotherapeutic based on bis-diketopyrrolopyrrole (BDPP) conjugated polymer nanoparticles (PBDPP NPs) with remarkable near-infrared (NIR) absorption at 808â¯nm and high photothermal energy conversion efficiency up to 60%. In particular, precise glioblastoma-specific capability and killing ability for glioblastoma cells were effectively achieved in vitro by treating with only PBDPP NPs to induce cell apoptosis or by interaction with PBDPP NPs under NIR laser irradiation to trigger cell necrosis. Impressively, a half-maximal inhibitory concentration as low as of â¼0.15⯵gâ¯mL-1 was achieved, and the magnitude is 5 to 4.4â¯×â¯104-fold lower than those of reported agents. In vivo experiment with mice further shows that the PBDPP NPs show good efficacy of photothermal therapy and complete tumor elimination using a record-low dosage of 0.35â¯mgâ¯mL-1 under 808â¯nm irradiation of low power (0.5â¯Wâ¯cm-2). This study thus demonstrates a promising strategy of low-dose, high-efficacy polymer-based nanoagonist for specific phototherapy of glioblastoma.