Assessing the Charge Carrier Dynamics at Hybrid Interfaces of Organic Photoanodes for Solar Fuels.

Organic semiconductors (OSCs) have emerged as promising active layers for photoanodes to drive photoelectrochemical (PEC) oxidation reactions. Interfacing an OSC with an inorganic electron transport layer (ETL) is key to enabling both high performance and stability. While spectroelectrochemical techniques have been established for the evaluation of inorganic interfaces, allowing rational optimization toward higher performances, a similar level of understanding for hybrid organic-inorganic interfaces remains elusive. To close this knowledge gap, we first perform a systematic parameter study (ETL thickness, potential dependency, and light intensity) on a state-of-the-art organic photoanode to establish factors determining the photoelectrochemical impedance spectroscopy (PEIS) response. Coupled with in situ UV-Vis characterizations, key charge transfer processes are clearly assigned to the PEIS features.

Nano-Delivery of Immunogenic Cell Death Inducers and Immune Checkpoint Blockade Agents: Single-Nanostructure Strategies for Enhancing Immunotherapy.

Cancer immunotherapy has revolutionized oncology by harnessing the patient's immune system to target and eliminate cancer cells. However, immune checkpoint blockades (ICBs) face limitations such as low response rates, particularly in immunologically 'cold' tumors. Enhancing tumor immunogenicity through immunogenic cell death (ICD) inducers and advanced drug delivery systems represents a promising solution. This review discusses the development and application of various nanocarriers, including polymeric nanoparticles, liposomes, peptide-based nanoparticles, and inorganic nanoparticles, designed to deliver ICD inducers and ICBs effectively. These nanocarriers improve therapeutic outcomes by converting cold tumors into hot tumors, thus enhancing immune responses and reducing systemic toxicity. By focusing on single-nanoparticle systems that co-deliver both ICD inducers and ICBs, this review highlights their potential in achieving higher drug concentrations at tumor sites, improving pharmacokinetics and pharmacodynamics, and facilitating clinical translation. Future research should aim to optimize these nanocarrier systems for better in vivo performance and clinical applications, ultimately advancing cancer immunotherapy.

Iodinated Cyanoacrylate-based Novel Liquid Embolic Compositions with Inherent Radiopacity for Endovascular Embolization.

Endovascular embolization is a promising therapeutic approach broadening its application area due to its minimal invasiveness and short operation time, wherein lesional blood vessels are occluded with liquid embolic agents under X-ray imaging guidance. Histoacryl and its composition with Lipiodol are one of the most widely used liquid embolic agents, however, Histoacryl has critical limitations such as lack of innate X-ray visibility and strong adhesion to microcatheter. In this study, three different iodinated cyanoacrylates are newly synthesized as alternatives to Histoacryl and employed to develop liquid embolic compositions. Among them, 4-iodobutyl 2-cyanoacrylate (IBCA) was most preferable with high iodine content (730 mgI/mL) and fast polymerization. The IBCA-based embolic compositions containing ethyl oleate and acetic acid showed moderate viscosity and reduced catheter adhesiveness (∼ 0.80 N), and their polymerization time was freely controllable from 2 to 15 s. In the embolization test with rabbit models, the renal artery was successfully occluded by IBCA-based embolic compositions without vascular recanalization or non-target embolization for 4 w. Their embolic effect was further evaluated using swine models, demonstrating the practical applicability in the clinic. In conclusion, IBCA and its compositions are determined to have great potential as novel liquid embolic agents. This article is protected by copyright. All rights reserved.

Hydrophilic Photocrosslinkers as a Universal Solution to Endow Water Affinity to a Polymer Photocatalyst for an Enhanced Hydrogen Evolution Rate.

A universal approach for enhancing water affinity in polymer photocatalysts by covalently attaching hydrophilic photocrosslinkers to polymer chains is presented. A series of bisdiazirine photocrosslinkers, each comprising bisdiazirine photophores linked by various aliphatic (CL-R) or ethylene glycol-based bridge chains (CL-TEG), is designed to prevent crosslinked polymer photocatalysts from degradation through a safe and efficient photocrosslinking reaction at a wavelength of 365 nm. When employing the hydrophilic CL-TEG as a photocrosslinker with polymer photocatalysts (F8BT), the hydrogen evolution reaction (HER) rate is considerably enhanced by 2.5-fold compared to that obtained using non-crosslinked F8BT photocatalysts, whereas CL-R-based photocatalysts yield HER rates comparable to those of non-crosslinked counterparts. Photophysical analyses including time-resolved photoluminescence and transient absorption measurements reveal that adding CL-TEG accelerates exciton separation, forming long-lived charge carriers. Additionally, the in-depth study using molecular dynamics simulations elucidates the dual role of CL-TEG: it enhances water penetration into the polymer matrix and stabilizes charge carriers after exciton generation against undesirable recombination. Therefore, the strategy highlights endowing a high-permittivity environment within polymer photocatalyst in a controlled manner is crucial for enhancing photocatalytic redox reactivity. Furthermore, this study shows that this hydrophilic crosslinker approach has a broad applicability in general polymer semiconductors and their nanoparticulate photocatalysts.

Multi-functional nanomedicines for combinational cancer immunotherapy that transform cold tumors to hot tumors.

INTRODUCTION: Currently, cancer immunotherapy is widely used as a groundbreaking method that can completely cure advanced cancers. However, this new immunotherapy has the challenge of low patient response, which is often due to many patients' tumors having an immunosuppressive environment, known as cold tumors. AREAS COVERED: This review aims to introduce various nanomedicine-derived combinational cancer immunotherapy that can transform cold tumor into hot tumors. Initially, we discuss new technologies for combinational immunotherapy based on multifunctional nanomedicines that can deliver combinational immunogenic cell death (ICD) inducers, immune checkpoint blockades (ICBs) and immune modulators (IMs) to targeted tumor tissues at the same time. Ultimately, we highlight how multifunctional nanomedicines for combinational cancer immunotherapy can be used to transform cold tumor into hot tumors against advanced cancers. EXPERT OPINION: Nanomedicine-derived combinational cancer immunotherapy for delivering multiple ICD inducers, ICBs, and IMs at the same time is recognized as a new potential technology that can activate tumor immunity and simultaneously increase the therapeutic efficacy of immune cells that can transform effectively the cold tumors into hot tumors. Finally, nanomedicine-derived combinational cancer immunotherapy can solve the serious problems of low therapeutic efficacy that occurs when treating single drug or simple combinational drugs in cancer immunotherapy.

Cancer cell-specific and pro-apoptotic SMAC peptide-doxorubicin conjugated prodrug encapsulated aposomes for synergistic cancer immunotherapy.

BACKGROUND: Immunogenic cell death (ICD) is a crucial approach to turn immunosuppressive tumor microenvironment (ITM) into immune-responsive milieu and improve the response rate of immune checkpoint blockade (ICB) therapy. However, cancer cells show resistance to ICD-inducing chemotherapeutic drugs, and non-specific toxicity of those drugs against immune cells reduce the immunotherapy efficiency. METHODS: Herein, we propose cancer cell-specific and pro-apoptotic liposomes (Aposomes) encapsulating second mitochondria-derived activator of caspases mimetic peptide (SMAC-P)-doxorubicin (DOX) conjugated prodrug to potentiate combinational ICB therapy with ICD. The SMAC-P (AVPIAQ) with cathepsin B-cleavable peptide (FRRG) was directly conjugated to DOX, and the resulting SMAC-P-FRRG-DOX prodrug was encapsulated into PEGylated liposomes. RESULTS: The SMAC-P-FRRG-DOX encapsulated PEGylated liposomes (Aposomes) form a stable nanostructure with an average diameter of 109.1 ± 5.14 nm and promote the apoptotic cell death mainly in cathepsin B-overexpressed cancer cells. Therefore, Aposomes induce a potent ICD in targeted cancer cells in synergy of SMAC-P with DOX in cultured cells. In colon tumor models, Aposomes efficiently accumulate in targeted tumor tissues via enhanced permeability and retention (EPR) effect and release the encapsulated prodrug of SMAC-P-FRRG-DOX, which is subsequently cleaved to SMAC-P and DOX in cancer cells. Importantly, the synergistic activity of inhibitors of apoptosis proteins (IAPs)-inhibitory SMAC-P sensitizing the effects of DOX induces a potent ICD in the cancer cells to promote dendritic cell (DC) maturation and stimulate T cell proliferation and activation, turning ITM into immune-responsive milieu. CONCLUSIONS: Eventually, the combination of Aposomes with anti-PD-L1 antibody results in a high rate of complete tumor regression (CR: 80%) and also prevent the tumor recurrence by immunological memory established during treatments.

Fluorescence-Based Mono- and Multimodal Imaging for In Vivo Tracking of Mesenchymal Stem Cells.

The advancement of stem cell therapy has offered transformative therapeutic outcomes for a wide array of diseases over the past decades. Consequently, stem cell tracking has become significant in revealing the mechanisms of action and ensuring safe and effective treatments. Fluorescence stands out as a promising choice for stem cell tracking due to its myriad advantages, including high resolution, real-time monitoring, and multi-fluorescence detection. Furthermore, combining fluorescence with other tracking modalities-such as bioluminescence imaging (BLI), positron emission tomography (PET), photoacoustic (PA), computed tomography (CT), and magnetic resonance (MR)-can address the limitations of single fluorescence detection. This review initially introduces stem cell tracking using fluorescence imaging, detailing various labeling strategies such as green fluorescence protein (GFP) tagging, fluorescence dye labeling, and nanoparticle uptake. Subsequently, we present several combinations of strategies for efficient and precise detection.

Micro-syringe chip-guided intratumoral administration of lipid nanoparticles for targeted anticancer therapy.

BACKGROUND: Nano-sized drug delivery system has been widely studied as a potential technique to promote tumor-specific delivery of anticancer drugs due to its passive targeting property, but resulting in very restricted improvements in its systemic administration so far. There is a requirement for a different approach that dramatically increases the targeting efficiency of therapeutic agents at targeted tumor tissues. METHODS: To improve the tumor-specific accumulation of anticancer drugs and minimize their undesirable toxicity to normal tissues, a tumor-implantable micro-syringe chip (MSC) with a drug reservoir is fabricated. As a clinically established delivery system, six liposome nanoparticles (LNPs) with different compositions and surface chemistry are prepared and their physicochemical properties and cellular uptake are examined in vitro. Subsequently, MSC-guided intratumoral administration is studied to identify the most appropriate for the higher tumor targeting efficacy with a uniform intratumoral distribution. For efficient cancer treatment, pro-apoptotic anticancer prodrugs (SMAC-P-FRRG-DOX) are encapsulated to the optimal LNPs (SMAC-P-FRRG-DOX encapsulating LNPs; ApoLNPs), then the ApoLNPs are loaded into the 1 µL-volume drug reservoir of MSC to be delivered intratumorally for 9 h. The tumor accumulation and therapeutic effect of ApoLNPs administered via MSC guidance are evaluated and compared to those of intravenous and intratumoral administration of ApoLNP in 4T1 tumor-bearing mice. RESULTS: MSC is precisely fabricated to have a 0.5 × 4.5 mm needle and 1 µL-volume drug reservoir to achieve the uniform intratumoral distribution of LNPs in targeted tumor tissues. Six liposome nanoparticles with different compositions of 1-palmitoyl-2-oleoyl-glycero-3-phosphocholine (PC), 1,2-dioleoyl-sn-glycero-3-phospho-L-serine (PS), 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP), and 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy (polyethylene glycol)2000] (PEG2000-DSPE) are prepared with average sizes of 100-120 nm and loaded into the 1 µL-volume drug reservoir in MSC. Importantly negatively charged 10 mol% of PS-containing LNPs are very slowly infused into the tumor tissue through the micro-syringe of the MSC over 6 h. The intratumoral targeting efficiency of MSC guidance is 93.5%, effectively assisting the homogeneous diffusion of LNPs throughout the tumor tissue at 3.8- and 2.7-fold higher concentrations compared to the intravenous and intratumoral administrations of LNPs, respectively. Among the six LNP candidates 10 mol% of PS-containing LNPs are finally selected for preparing pro-apoptotic SMAC-P-FRRG-DOX anticancer prodrug-encapsulated LNPs (ApoLNPs) due to their moderate endocytosis rate high tumor accumulation and homogenous intratumoral distribution. The ApoLNPs show a high therapeutic effect specifically to cathepsin B-overexpressing cancer cells with 6.6 µM of IC50 value while its IC50 against normal cells is 230.7 µM. The MSC-guided administration of ApoLNPs efficiently inhibits tumor growth wherein the size of the tumor is 4.7- and 2.2-fold smaller than those treated with saline and intratumoral ApoLNP without MSC, respectively. Moreover, the ApoLNPs remarkably reduce the inhibitor of apoptosis proteins (IAPs) level in tumor tissues confirming their efficacy even in cancers with high drug resistance. CONCLUSION: The MSC-guided administration of LNPs greatly enhances the therapeutic efficiency of anticancer drugs via the slow diffusion mechanism through micro-syringe to tumor tissues for 6 h, whereas they bypass most hurdles of systemic delivery including hepatic metabolism, rapid renal clearance, and interaction with blood components or other normal tissues, resulting in the minimum toxicity to normal tissues. The negatively charged ApoLNPs with cancer cell-specific pro-apoptotic prodrug (SMAC-P-FRRG-DOX) show the highest tumor-targeting efficacy when they are treated with the MSC guidance, compared to their intravenous or intratumoral administration in 4T1 tumor-bearing mice. The MSC-guided administration of anticancer drug-encapsulated LNPs is expected to be a potent platform system that facilitates overcoming the limitations of systemic drug administration with low delivery efficiency and serious side effects.

All-in-one glycol chitosan nanoparticles for co-delivery of doxorubicin and anti-PD-L1 peptide in cancer immunotherapy.

Synergistic immunotherapy of immune checkpoint blockade (ICB) and immunogenic cell death (ICD) has shown remarkable therapeutic efficacy in various cancers. However, patients show low response rates and undesirable outcomes to these combination therapies owing to the recycling mechanism of programmed death-ligand 1 (PD-L1) and the systemic toxicity of ICD-inducing chemotherapeutic drugs. Herein, we propose all-in-one glycol chitosan nanoparticles (CNPs) that can deliver anti-PD-L1 peptide (PP) and doxorubicin (DOX) to targeted tumor tissues for a safe and more effective synergistic immunotherapy. The PP-CNPs, which are prepared by conjugating ᴅ-form PP (NYSKPTDRQYHF) to CNPs, form stable nanoparticles that promote multivalent binding with PD-L1 proteins on the targeted tumor cell surface, resulting in effective lysosomal PD-L1 degradation in contrast with anti-PD-L1 antibody, which induces recycling of endocytosed PD-L1. Consequently, PP-CNPs prevent subcellular PD-L1 recycling and eventually destruct immune escape mechanism in CT26 colon tumor-bearing mice. Moreover, the ICD inducer, DOX is loaded into PP-CNPs (DOX-PP-CNPs) for synergistic ICD and ICB therapy, inducing a large number of damage-associated molecular patterns (DAMPs) in targeted tumor tissues with minimal toxicity in normal tissues. When the DOX-PP-CNPs are intravenously injected into CT26 colon tumor-bearing mice, PP and DOX are efficiently delivered to the tumor tissues via nanoparticle-derived passive and active targeting, which eventually induce both lysosomal PD-L1 degradation and substantial ICD, resulting in a high rate of complete tumor regression (CR: 60%) by a strong antitumor immune response. Collectively, this study demonstrates the superior efficacy of synergistic immunotherapy using all-in-one nanoparticles to deliver PP and DOX to targeted tumor tissues.

Perspectives for Improving the Tumor Targeting of Nanomedicine via the EPR Effect in Clinical Tumors.

Over the past few decades, the enhanced permeability and retention (EPR) effect of nanomedicine has been a crucial phenomenon in targeted cancer therapy. Specifically, understanding the EPR effect has been a significant aspect of delivering anticancer agents efficiently to targeted tumors. Although the therapeutic effect has been demonstrated in experimental models using mouse xenografts, the clinical translation of the EPR effect of nanomedicine faces several challenges due to dense extracellular matrix (ECM), high interstitial fluid pressure (IFP) levels, and other factors that arise from tumor heterogeneity and complexity. Therefore, understanding the mechanism of the EPR effect of nanomedicine in clinics is essential to overcome the hurdles of the clinical translation of nanomedicine. This paper introduces the basic mechanism of the EPR effect of nanomedicine, the recently discussed challenges of the EPR effect of nanomedicine, and various strategies of recent nanomedicine to overcome the limitations expected from the patients' tumor microenvironments.

In situ albumin-binding and esterase-specifically cleaved BRD4-degrading PROTAC for targeted cancer therapy.

Proteolysis-targeting chimeras (PROTACs) have recently been of great interest in cancer therapy. However, the bioavailability of PROTACs is considerably restricted due to their high hydrophobicity, poor cell permeability, and thereby low tumor targeting ability. Herein, esterase-cleavable maleimide linker (ECMal)-conjugated bromodomain 4 (BRD4)-degrading PROTAC (ECMal-PROTAC) is newly synthesized to exploit plasma albumin as an 'innate drug carrier' that can be accumulated in targeted tumor tissues. The BRD4-degrading ECMal-PROTAC is spontaneously bound to albumins via the thiol-maleimide click chemistry and its esterase-specific cleavage of ECMal-PROTAC is characterized in physiological conditions. The albumin-bound ECMal-PROTACs (Alb-ECMal-PROTACs) have an average size of 6.99 ± 1.38 nm, which is similar to that of free albumins without denaturation or aggregation. When Alb-ECMal-PROTACs are treated to 4T1 tumor cells, they are actively endocytosed and reach their highest intracellular level within 12 h. Furthermore, the maleimide linkers of Alb-ECMal-PROTACs are cleaved by the esterase to release free BRD-4 degrading PROTACs and the cell-internalized PROTACs successfully catalyze the selective degradation of BRD4 proteins, resulting in BRD4 deficiency-related apoptosis. When ECMal-PROTACs are intravenously injected into tumor-bearing mice, they exhibit a 16.3-fold higher tumor accumulation than free BRD4-PROTAC, due to the shuttling effect of albumin for tumor targeting. Finally, ECMal-PROTACs show 5.3-fold enhanced antitumor efficacy compared to free BRD4-PROTAC, without provoking any severe systemic toxicity. The expression of Bcl-2 and c-Myc, the downstream oncogenic proteins of BRD4, are also effectively suppressed. In summary, the in situ albumin binding of ECMal-PROTAC is proven as a promising strategy that effectively modulates its pharmacokinetics and therapeutic performance with high applicability to other types of PROTACs.

Tumor-Specific Monomethyl Auristatin E (MMAE) Prodrug Nanoparticles for Safe and Effective Chemotherapy.

A prodrug is bioreversible medication that is specifically converted to the active drugs by enzymes overexpressed in the tumor microenvironment, which can considerably reduce the chemotherapy-induced side effects. However, prodrug strategies usually have low antitumor efficacy compared to free drugs by delayed drug release. This is because they need time to be activated by enzymatic cleavage and they also cannot be fully recovered to the active drugs. Therefore, highly potent anticancer drug should be considered to expect a sufficient antitumor efficacy. Herein, we propose tumor-specific monomethyl auristatin E (MMAE) prodrug nanoparticles for safe and effective chemotherapy. The cathepsin B-specific cleavable FRRG peptide and MMAE are chemically conjugated via one-step simple synthetic chemistry. The resulting FRRG-MMAE molecules form stable nanoparticles without any additional carrier materials by hydrophobic interaction-derived aggregations. The FRRG-MMAE nanoparticles efficiently accumulate within the tumor tissues owing to the enhanced permeability and retention (EPR) effect and inhibit the tubulin polymerization by releasing free MMAE in the cathepsin B-overexpressed tumor cells. In contrast, FRRG-MMAE nanoparticles maintain a non-toxic inactive state in the normal tissues owing to innately low cathepsin B expression, thereby reducing MMAE-related severe toxicity. Collectively, this study provides a promising approach for safe and effective chemotherapy via MMAE-based prodrug nanoparticles, which may open new avenues for advanced drug design for translational nanomedicine.

Liposome-mediated PD-L1 multivalent binding promotes the lysosomal degradation of PD-L1 for T cell-mediated antitumor immunity.

Immune checkpoint blockade (ICB) has shown remarkable therapeutic efficacy in a variety of cancers. However, patients exhibit unexpectedly low response rates to ICB therapy owing to the unwanted recycling and cellular abundance of PD-L1. Herein, rational design of PD-L1 multivalent binding liposome is investigated through PEGylated liposomes incorporating different ratios of PD-L1 binding peptide. Liposomes incorporating 10 mol% PD-L1 binding peptides (10-PD-L1-Lipo) promote the multivalent binding with PD-L1 on tumor cell surface, which is endocytosed for its trafficking toward the lysosomes instead of the recycling endosomes. Thereby, 10-PD-L1-Lipo leads to a significant PD-L1 degradation that prevents its recycling and cellular abundance compared to anti-PD-L1 antibody, disrupting immune escape mechanism of tumor cells and enhancing T cell-mediated antitumor immunity. Moreover, a clinically applicable doxorubicin (DOX) liposomal formulation is established via drug encapsulation into 10-PD-L1-Lipo. The resulting DOX-PD-L1-Lipo primes tumors via immunogenic chemotherapy by preferential DOX accumulation by the EPR effect and overcomes PD-L1 abundance induced following chemotherapy through multivalent binding-mediated PD-L1 degradation. As a result, the synergistic immunogenic chemotherapy and multivalent binding-mediated PD-L1 degradation by DOX-PD-L1-Lipo show significantly enhanced antitumor efficacy and immune responses in colon tumor models. Collectively, this study suggests the rationally designed PEGylated liposomes to promote PD-L1 multivalent binding providing a new route for safe and more effective ICB therapy.

Emerging Albumin-Binding Anticancer Drugs for Tumor-Targeted Drug Delivery: Current Understandings and Clinical Translation.

Albumin has shown remarkable promise as a natural drug carrier by improving pharmacokinetic (PK) profiles of anticancer drugs for tumor-targeted delivery. The exogenous or endogenous albumin enhances the circulatory half-lives of anticancer drugs and passively target the tumors by the enhanced permeability and retention (EPR) effect. Thus, the albumin-based drug delivery leads to a potent antitumor efficacy in various preclinical models, and several candidates have been evaluated clinically. The most successful example is Abraxane, an exogenous human serum albumin (HSA)-bound paclitaxel formulation approved by the FDA and used to treat locally advanced or metastatic tumors. However, additional clinical translation of exogenous albumin formulations has not been approved to date because of their unexpectedly low delivery efficiency, which can increase the risk of systemic toxicity. To overcome these limitations, several prodrugs binding endogenous albumin covalently have been investigated owing to distinct advantages for a safe and more effective drug delivery. In this review, we give account of the different albumin-based drug delivery systems, from laboratory investigations to clinical applications, and their potential challenges, and the outlook for clinical translation is discussed. In addition, recent advances and progress of albumin-binding drugs to move more closely to the clinical settings are outlined.

Sustained and Long-Term Release of Doxorubicin from PLGA Nanoparticles for Eliciting Anti-Tumor Immune Responses.

Immunogenic cell death (ICD) is a powerful trigger eliciting strong immune responses against tumors. However, traditional chemoimmunotherapy (CIT) does not last long enough to induce sufficient ICD, and also does not guarantee the safety of chemotherapeutics. To overcome the disadvantages of the conventional approach, we used doxorubicin (DOX) as an ICD inducer, and poly(lactic-co-glycolic acid) (PLGA)-based nanomedicine platform for controlled release of DOX. The diameter of 138.7 nm of DOX-loaded PLGA nanoparticles (DP-NPs) were stable for 14 days in phosphate-buffered saline (PBS, pH 7.4) at 37 °C. Furthermore, DOX was continuously released for 14 days, successfully inducing ICD and reducing cell viability in vitro. Directly injected DP-NPs enabled the remaining of DOX in the tumor site for 14 days. In addition, repeated local treatment of DP-NPs actually lasted long enough to maintain the enhanced antitumor immunity, leading to increased tumor growth inhibition with minimal toxicities. Notably, DP-NPs treated tumor tissues showed significantly increased maturated dendritic cells (DCs) and cytotoxic T lymphocytes (CTLs) population, showing enhanced antitumor immune responses. Finally, the therapeutic efficacy of DP-NPs was maximized in combination with an anti-programmed death-ligand 1 (PD-L1) antibody (Ab). Therefore, we expect therapeutic efficacies of cancer CIT can be maximized by the combination of DP-NPs with immune checkpoint blockade (ICB) by achieving proper therapeutic window and continuously inducing ICD, with minimal toxicities.

Anti-PD-L1 peptide-conjugated prodrug nanoparticles for targeted cancer immunotherapy combining PD-L1 blockade with immunogenic cell death.

Rationale: Cancer immunotherapy combining immune checkpoint blockade (ICB) with chemotherapeutic drugs has provided significant clinical advances. However, such combination therapeutic regimen has suffered from severe toxicity of both drugs and low response rate of patients. In this study, we propose anti-PD-L1 peptide-conjugated prodrug nanoparticles (PD-NPs) to overcome these obstacles of current cancer immunotherapy. Methods: The functional peptide, consisted of anti-PD-L1 peptide and cathepsin B-specific cleavable peptide, is conjugated to a doxorubicin (DOX), resulting in prodrug nanoparticles of PD-NPs via intermolecular interactions. The antitumor efficacy and immune responses with minimal side effects by PD-NPs combining PD-L1 blockade and ICD are evaluated in breast tumor models. Results: The PD-NPs are taken up by PD-L1 receptor-mediated endocytosis and then induce ICD in cancer cells by DOX release. Concurrently, PD-L1 blockade by PD-NPs disrupt the immune-suppressing pathway of cancer cells, resulting in proliferation and reinvigoration of T lymphocytes. In tumor models, PD-NPs accumulate within tumor tissues via enhanced permeability and retention (EPR) effect and induce immune-responsive tumors by recruiting a large amount of immune cells. Conclusions: Collectively, targeted tumor delivery of anti-PD-L1 peptide and DOX via PD-NPs efficiently inhibit tumor progression with minimal side effects.

Bulk Heterojunction Organic Semiconductor Photoanodes: Tuning Energy Levels to Optimize Electron Injection.

The use of a bulk heterojunction of organic semiconductors to drive photoelectrochemical water splitting is an emerging trend; however, the optimum energy levels of the donor and acceptor have not been established for photoanode operation with respect to electrolyte pH. Herein, we prepare a set of donor polymers and non-fullerene acceptors with varying energy levels to probe the effect of photogenerated electron injection into a SnO2-based substrate under sacrificial photo-oxidation conditions. Photocurrent density (for sacrificial oxidation) up to 4.1 mA cm-2 was observed at 1.23 V vs reversible hydrogen electrode in optimized photoanodes. Moreover, we establish that a lower-lying donor polymer leads to improved performance due to both improved exciton separation and better charge collection. Similarly, lower-lying acceptors also give photoanodes with higher photocurrent density but with a later photocurrent onset potential and a narrower range of pH for good operation due to the Nernstian behavior of the SnO2, which leads to a smaller driving force for electron injection at high pH.

Visible-Light-Triggered Prodrug Nanoparticles Combine Chemotherapy and Photodynamic Therapy to Potentiate Checkpoint Blockade Cancer Immunotherapy.

Immune checkpoint blockade is a promising approach for cancer immunotherapy, but many patients do not respond due to the immunosuppressive tumor microenvironment (ITM). Herein, we propose visible-light-triggered prodrug nanoparticles (LT-NPs) for reversing ITM into high immunogenic tumors to potentiate checkpoint blockade immunotherapy. The photosensitizer (verteporfin; VPF), cathepin B-specific cleavable peptide (FRRG), and doxorubicin (DOX) conjugates are self-assembled into LT-NPs without any additional carrier material. The LT-NPs are specifically cleaved to VPF and DOX in cathepsin B-overexpressing cancer cells, thereby inducing cancer-specific cytotoxicity and immunogenic cell death (ICD) upon visible light irradiation. In tumor models, LT-NPs highly accumulate within tumors via the enhanced permeability and retention effect, and photochemotherapy of VPF and DOX induces effective ICD and maturation of dendritic cells to stimulate cross-presentation of cancer-antigens to T cells. Furthermore, LT-NPs with PD-L1 blockade greatly inhibit tumor growth, tumor recurrence, and lung metastasis by initiating a strong antitumor immune response. The photochemotherapy by LT-NPs provides a promising strategy for effective checkpoint blockade immunotherapy.

Benzodithiophene-Based Spacers for Layered and Quasi-Layered Lead Halide Perovskite Solar Cells.

Incorporating extended pi-conjugated organic cations in layered lead halide perovskites is a recent trend promising to merge the fields of organic semiconductors and lead halide perovskites. Herein, we integrate benzodithiophene (BDT) into Ruddlesden-Popper (RP) layered and quasi-layered lead iodide thin films (with methylammonium, MA) of the form (BDT)2 MAn-1 Pbn I3n+1 . The importance of tuning the ligand chemical structure is shown as an alkyl chain length of at least six carbon atoms is required to form a photoactive RP (n=1) phase. With N=20 or 100, as prepared in the precursor solution following the formula (BDT)2 MAN-1 PbN I3N+1 , the performance and stability of devices surpassed those with phenylethylammonium (PEA). For N=100, the BDT cation gave a power conversion efficiency of up to 14.7 % vs. 13.7 % with PEA. Transient photocurrent, UV photoelectron spectroscopy, and Fourier transform infrared spectroscopy point to improved charge transport in the device active layer and additional electronic states close to the valence band, suggesting the formation of a Lewis adduct between the BDT and surface iodide vacancies.

Cathepsin B-Overexpressed Tumor Cell Activatable Albumin-Binding Doxorubicin Prodrug for Cancer-Targeted Therapy.

Prodrugs are bioreversible medications that should undergo an enzymatic or chemical transformation in the tumor microenvironment to release active drugs, which improve cancer selectivity to reduce toxicities of anticancer drugs. However, such approaches have been challenged by poor therapeutic efficacy attributed to a short half-life and low tumor targeting. Herein, we propose cathepsin B-overexpressed tumor cell activatable albumin-binding doxorubicin prodrug, Al-ProD, that consists of a albumin-binding maleimide group, cathepsin B-cleavable peptide (FRRG), and doxorubicin. The Al-ProD binds to in situ albumin, and albumin-bound Al-ProD indicates high tumor accumulation with prolonged half-life, and selctively releases doxorubicin in cathepsin B-overexpressed tumor cells, inducing a potent antitumor efficacy. Concurrently, toxicity of Al-ProD toward normal tissues with innately low cathepsin B expression is significantly reduced by maintaining an inactive state, thereby increasing the safety of chemotherapy. This study offers a promising approach for effective and safe chemotherapy, which may open new avenues for drug design and translational medicine.