Thioketal Linker Research Articles

Macrophage Membrane-Cloaked ROS-Responsive Albumin Nanoplatforms for Targeted Delivery of Curcumin to Alleviate Acute Liver Injury.

Developing low-toxicity, high-efficacy, and fast-acting strategies to manage acute liver injury (ALI) is critical due to its rapid progression and potential for severe outcomes. Curcumin (CUR) has shown promise in ALI therapy due to its ability to modulate the inflammatory microenvironment by scavenging reactive oxygen species (ROS). Nevertheless, CUR is highly hydrophobic limiting its bioavailability and effective in vivo transport, which hinders its further application. In this study, we developed an inflammatory microenvironment-targeted drug delivery system by covalently coupling human serum albumin (HSA) with ROS-sensitive thioketal linkers and loading it with CUR to form nanoparticles (HSA-TK/CUR). These nanoparticles were then coated with a macrophage membrane (CM@HSA-TK/CUR), resulting in negatively charged spherical particles (≈ -23.26 mV) with an average particle size of around 165 nm. ROS responsiveness was confirmed through drug release assays and enhanced ROS depletion was further demonstrated by Diacetyldichlorofluorescein (DCFH-DA) ROS detection experiments. CM@HSA-TK/CUR treatment resulted in a 94.7% reduction in ROS levels in inflammatory cells. In addition, cellular uptake and in vivo distribution experiments demonstrated that camouflaging HSA-TK/CUR with macrophage membranes significantly enhanced its targeting of the inflammatory microenvironment. The findings revealed that CM@HSA-TK/CUR rapidly accumulated in the injured liver within 6 h, inhibited the production of pro-inflammatory factors (IL-1β, IL-6, and TNF-α), shifted macrophage polarization from M1 to M2 in vivo, and protected hepatocytes from oxidative stress-associated cell death, significantly attenuating the inflammatory response in ALI mice. In conclusion, CM@HSA-TK/CUR has excellent potential in treating mice with ALI.

Multicomponent Polymerization toward Poly(BODIPY-sulfonamide)s as Unique SO2 Generators for Sonodynamic and Gas Combination Therapy.

In this work, a multicomponent polymerization (MCP) approach involving bipyrroles, sulfonyl azides, and diynes was developed to afford a library of poly(bipyrrole-sulfonylimide)s (PPSIs) in high yields and molecular weights, which were further modified to form unique sulfur dioxide (SO2) generators. Bipyrroles served as carbon-based nucleophiles to undergo Cu-catalyzed C-C coupling during the MCP. Upon post-MCP modification by transforming the bipyrrole unit to boron dipyrromethene (BODIPY) and the sulfonylimide moiety to sulfonamide, poly(BODIPY-sulfonamide)s (PBSAs) were obtained as potent anticancer therapeutic agents. This study disclosed the decomposition and SO2-releasing ability of PBSAs under ultrasound (US) irradiation. Furthermore, one of these polymers having a reactive oxygen species-cleavable thioketal linker was modified with triethylene glycol chains to give PBSA-EG, which was further studied for in vitro and in vivo US-induced anti-cancer therapy. Upon tail veil administration of PBSA-EG nanoparticles into tumor-bearing mice followed by US irradiation, remarkable tumor suppression was observed. This study demonstrates that the innovative and efficient MCP method can construct polymers bearing the BODIPY-sulfonamide moieties, which show a great potential as safe and potent materials for combined gas and sonodynamic therapy against cancer.

Spatiotemporal-controllable ROS-responsive camptothecin nano-bomb for chemo/photo/immunotherapy in triple-negative breast cancer

Chemotherapy is still one of the major approaches in triple-negative breast cancer (TNBC) treatment. The development of new formulations for classic chemotherapeutic drugs remains interests in studies. Camptothecin (CPT) is powerful antitumor agents in TNBC treatment though its clinic applications are limited by its low water solubility and systemic toxicity. To prepare a spatiotemporal controllable CPT nano-formulation, we construct a ROS-responsive self-assembly nanoparticle by combining hydrophobic CPT and hydrophilic 5-floxuridine (FUDR). A ROS-sensitive thioketal (TK) linker is used to prepare CPT-TK-FUDR (CTF). Next, we introduced IR780-based phototherapy to elicit massive ROS regeneration due to the endogenous ROS is not sufficient. IR780 is modified with hyaluronic acid (HA) to prepare HA-modified IR780 (HAIR) for its biocompatibility and tumor targeting ability improvement. CTF and HAIR self-assemble to form an attractive nano-bomb (HAIR/CTF NPs). HA accurately guides the NPs to tumor sites via HA-receptor recognition on tumor cells. After internalization, overexpressed intracellular HAase in tumor cells disassembles the NPs to free the contents. Due to the presence of IR780 molecules, the scheduled irradiation of 808 nm laser induces massive reactive oxygen species (ROS) generation, which further result in the cleavage of TK linker for free drugs release. Additionally, ROS-mediated photodynamic therapy (PDT) and near-infrared laser-mediated photothermal therapy (PTT) synergistically worked to eradicate tumor cells. Then immunogenic cell death (ICD) was evoked by CPT and phototherapy to amplify antitumor immunity, thereby achieving primary and abscopal tumor inhibition. In conclusion, the HAIR/CTF nano-bomb realized spatiotemporal controllable drug release, exciting tumor eradication and attractive anti-metastasis efficacy via combination chemo/photo/immunotherapy, offering a valuable reference for the re-development of classic drug in future clinical practice.Graphical

Reactive Oxygen Species-Sensitive Nanophotosensitizers Composed of Buthionine Sulfoximine-Conjugated Chitosan Oligosaccharide for Enhanced Photodynamic Treatment of Cancer Cells.

The efficacy of photodynamic therapy (PDT) based on traditional photosensitizers is generally limited by the cellular redox homeostasis system due to the reactive oxygen species (ROS) scavenging effect of glutathione (GSH). In this study, buthionine sulfoximine (BSO), a GSH inhibitor, was conjugated with the amine group of chitosan oligosaccharide (COS) using a thioketal linker (COSthBSO) to liberate BSO and chlorine e6 (Ce6) under oxidative stress, and then, Ce6-COSthBSO NP (Ce6-COSthBSO NP), fabricated by a dialysis procedure, showed an accelerated release rate of BSO and Ce6 by the addition of hydrogen peroxide, indicating that nanophotosensitizers have ROS sensitivity. In the in vitro cell culture study using HCT116 colon carcinoma cells, a combination of BSO and Ce6 efficiently suppressed the intracellular GSH and increased ROS production compared to the sole treatment of Ce6. In particular, Ce6-COSthBSO NP showed higher efficacy in the suppression of GSH levels and ROS production compared to the free Ce6 and Ce6/BSO combination. These results were due to the fact that Ce6-COSthBSO NP was efficiently delivered to the intracellular region, suppressed intracellular GSH levels, and elevated ROS levels. The in vivo animal tumor xenograft study demonstrated Ce6-COSthBSO NP being efficiently delivered to the tumor tissue, i.e., the fluorescence intensity in the tumor tissue was higher than those of other organs. The combination of Ce6 and BSO efficiently suppressed tumor growth compared to the sole treatment of Ce6, indicating that BSO might efficiently suppress GSH levels and increase ROS levels in the tumor microenvironment. Specifically, Ce6-COSthBSO NP showed the strongest performance in inhibition of tumor growth than those of Ce6 or the CE6/BSO combination, indicating that they were efficiently delivered to tumor tissue, increased ROS levels, and then efficiently inhibited tumor growth. We suggest that COSthBSO nanophotosensitizers are promising candidates for PDT treatment of cancer cells.

Self-Boosting Programmable Release of Multiple Therapeutic Agents by Activatable Heterodimeric Prodrug-Enzyme Assembly for Antitumor Therapy.

Endogenous stimuli-responsive prodrugs, due to their disease lesion specificity and reduced systemic toxicity, have been widely explored for antitumor therapy. However, reactive oxygen species (ROS) as classical endogenous stimuli in the tumor microenvironment (TME) are not enough to achieve the expected drug release. Herein, a ROS-activatable heterodimeric prodrug-loaded enzyme assembly is developed for self-boosting programmable release of multiple therapeutic agents. The heterodimeric prodrug NBS-TK-PTX (namely NTP) is composed of 5-(ethylamino)-9-diethylaminobenzo[a]phenothiazinium chloride analog (NBS), paclitaxel (PTX) and ROS-responsive thioketal (TK) linker, which shows a strong binding affinity with glucose oxidase (GOx), thus obtaining NTP@GOx assembly. Notably, the enzymatic activity of GOx in NTP@GOx is inhibited by NTP. The programmable release is achieved by following steps: i) NTP@GOx is partially dissociated in acidic TME, thus releasing a small segment of NTP and GOx. Thereupon, the enzymatic activity of GOx is recovered; ii) GOx-triggered pH reduction further facilitates the dissociation of NTP@GOx, thus accelerating a large amount of NTP and GOx release; iii) The TK linker of prodrug NTP is cleaved by hydrogen peroxide generated by GOx catalysis, thus expediting the release of NBS for Type-I photodynamic therapy and PTX for chemotherapy, respectively. The NTP@GOx shows great potential for multimodal synergistic cancer therapy.

ROS-responsive glycol chitosan-linked prodrug nanoparticle as a nanoplatform for tumor chemo-photodynamic therapy

Herein, we designed and synthesized novel reactive oxygen species (ROS)-responsive glycol chitosan-doxorubicin (DOX) prodrug via a ROS-cleavable thioketal (TK) linker. The obtained GC-TK-DOX formed self-assembled nanoparticles of 312 nm in aqueous media. Photosensitizers zinc phthalocyanine (ZnPc)-loaded GC-TK-DOX (GC-TK-DOX/ZnPc) nanoparticles were fabricated by using a dialysis approach. The GC-TK-DOX and GC-TK-DOX/ZnPc nanoparticles were nearly spherical by transmission electron microscopy (TEM) observation. Under 660-nm laser irradiation, GC-TK-DOX/ZnPc could generate singlet oxygen. Further, GC-TK-DOX/ZnPc nanoparticles exhibited ROS-sensitive release of DOX and ZnPc in vitro. GC-TK-DOX/ZnPc with laser irradiation showed more drug uptake and higher cytotoxic effects than GC-TK-DOX/ZnPc without irradiation, free DOX and GC-TK-DOX in HeLa tumor cells. Overall, these findings suggested that GC-TK-DOX/ZnPc could be a promising nanoarchitecture for synergetic chemo-photodynamic therapy against tumors.

Reactive Oxygen Species-Regulated Conjugates Based on Poly(jasmine) Lactone for Simultaneous Delivery of Doxorubicin and Docetaxel.

In cancer therapy, it is essential to selectively release cytotoxic agents into the tumor to prevent the adverse effects associated with anticancer drugs. Thus, in this study, a stimuli-sensitive polymer-drug conjugate was synthesized for selective drug release. Doxorubicin (DOX) and docetaxel (DTX) were conjugated onto novel poly(jasmine lactone) based copolymer via a thioketal (TK) linker. In addition, a photosensitizer (chlorin e6) was attached to the polymer, which served as a reactive oxygen species generator to cleave the TK linker. The conjugate is readily self-assembled into micelles less than 100 nm in size. Micelles demonstrate a notable increase in their ability to cause cell death when exposed to near-infrared (NIR) light on MDA-MB-231 breast cancer cells. The increase in cytotoxicity is higher than that observed with the combination of free DOX and DTX. The accumulation of DOX in the nucleus after release from the micelles (laser irradiation) was also confirmed by confocal microscopy. In the absence of light, micelles did not show any toxicity while the free drugs were found toxic irrespective of the light exposure. The obtained results suggest the targeted drug delivery potential of micelles regulated by the external stimuli, i.e., NIR light.

Triterpene-Based Prodrug for Self-Boosted Drug Release and Targeted Oral Squamous Cell Carcinoma Chemotherapy.

Chemotherapy is one of the main treatments for oral squamous cell carcinoma (OSCC), especially as a combined modality approach with and after surgery or radiotherapy. Limited therapeutic efficiency and serious side effects greatly restrict the clinical performance of chemotherapeutic drugs. The development of smart nanomedicines has provided new research directions, to some extent. However, the involvement of complex carrier compositions inevitably brings biosafety concerns and greatly limits the "bench-to-bed" translation of most nanomedicines reported. In this study, a carrier-free self-assembled prodrug was fabricated by two triterpenes (glycyrrhetinic acid, GA and ginsenoside Rh2, Rh2) isolated from medicinal plants, licorice, and ginseng, for the targeted and highly effective treatment of OSCC. Reactive oxygen species (ROS) self-supplied molecule TK-GA2 was synthesized with ROS-responsive thioketal linker and prodrug was prepared by a rapid-solvent-exchange method with TK-GA2 and Rh2. After administration, oral tumor cells transported large amounts of prodrugs with glucose ligands competitively. Endogenous ROS in oral tumor cells then promoted the release of GA and Rh2. GA further evoked the generation of a large number of ROS to help self-boosted drug release and increase oxidative stress, synergistically causing tumor cell apoptosis with Rh2. Overall, this carrier-free triterpene-based prodrug might provide a preeminent opinion on the design of effective chemotherapeutics with low systemic toxicity against OSCC.

Orally Delivered Stimulus-Sensitive Nanomedicine to Harness Teduglutide Efficacy in Inflammatory Bowel Disease.

Inflammatory Bowel Disease (IBD) is a chronic inflammatory condition affecting the gastrointestinal tract (GIT). Glucagon-like peptide-2 (GLP-2) analogs possess high potential in the treatment of IBD by enhancing intestinal repair and attenuating inflammation. Due to the enzymatic degradation and poor intestinal absorption, GLP-2 analogs are administered parenterally, which leads to poor patient compliance. This work aims to develop IBD-targeted nanoparticles (NPs) for the oral delivery of the GLP-2 analog, Teduglutide (TED). Leveraging the overproduction of Reactive Oxygen Species (ROS) in the IBD environment, ROS-sensitive NPs are developed to target the intestinal epithelium, bypassing the mucus barrier. PEGylation of NPs facilitates mucus transposition, but subsequent PEG removal is crucial for cellular internalization. This de-PEGylation is possible by including a ROS-sensitive thioketal linker within the system. ROS-sensitive NPs are established, with the ability to fully de-PEGylate via ROS-mediated cleavage. Encapsulation of TED into NPs resulted in the absence of absorption in 3D in vitro models, potentially promoting a localized action, and avoiding adverse effects due to systemic absorption. Upon oral administration to colitis-induced mice, ROS-sensitive NPs are located in the colon, displaying healing capacity and reducing inflammation. Cleavable PEGylated NPs demonstrate effective potential in managing IBD symptoms and modulating the disease's progression.

Ultrasound-Activated PROTAC Prodrugs Overcome Immunosuppression to Actuate Efficient Deep-Tissue Sono-Immunotherapy in Orthotopic Pancreatic Tumor Mouse Models.

The degradation of oncoproteins mediated by proteolysis-targeting chimera (PROTAC) has emerged as a potent strategy in cancer therapy. However, the clinical application of PROTACs is hampered by challenges such as poor water solubility and off-target adverse effects. Herein, we present an ultrasound (US)-activatable PROTAC prodrug termed NPCe6+PRO for actuating efficient sono-immunotherapy in a spatiotemporally controllable manner. Specifically, US irradiation, which exhibits deep-tissue penetration capability, results in Ce6-mediated generation of ROS, facilitating sonodynamic therapy (SDT) and inducing immunogenic cell death (ICD). Simultaneously, the generated ROS cleaves the thioketal (TK) linker through a ROS-responsive mechanism, realizing the on-demand activation of the PROTAC prodrug in deep tissues. This prodrug activation results in the degradation of the target protein BRD4, while simultaneously reversing the upregulation of PD-L1 expression associated with the SDT process. In the orthotopic mouse model of pancreatic tumors, NPCe6+PRO effectively suppressed tumor growth in conjunction with US stimulation.

Eosinophil‐Activating Semiconducting Polymer Nanoparticles for Cancer Photo‐Immunotherapy

AbstractEosinophils are important immune effector cells that affect T cell‐mediated antitumor immunity. However, the low frequency and restrained activity of eosinophils restricted the outcome of cancer immunotherapies. We herein report an eosinophil‐activating semiconducting polymer nanoparticle (SPNe) to improve photodynamic tumor immunogenicity, modulate eosinophil chemotaxis, and reinvigorate T‐cell immunity for activated cancer photo‐immunotherapy. SPNe comprises an amphiphilic semiconducting polymer and a dipeptidyl peptidase 4 (DPP4) inhibitor sitagliptin via a 1O2‐cleavable thioketal linker. Upon localized NIR photoirradiation, SPNe generates 1O2 to elicit immunogenic cell death of tumors and induce specific activation of sitagliptin. The subsequent inhibition of DPP4 increases intratumoral CCL11 levels to promote eosinophil chemotaxis and activation. SPNe‐mediated photo‐immunotherapy synergized with immune checkpoint blockade greatly promotes tumor infiltration and activation of both eosinophils and T cells, effectively inhibiting tumor growth and metastasis. Thus, this study presents a generic polymeric nanoplatform to modulate specific immune cells for precision cancer immunotherapy.

Eosinophil-Activating Semiconducting Polymer Nanoparticles for Cancer Photo-Immunotherapy.

Eosinophils are important immune effector cells that affect T cell-mediated antitumor immunity. However, the low frequency and restrained activity of eosinophils restricted the outcome of cancer immunotherapies. We herein report an eosinophil-activating semiconducting polymer nanoparticle (SPNe) to improve photodynamic tumor immunogenicity, modulate eosinophil chemotaxis, and reinvigorate T-cell immunity for activated cancer photo-immunotherapy. SPNe comprises an amphiphilic semiconducting polymer and a dipeptidyl peptidase 4 (DPP4) inhibitor sitagliptin via a 1O2-cleavable thioketal linker. Upon localized NIR photoirradiation, SPNe generates 1O2 to elicit immunogenic cell death of tumors and induce specific activation of sitagliptin. The subsequent inhibition of DPP4 increases intratumoral CCL11 levels to promote eosinophil chemotaxis and activation. SPNe-mediated photo-immunotherapy synergized with immune checkpoint blockade greatly promotes tumor infiltration and activation of both eosinophils and T cells, effectively inhibiting tumor growth and metastasis. Thus, this study presents a generic polymeric nanoplatform to modulate specific immune cells for precision cancer immunotherapy.

Inhibiting the cGAS-STING Pathway in Ulcerative Colitis with Programmable Micelles.

Ulcerative colitis is a chronic condition in which a dysregulated immune response contributes to the acute intestinal inflammation of the colon. Current clinical therapies often exhibit limited efficacy and undesirable side effects. Here, programmable nanomicelles were designed for colitis treatment and loaded with RU.521, an inhibitor of the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway. STING-inhibiting micelles (SIMs) comprise hyaluronic acid-stearic acid conjugates and include a reactive oxygen species (ROS)-responsive thioketal linker. SIMs were designed to selectively accumulate at the site of inflammation and trigger drug release in the presence of ROS. Our in vitro studies in macrophages and in vivo studies in a murine model of colitis demonstrated that SIMs leverage HA-CD44 binding to target sites of inflammation. Oral delivery of SIMs to mice in both preventive and delayed therapeutic models ameliorated colitis's severity by reducing STING expression, suppressing the secretion of proinflammatory cytokines, enabling bodyweight recovery, protecting mice from colon shortening, and restoring colonic epithelium. In vivo end points combined with metabolomics identified key metabolites with a therapeutic role in reducing intestinal and mucosal inflammation. Our findings highlight the significance of programmable delivery platforms that downregulate inflammatory pathways at the intestinal mucosa for managing inflammatory bowel diseases.

Poly-l-lysine modified MOF nanoparticles with pH/ROS sensitive CIP release and CUR triggered photodynamic therapy against drug-resistant bacterial infection

The challenge of drug resistance in bacteria caused by the over use of biotics is increasing during the therapy process, which has attracted great attentions of the clinicians and scientists around the world. Recently, photodynamic therapy (PDT) triggered by photosensitizer (PS) has become a promising treatment method because of its high efficacy, easy operation, and low side effect. Herein, the poly-l-lysine (PLL) modified metal-organic framework (MOF) nanoparticles, ZIF/PLL-CIP/CUR, were synthesized to allow both reactive oxygen species (ROS) responsive drug release and photodynamic effect for synergistic therapy against drug resistant bacterial infections. The PLL was modified on the shell of the zeolite imidazole framework (ZIF) by the ROS-responsive thioketal linker for controllable CIP release. CUR were encapsulated in ZIF as the photosensitizer for blue light mediated photodynamic effect to produce singlet oxygen (1O2) and superoxide anion radical (O2−) for efficient inhibition towards methicillin-resistant Staphylococcus aureus (MRSA). The charge conversion from negative charge (−4.6 mV) to positive charge (2.6 mV) was observed at pH 7.4 and pH 5.5, and 70.9 % CIP was found released at pH 5.5 in the presence of H2O2, which suggests the good biosafety at physiological pH and ROS-responsive drug release of the as-prepared nanoparticle in the bacterial microenvironment. The as-prepared nanoparticles could effectively kill MRSA and disrupt bacterial biofilm by combination of chemo- and photodynamic therapy. In mice model, the as-prepared nanoparticles exhibited excellent biosafety and synergistic effect with 98.81 % healing rate in treatment of MRSA infection, which is considered as a promising candidate in combating drug resistant bacterial infection.

“Integrated diagnosis and treatment” of upconversion nanocomposite hydrogel for osteoarthritis treatment

Osteoarthritis (OA) is a common degenerative joint disease for which there is no definitive treatment. Mesenchymal stem cells (MSCs) can be differentiated into many types of cells such as chondrocytes, which have been used for OA treatment. How to keep the cell viability and promote the chondrogenic differentiation after MSCs transplantation into the knee joint cavityiscrucial. In this study, upconversion nanocomposite hydrogel was developed for integrated diagnosis and treatment of OA. The Er doped core–shell upconversion nanoparticles (UCNPs) were synthesized first and coated on mesoporous silica (UCNP@mSiO2). Then, an H2O2-sensitive thioketal (TK) linker (MAL-PEG-TK-NHS) was attached to the UCNP@mSiO2 surface to link capsular β-cyclodextrin (NH2-β-CD) and black hole quencher (NH2-BHQ3) to form functionalized UCNPs. After loading the drug kartogenin (KGN) that can induce chondrogenic differentiation of MSCs, the UCNP/KGN nanocomposites were mixed with VitroGel to formed the upconversion nanocomposite hydrogel (UCNP/VitroGel). The UCNP/VitroGel could allow MSCs to be implanted well and maintain good survival in vitro. In the presence of hydrogen peroxide (H2O2), the TK bond breakage and triggered release BHQ to recover the fluorescence of UCNPs for ROS detection, and the β-CD also left from the surface of UCNPs to release KGN for inducing the chondrogenic differentiation of MSCs. Thus, the UCNP/VitroGel could detect the ROS after inject into the knee joint cavity for OA diagnosis first via the fluorescence recovery of UCNPs under the 980 nm near-infrared light. And then the KGN release from UCNP/KGN nanocomposites in the environment of OA to induce the chondrogenic differentiation of MSCs for the treatment of OA. This UCNP/VitroGel will be a powerful tool for “integrated diagnosis and treatment” of OA.

Intraoperative application of intelligent, responsive, self-assembling hydrogel rectifies oxygen and energy metabolism in traumatically injured brain

In managing severe traumatic brain injury (TBI), emergency surgery involving the removal of damaged brain tissue and intracerebral hemorrhage is a priority. Secondary brain injury caused by oxidative stress and energy metabolic disorders, triggered by both primary mechanical brain damage and surgical insult, is also a determining factor in the prognosis of TBI. Unfortunately, the effectiveness of traditional postoperative intravenous neuroprotective agents therapy is often limited by the lack of targeting, timeliness, and side effects when neuroprotective agents systemically delivered. Here, we have developed injectable, intelligent, self-assembling hydrogels (P-RT/2DG) that can achieve precise treatment through intraoperative application to the target area. P-RT/2DG hydrogels were prepared by integrating a reactive oxygen species (ROS)-responsive thioketal linker (RT) into polyethylene glycol. By scavenging ROS and releasing 2-deoxyglucose (2DG) during degradation, these hydrogels functioned both in antioxidation and energy metabolism to inhibit the vicious cycle of post-TBI ROS–lactate which provoked secondary injury. In vitro and in vivo tests confirmed the absence of systemic side effects and the neuroprotective function of P-RT/2DG hydrogels in reducing edema, nerve cell apoptosis, neuroinflammation, and maintaining the blood-brain barrier. Our study thus provides a potential treatment strategy with novel hydrogels in TBI.

A Factor-Free Hydrogel with ROS Scavenging and Responsive Degradation for Enhanced Diabetic Bone Healing.

In view of the increased levels of reactive oxygen species (ROS) that disturb the osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs), the repair of diabetic bone defects remains a great challenge. Herein, a factor-free hydrogel is reported with ROS scavenging and responsive degradation properties for enhanced diabetic bone healing. These hydrogels contain ROS-cleavable thioketal (TK) linkers and ultraviolet (UV)-responsive norbornene (NB) groups conjugated with 8-arm PEG macromers, which are formed via UVcrosslinking-mediated gelation. Upon reacting with high levels of ROS in the bone defect microenvironment, ROS-cleavable TK linkers are destroyed, allowing the responsive degradation of hydrogels, which promotes the migration of BMSCs. Moreover, ROS levels are reduced through hydrogel-mediated ROS scavenging to reverse BMSC differentiation from adipogenic to osteogenic phenotype. As such, a favorable microenvironment is created after simultaneous ROS scavenging and hydrogel degradation, leading to the effective repair of bone defects in diabetic mouse models, even without the addition of growth factors. Thus, this study presents a responsive hydrogel platform that regulates ROS scavenging and stromal degradation in bone engineering.

ROS-responsive camptothecin-linked thioketal drug delivery system based on ring-closing polymerization

This study develops a drug delivery system that is ROS-responsive and can be triggered by endogenous ROS. A polyethylene glycol (PEG) tail end is attached to a ring-closing polymer (PMPSD), which is conjugated to camptothecin (CPT) via a thioketal linker (TK) to produce a TK-CPT-PMPSD conjugate. An in-depth characterization of the TK-CPT-PMPSD is performed using GPC, FTIR, and 1H NMR.Using DLS, three days of physiological conditions (0 µM H2O2) result in a stable size of 69 ± 2.3 nm with 0.31 PDI, which is then validated by TEM, which shows good agreement with DLS. Additionally, TEM research revealed that the TK-CPT-PMPSD particles were spherical in form and assembled in a controlled manner. The observed drug release from TK-CPT-PMPSD is significantly accelerated at 10 µM and 25 µM H2O2 in the range of 63% and 80% in a 72-hour time frame, implying that the thioketal linker is ROS-sensitive. Furthermore, MTT tests show that the resulting TK-CPT-PMPSD NPs are harmless to normal cells at a concentration of 250 µg mL−1, while research on cancer cells substantiates a promising anti-tumor characteristic with a 37% apoptosis at a 10 µg mL−1 concentration. Fluorescence imaging studies indicate that TK-CPT-PMPSD has improved anticancer efficacy and efficient nuclei internalization after 12 h of incubation. As far as we are aware, the delivery of CPT-conjugated, thioketal PMPSD using ring-closing metathesis polymerization (RCMP) is a novel concept.

Targeting Hypoxic Tumor Plasticity for Recapturing Photodynamic‐Immunotherapy Sensitivity via Fluorinated Polysensitizers

AbstractMetabolic reprogramming is a key characteristics of tumor cells, mainly manifested by abnormal metabolism and tumor hypoxia. Here, the design of PolyFBODIPY characterized by the presence of BODIPY photosensitizers, fluorinated aliphatic chains as Oxygen affinity materials, and reactive oxygen species‐sensitive thioketal linkers is reported. PolyFBODIPY subsequently self‐assembles into NP@PolyFBODIPY which is capable of delivering oxygen and photosensitizers simultaneously and generating ROS under light irradiation, resulting in rapid polymer degradation and nanoparticle dissociation via breaking ROS‐sensitive thiol ketal linkers. NP@PolyFBODIPY can target hypoxic tumor plasticity to reprogram metabolism for recapturing photodynamic‐immunotherapy sensitivity for completely inhibiting tumor growth on multi‐drug‐resistant patient‐derived lung cancer xenografts (PDXMDR). Moreover, NP@PolyFBODIPY‐mediated photodynamic‐immunotherapy activates antitumor immune responses and effectively inhibits tumor growth and lung metastasis on an orthotropic metastatic triple‐negative breast cancer model. Mechanistically, metabolomics and lipidomics analysis reveals that NP@PolyFBODIPY‐mediated photodynamic‐immunotherapy not only destroys the redox state of cancer cells, but also affects the metabolism of lipid, amino acid, and d‐glutamine, thereby finally promoting autophagy and apoptosis and inhibiting the proliferation of cancer cells. These results highlight the potential of clinical translation of NP@PolyFBODIPY in targeting hypoxic tumor plasticity via oxygen supply, which reprograms the cellular metabolism for recapturing photodynamic‐immunotherapy sensitivity.

Reactive Oxygen Species (ROS)-Assisted Nano-Therapeutics Surface-Decorated with Epidermal Growth Factor Fragments for Enhanced Wound Healing.

In this study, stimuli-responsive liberation of an epidermal growth factor fragment (EGFfr) is accomplished using nanofibrous meshes to improve wound healing effects. Electrospun nanofibers are fragmented by mechanical milling, followed by aminolysis to fabricate powdered nanofibrils (NFs). EGFfrs are covalently immobilized on NFs via thioketal linkers (EGFfr@TK@NF) for reactive oxygen species (ROS)-dependent liberation. EGFfr@TK@NF exhibits ROS-responsive liberation of EGFfr from the matrix at hydrogen peroxide (H2 O2 ) concentrations of 0-250mm. Released EGFfr is confirmed to enhance the migration of HaCaT cell monolayers, and keratinocytic gene expression levels are significantly enhanced when H2 O2 is added to obtain the released fraction of NFs. An in vivo study on the dorsal wounds of mice reveals that EGFfr-immobilized NFs improve the expression levels of keratin1, 5, and 14 for 2 weeks when H2 O2 is added to the wound sites, suggesting that the wounded skin is re-epithelized with the original epidermis. Thus, EGFfrs-immobilized NFs are anticipated to be potential nanotherapeutics for wound treatment in combination with the conventional disinfection process with H2 O2 .