Thioketal Linker Research Articles

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 .

Redox-Sensitive Delivery of Doxorubicin from Nanoparticles of Poly(ethylene glycol)-Chitosan Copolymer for Treatment of Drug-Resistant Oral Cancer Cells.

Reactive oxygen species (ROS)-sensitive polymer nanoparticles were synthesized for tumor targeting of an anticancer drug, doxorubicin (DOX). For this purpose, chitosan-methoxy poly(ethylene glycol) (mPEG) (ChitoPEG)-graft copolymer was synthesized and then DOX was conjugated to the backbone of chitosan using a thioketal linker. Subsequently, the chemical structure of the DOX-conjugated ChitoPEG copolymer (ChitoPEGthDOX) was confirmed via 1H nuclear magnetic resonance (NMR) spectra. Nanoparticles of the ChitoPEGthDOX conjugates have spherical shapes and a size of approximately 100 nm. Transmission electron microscopy (TEM) has shown that ChitoPEGthDOX nanoparticles disintegrate in the presence of hydrogen peroxide and the particle size distribution also changes from a monomodal/narrow distribution pattern to a multi-modal/wide distribution pattern. Furthermore, DOX is released faster in the presence of hydrogen peroxide. These results indicated that ChitoPEGthDOX nanoparticles have ROS sensitivity. The anticancer activity of the nanoparticles was evaluated using AT84 oral squamous carcinoma cells. Moreover, DOX-resistant AT84 cells were prepared in vitro. DOX and its nanoparticles showed dose-dependent cytotoxicity in both DOX-sensitive and DOX-resistant AT84 cells in vitro. However, DOX itself showed reduced cytotoxicity against DOX-resistant AT84 cells, while the nanoparticles showed almost similar cytotoxicity to DOX-sensitive and DOX-resistant AT84 cells. This result may be due to the inhibition of intracellular delivery of free DOX, while nanoparticles were efficiently internalized in DOX-resistant cells. The in vivo study of a DOX-resistant AT84 cell-bearing tumor xenograft model showed that nanoparticles have higher antitumor efficacy than those found in free DOX treatment. These results may be related to the efficient accumulation of nanoparticles in the tumor tissue, i.e., the fluorescence intensity in the tumor tissue was stronger than that of any other organs. Our findings suggest that ChitoPEGthDOX nanoparticles may be a promising candidate for ROS-sensitive anticancer delivery against DOX-resistant oral cancer cells.

Reactive oxygen species-responsive thymine-conjugated chitosan: Synthesis and evaluation as cryogel

Chitosan (CS) is a biodegradable, biocompatible cationic polysaccharide based natural polymer with antibacterial and anti-inflammatory properties. Hydrogels made from CS have found their applications in wound healing, tissue regeneration and drug delivery. Although, mucoadhesive properties are resulted from the polycationic nature of CS, in hydrogel form amines are engaged in interactions with water leading to decrease in mucoadhesive properties. In case of injury, presence of elevated level of reactive oxygen species (ROS) has inspired many drug delivery platforms to conjugate ROS responsive linkers for on demand drug delivery. In this report we have conjugated a reactive oxygen species (ROS) responsive thioketal (Tk) linker and nucleobase thymine (Thy) with CS. Cryogel from this doubly functionalized polymer CS-Thy-Tk was prepared through crosslinking with sodium alginate. Inosine was loaded on the scaffold and studied for its release under oxidative condition. We anticipated that the presence of thymine shall retain the mucoadhesive nature of the CS-Thy-Tk polymer in hydrogel form and when placed at the site of injury, due to the presence of excessive ROS at inflammatory condition, loaded drug shall release due to degradation of the linker. Porous cryogel scaffold was prepared via chemical crosslinking of amine functional group of chitosan with carboxylic acid containing polysaccharide sodium alginate. The cryogel was evaluated for porosity (FE-SEM), rheology, swelling, degradation, mucoadhesive properties and biocompatibility. Resulted scaffold was found to be porous with average pore size of 107 ± 23 μm, biocompatible, hemocompatible and possesses improved mucoadhesive property (mucin binding efficiency of 19.54 %) which was found to be 4 times better as compared to chitosan (4.53 %). The cumulative drug release found to be better in the presence of H2O2 (∼90 %) when compared to that of PBS alone (∼60–70 %). Therefore, the modified CS-Thy-TK polymer may hold potential as interesting scaffold in case of conditions associated with elevated ROS level such as injury and tumor.

Combined chemo and photo therapy of programmable prodrug carriers to overcome delivery barriers against nasopharyngeal carcinoma

Indocyanine green (ICG) has been employed in medical diagnostics due to its superior photophysical characteristics. However, these advantages are offset by its quick body clearance and inferior photo-stability. In this work, programmable prodrug carriers for chemotherapy/PDT/PTT against nasopharyngeal carcinoma (NPC) were created in order to increase photo-stability and get around biochemical hurdles. The programmable prodrug carriers (PEG-PLA@DIT-PAMAM) that proactively penetrated deeply into NPC tumors and produced the deep phototherapy and selective drug release under laser irradiation was created by dendrimer-DOX/ICG/TPP (DIT-PAMAM) and PEGylated poly (α-lipoic acid) (PLA) copolymer. Long circulation times and minimal toxicity to mammalian cells are two benefits of PEG-coated carriers. The overexpressed GSH on the tumor cell or vascular endothelial cell of the NPC disintegrated the PEG-g-PLA chains and released the DIT-PAMAM nanoparticles after the carriers had reached the NPC tumor periphery. Small, positively charged DIT-PAMAM nanoparticles may penetrate tumors effectively and remain inside tumor for an extended period of time. In addition, the induced ROS cleaved the thioketal linkers for both DOX and nanoparticles and product hyperthermia (PTT) to kill cancer cells under laser irradiation, facilitating faster diffusion of nanoparticles and more effective tumor penetration with a programmable publication of DOX. The programmable prodrug carries showed high photo-stability high photo-stability, which enabled very effective PDT, PTT, and tumor-specific DOX release. With the goal of combining the effects of chemotherapy, PDT, and PTT against NPC, this research showed the great efficacy of programmable prodrug carriers.

Polymeric Phthalocyanine-Based Nanosensitizers for Enhanced Photodynamic and Sonodynamic Therapies.

Photodynamic therapy and sonodynamic therapy are two highly promising modalities for cancer treatment. The latter holds an additional advantage in deep-tumor therapy owing to the deep penetration of the ultrasonic radiation. The therapeutic efficacy depends highly on the photo/ultrasound-responsive properties of the sensitizers as well as their tumor-localization property and pharmacokinetics. A novel nanosensitizer system based on a polymeric phthalocyanine (pPC-TK) is reported herein in which the phthalocyanine units are connected with cleavable thioketal linkers. Such polymer could self-assemble in water forming nanoparticles with a hydrodynamic diameter of 48nm. The degradable and flexible thioketal linkers could effectively inhibit the π-π stacking of the phthalocyanine units, rendering the resulting nanoparticles an efficient generator of reactive oxygen species upon light or ultrasonic irradiation. The nanosensitizer could be internalized into cancer cells readily, inducing cell death by efficient photodynamic and sonodynamic effects. The potency is significantly higher than that of the monomeric phthalocyanine (PC-4COOH). The nanosensitizer could also effectively inhibit the growth of tumor in liver tumor-bearing mice by these two therapies without causing noticeable side effects. More importantly, it could also retard the growth of a deep-located orthotopic liver tumor in vivo by sonodynamic therapy.

Redox Homeostasis Strategy for Inflammatory Macrophage Reprogramming in Rheumatoid Arthritis Based on Ceria Oxide Nanozyme-Complexed Biopolymeric Micelles.

The synovial tissues under rheumatoid arthritis conditions are usually infiltrated by inflammatory cells, particularly M1 macrophages with aberrant redox homeostasis, which causes rapid deterioration of articular structure and function. Herein, we created an ROS-responsive micelle (HA@RH-CeOX) through the in situ host-guest complexation between ceria oxide nanozymes and hyaluronic acid biopolymers, which precisely delivered nanozyme and clinically approved rheumatoid arthritis drug Rhein (RH) to proinflammatory M1 macrophage populations in inflamed synovial tissues. The abundant cellular ROS could cleave the thioketal linker to trigger the release of RH and Ce. Specifically, the Ce3+/Ce4+ redox pair could present SOD-like enzymatic activity to rapidly decompose ROS and alleviate the oxidative stress in M1 macrophages, while RH could inhibit the TLR4 signaling in M1 macrophages, both of which could act in a concerted manner to induce their repolarization into anti-inflammatory M2 phenotype to ameliorate local inflammation and promote cartilage repair. Notably, rats bearing rheumatoid arthritis showed a drastic increase in the M1-to-M2 macrophage ratio from 1:0.48 to 1:1.91 in the inflamed tissue and significantly reduced inflammatory cytokine levels including TNF-α and IL-6 following the intra-articular injection of HA@RH-CeOX, accompanied by efficient cartilage regeneration and restored articular function. Overall, this study revealed an approach to in situ modulate the redox homeostasis in inflammatory macrophages and reprogram their polarization states through micelle-complexed biomimetic enzymes, which offers alternative opportunities for the treatment of rheumatoid arthritis.