establishing-a-mouse-model-of-thin-endometrium

Establishing a Mouse Model of Thin Endometrium

Thin endometrium (TE) has been widely recognized as a critical cause of infertility. However, the pathogenesis of TE remains unclear, and satisfactory ...

Shenzhen Campus of Sun Yat-sen University

Combination therapy has been widely studied due to its promising applications in tumor therapy. However, a sophisticated nanoplatform and sequential irradiation with different laser sources for phototherapy complicate the treatment process. Unlike the integration of therapeutic agents, we report a FeS@SRF@BSA nanoplatform for the combination of chemo-combined photothermal therapy (PTT) enhanced photodynamic therapy (PDT) and chemodynamic therapy (CDT) to achieve an "all-in-one" therapeutic agent. Ultrasmall FeS nanoparticles (NPs) with a size of 7 nm exhibited higher Fenton reaction rates due to their large specific surface areas. A photodynamic reaction could be triggered and could generate O to achieve PDT under 808 nm irradiation. FeS NPs also exhibited the desired photothermal properties under the same wavelength of the laser. The Fenton reaction and photodynamic reaction were both significantly improved to accumulate more reactive oxygen species (ROS) with an increase of temperature under laser irradiation. Besides, loading of the chemotherapeutic drug sorafenib (SRF) further improved the efficacy of tumor treatment. To realize long blood circulation, bovine serum albumin (BSA) was used as a carrier to encapsulate FeS NPs and SRF, remarkably improving the biocompatibility and tumor enrichment ability of the nanomaterials. Additionally, the tumors on mice treated with FeS@SRF@BSA almost disappeared under 808 nm irradiation. To sum up, FeS@SRF@BSA NPs possess good biocompatibility, stability, and sufficient therapeutic efficacy in combination therapy for cancer treatment. Our study pointed out a smart design of the nanoplatform as a multifunctional therapeutic agent for combination cancer therapy in the near future.

Multifunctional FeS@SRF@BSA nanoplatform for chemo-combined photothermal enhanced photodynamic/chemodynamic combination therapy.

The enzyme-mediated elevation of reactive oxygen species (ROS) at the tumor sites has become an emerging strategy for regulating intracellular redox status for anticancer treatment. Herein, we proposed a camouflaged bionic cascaded-enzyme nanoreactor based on TiC nanosheets for combined tumor enzyme dynamic therapy (EDT), phototherapy and deoxygenation-activated chemotherapy. Briefly, glucose oxidase (GOX) and chloroperoxidase (CPO) were chemically conjugated onto TiC nanosheets, where the deoxygenation-activated drug tirapazamine (TPZ) was also loaded, and the TiC-GOX-CPO/TPZ (TGCT) was embedded into nanosized cancer cell-derived membrane vesicles with high-expressed CD47 (mTGCT). Due to biomimetic membrane camouflage and CD47 overexpression, mTGCT exhibited superior immune escape and homologous targeting capacities, which could effectively enhance the tumor preferential targeting and internalization. Once internalized into tumor cells, the cascade reaction of GOX and CPO could generate HClO for efficient EDT. Simultaneously, additional laser irradiation could accelerate the enzymic-catalytic reaction rate and increase the generation of singlet oxygen (O). Furthermore, local hypoxia environment with the oxygen depletion by EDT would activate deoxygenation-sensitive prodrug for additional chemotherapy. Consequently, mTGCT exhibits amplified synergistic therapeutic effects of tumor phototherapy, EDT and chemotherapy for efficient tumor inhibition. This intelligent cascaded-enzyme nanoreactor provides a promising approach to achieve concurrent and significant antitumor therapy.

A MXene-Based Bionic Cascaded-Enzyme Nanoreactor for Tumor Phototherapy/Enzyme Dynamic Therapy and Hypoxia-Activated Chemotherapy.

Sonodynamic therapy (SDT) benefiting from its intrinsic merits, such as noninvasiveness and deep tissue penetrability, is receiving increasing considerable attention in reactive oxygen species (ROS)-based tumor treatment. However, current sonosensitizers usually suffer from low tumor lesion accumulation, insufficient ROS generation efficiency under ultrasound, and non-biodegradability, which seriously impede the therapeutic outcomes. Additionally, it is difficult that SDT alone can completely eradicate tumors because of the complex and immunosuppressive tumor microenvironment (TME). Herein, we simultaneously employ sonosensitive porphyrin building blocks and glutathione (GSH)-responsive disulfide bonds to construct a novel degradable multifunctional porphyrin-based hollow porous organic polymer (POP) nanosonosensitizer (H-Pys-HA@M/R), which combine SDT, "on-demand" chemotherapy, and immunotherapy. Taking the unique advantages of POPs with designable structures and high specific surface area, this H-Pys-HA@M/R nanosonosensitizer can achieve tumor target accumulation, GSH-triggered drug release, and low-frequency ultrasound-activating ROS generation with encouraging results. Furthermore, this multifunctional nanosonosensitizer can effectively evoke immunogenic cell death (ICD) response through the combination of SDT and chemotherapy for both primary and distal tumor growth suppression. Meanwhile, H-Pys-HA@M/R exhibits favorable biodegradation and biosafety. Therefore, this study provides a new strategy for reasonably designing and constructing POP-related sonosensitizers combining SDT/chemotherapy/immunotherapy triple treatment modalities to eradicate malignant tumors.

Degradable Multifunctional Porphyrin-Based Porous Organic Polymer Nanosonosensitizer for Tumor-Specific Sonodynamic, Chemo- and Immunotherapy.

The use of bacteria as living vehicles has attracted increasing attentions in tumor therapy field. The combination of functional materials with bacteria dramatically facilitates the antitumor effect. Here, we presented a rationally designed living system formed by programmed Escherichia Coli MG1655 cells (Ec) and black phosphorus (BP) nanoparticles (NPs). The bacteria were genetically engineered to express tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), via an outer membrane YiaT protein (Ec-T). The Ec-T cells were associated with BP NPs on their surface to acquire BP@Ec-T. The designed living system could transfer the photoelectrons produced by BP NPs after laser irradiation and triggered the reductive metabolism of nitrate to nitric oxide for the in situ release at tumor sites, facilitating the therapeutic efficacy and the polarization of tumor associated macrophages to M1 phenotype. Meanwhile, the generation of reactive oxygen species induced the immunogenic cell death to further improve the antitumor efficacy. Additionally, the living system enhanced the immunological effect by promoting the apoptosis of tumor cells, activating the effect of T lymphocytes and releasing the pro-inflammatory cytokines. The integration of BP NPs, MG1655 cells and TRAIL led to an effective tumor therapy. Our work established an approach for the multifunctional antitumor living therapy.

Surface programmed bacteria as photo-controlled NO generator for tumor immunological and gas therapy.

Medical imaging contrast agents that are able to provide detailed biological information have attracted increasing attention. Among the new emerging imaging contrast agents, F magnetic resonance imaging contrast agents (F MRI CAs) are extremely promising for their weak background disturbing signal from the body. However, to prepare F MRI CAs with a long  relaxation time and excellent biocompatibility in a simple and highly effective strategy is still a challenge. Herein, we report a new type of F MRI hydrogel nanocontrast agents (F MRI HNCAs) synthesized by a surfactant-free emulsion polymerization with commercial fluorinated monomers. The  relaxation time of F MRI HNCA-1 was found to be 25-40 ms, guaranteeing its good imaging ability . In addition, according to an investigation into the relationship between the fluorine content and F MRI signal intensity, the F MRI signal intensity was not only determined by the fluorine content in F MRI HNCAs but also by the hydration microenvironment around the fluorine atoms. Moreover, F MRI HNCAs demonstrated excellent biocompatibility and imaging capability inside cells. The primary exploration demonstrated that F MRI HNCAs as a new type of F MRI contrast agent hold potential for imaging lesion sites and tracking cells  by F MRI technology.

Fluorinated hydrogel nanoparticles with regulable fluorine contents and  relaxation times as F MRI contrast agents.

Due to the immunosuppressive tumor microenvironment (ITM) resulting from tumor-associated macrophages (TAMs) and regulatory T cells, immune checkpoint blockade and vaccine therapies often lead to an inadequate immune response. Recently, cyclic guanosine monophosphate-adenosine monophosphate synthase/stimulator of interferon gene (cGAS/STING)-mediated innate immunity has emerged as a promising cancer therapeutic, as STING pathway activation could promote dendritic cells (DCs) maturation and tumor-specific cytotoxic T lymphocyte (CTL) and natural killer (NK) cell infiltration. Herein, multifunctional hybrid exosomes for cGAS/STING activation are designed by fusing genetically engineered exosomes carrying CD47 derived from tumor cells with exosomes from M1 macrophages, which are further encapsulated with DNA-targeting agent (SN38) and STING-agonist (MnO). The hybrid exosomes demonstrate great tumor-targeting capacity and prolong blood circulation time due to the surface decoration of CD47. At the tumor site, the hybrid exosomes induce TAMs polarization to the M1 phenotype and release SN38 to induce DNA damage and Mn to stimulate cGAS/STING activation. Furthermore, the resulting multifunctional hybrid exosomes (SN/Mn@gHE) promote DCs maturation and facilitate CTL infiltration and NK cell recruitment to the tumor region, leading to significant anti-tumor and antimetastatic efficacy. Our study suggests a novel strategy to enhance cancer immunotherapy by activating the STING pathway and ameliorating ITM.

Multifunctional hybrid exosomes enhanced cancer chemo-immunotherapy by activating the STING pathway.

Image-guided thermal ablation (TA), which is less invasive, has been widely applied for treating various kinds of tumors. However, TA still poses the potential risk of thermal damage to sensitive tissue nearby. Therefore, an adjunctive thermoprotective hydrodissection technique with constant injection of 5% glucose (5% Glu) has currently been adopted for clinical application, but this may be hazardous to humans. In this study, a multifunctional hyaluronic acid-based hydrogel (HA-Dc) was developed for hydrodissection. Compared with 5% Glu (the most clinically used solution) and the previously reported F127 hydrogel, the HA-Dc hydrogel was studied  in a porcine liver model and  in a rabbit model and showed good injectability and better tissue retention, stability, and thermoprotective properties throughout the TA procedure. Furthermore, in the preclinical evaluation in a  model, HA-Dc showed excellent performance in terms of stricter neuroprotection compared with 5% Glu. In addition, the HA-Dc hydrogel with good biocompatibility and controllable degradation behavior  could be a promising platform for thermal protection during clinical TA procedures.

Development and preclinical evaluation of multifunctional hydrogel for precise thermal protection during thermal ablation.

Photodynamic therapy (PDT) has emerged as an efficient approach for non-invasive cancer treatment. However, organic small-molecule photosensitizers are often associated with defects in hydrophobicity, poor photostability, and aggregation-caused quenching, which limit their application. Usually, the carrier-assisted drug delivery system is a common strategy to solve the above obstacles, but additional carrier material could increase the risk of potential biological toxicity. The carrier-free drug delivery system with easy preparation and high drug-loading capability is proposed subsequently as a potential strategy to develop the clinical use of hydrophobic drugs. Herein, we rationally designed three IR780-based carrier-free nanosystems formed by carbon/disulfide/diselenide bond conjugated IR780-based homodimers. The IR780-based homodimers could self-assemble to form nanoparticles (DC-NP, DS-NP, DSe-NP) and exhibited higher reactive oxygen species generation capability and photostability than free IR780, in which DSe-NP with 808 nm laser irradiation performed best and resulted in the strongest cytotoxicity to 4T1 cells. Meanwhile, the glutathione consumption ability of DSe-NP boosted its PDT effect and then induced excessive oxidative stress of 4T1 cells, increasing antitumor efficacy by enhancing immunogenic cell death further. In tumor-bearing mice, DSe-NP displayed obvious tumor site accumulation, which obviously inhibited tumor growth and metastasis, and enhanced the immunological effect by effectively inducing dendritic cells to mature and activating T lymphocytes and natural killer cells. In summary, our study presented an IR780-based carrier-free nanodelivery system for a combination of PDT and immunity therapy and established expanding the application of organic small-molecule photosensitizers by an approach of carrier-free drug delivery system.

Engineering Diselenide-IR780 Homodimeric Nanoassemblies with Enhanced Photodynamic and Immunotherapeutic Effects for Triple-Negative Breast Cancer Treatment.

Sonodynamic therapy (SDT), which involves the activation of sonosensitizers to generate cytotoxic reactive oxygen species under ultrasound irradiation, is a promising noninvasive modality for cancer treatment. However, the clinical translational application of SDT is impeded by the lack of efficient sonosensitizers, the inefficient accumulation of sonosensitizers at tumor sites, and the complicated immunosuppressive tumor microenvironment. Herein, we developed a facilely synthesized multifunctional porous organic polymer nanosonosensitizer (mHM@HMME) for enhanced SDT. Specifically, mHM@HMME nanosonosensitizers were prepared by incorporating chemotherapeutic mitoxantrone into the one-step synthesis process of disulfide bond containing porous organic polymers, followed by loading with organic sonosensitizer (HMME) and camouflaging with a cancer cell membrane. Due to the cancer cell membrane camouflage, this multifunctional mHM@HMME nanosonosensitizer showed prolonged blood circulation and tumor targeting aggregation. Under ultrasound irradiation, the mHM@HMME nanosonosensitizer exhibited a satisfactory SDT performance both in vitro and in vivo. Moreover, the potent SDT combined with glutathione-responsive drug release in tumor cells induced robust immunogenic cell death to enhance the antitumor effect of SDT in turn. Overall, this facilely synthesized multifunctional mHM@HMME nanosonosensitizer shows great potential application in enhanced SDT.

Facile Synthesis of a Multifunctional Porous Organic Polymer Nanosonosensitizer (mHM@HMME) for Enhanced Cancer Sonodynamic Therapy.

Prodrug-based self-assembled nanoparticles (PSNs) with tailored responses to tumor microenvironments show a significant promise for chemodynamic therapy (CDT) by generating highly toxic reactive oxygen species (ROS). However, the insufficient level of intracellular ROS and the limited drug accumulation remain major challenges for further clinical transformation. In this study, the PSNs for the delivery of artesunate (ARS) are demonstrated by designing the pH-responsive ARS-4-hydroxybenzoyl hydrazide (HBZ)-5-amino levulinic acid (ALA) nanoparticles (AHA NPs) with self-supplied ROS for excellent chemotherapy and CDT. The PSNs greatly improved the loading capacity of artesunate and the ROS generation from endoperoxide bridge using the electron withdrawing group attached directly to C10 site of artesunate. The ALA and ARS-HBZ could be released from AHA NPs under the cleavage of hydrazone bonds triggered by the acidic surroundings. Besides, the ALA increased the intracellular level of heme in mitochondria, further promoting the ROS generation and lipid peroxidation with ARS-HBZ for excellent anti-tumor effects. Our study improved the chemotherapy of ARS through the chemical modification, pointing out the potential applications in the clinical fields.

Endoperoxide-enhanced self-assembled ROS producer as intracellular prodrugs for tumor chemotherapy and chemodynamic therapy.

Pressure ulcers are a common issue in elderly and medically compromised individuals, posing significant challenges in healthcare. Human umbilical cord mesenchymal stem cells (HUMSCs) offer therapeutic benefits like inflammation modulation and tissue regeneration, yet challenges in cell survival, retention, and implantation rates limit their clinical application. Hydrogels in three-dimensional (3D) stem cell culture mimic the microenvironment, improving cell survival and therapeutic efficacy. A thermosensitive injectable hydrogel (adEHG) combining gallic acid-modified hydroxybutyl chitosan (HBC-GA) with soluble extracellular matrix (adECM) has been developed to address these challenges. The hybrid hydrogel, with favorable physical and chemical properties, shields stem cells from oxidative stress and boosts their therapeutic potential by clearing ROS. The adEHG hydrogel promotes angiogenesis, cell proliferation, and collagen deposition, further enhancing inflammation modulation and wound healing through the sustained release of therapeutic factors and cells. Additionally, the adEHG@HUMSC composite induces macrophage polarization towards an M2 phenotype, which is crucial for wound inflammation inhibition and successful healing. Our research significantly propels the field of stem cell-based therapies for pressure ulcer treatment and underscores the potential of the adEHG hydrogel as a valuable tool in advancing regenerative medicine.

Revolutionizing pressure ulcer regeneration: Unleashing the potential of extracellular matrix-derived temperature-sensitive injectable antioxidant hydrogel for superior stem cell therapy.

Article	Year
Multifunctional FeS@SRF@BSA nanoplatform for chemo-combined photothermal enhanced photodynamic/chemodynamic combination therapy. Biomaterials science\| PubMed ID: 34850790	2021
A MXene-Based Bionic Cascaded-Enzyme Nanoreactor for Tumor Phototherapy/Enzyme Dynamic Therapy and Hypoxia-Activated Chemotherapy. Nano-micro letters\| PubMed ID: 34882297	2021
Degradable Multifunctional Porphyrin-Based Porous Organic Polymer Nanosonosensitizer for Tumor-Specific Sonodynamic, Chemo- and Immunotherapy. ACS applied materials & interfaces\| PubMed ID: 36281484	2022
Surface programmed bacteria as photo-controlled NO generator for tumor immunological and gas therapy. Journal of controlled release : official journal of the Controlled Release Society\| PubMed ID: 36528194	2023
Fluorinated hydrogel nanoparticles with regulable fluorine contents and relaxation times as F MRI contrast agents. RSC advances\| PubMed ID: 37497094	2023
Multifunctional hybrid exosomes enhanced cancer chemo-immunotherapy by activating the STING pathway. Biomaterials\| PubMed ID: 37531777	2023
Development and preclinical evaluation of multifunctional hydrogel for precise thermal protection during thermal ablation. Bioactive materials\| PubMed ID: 37637083	2024
Engineering Diselenide-IR780 Homodimeric Nanoassemblies with Enhanced Photodynamic and Immunotherapeutic Effects for Triple-Negative Breast Cancer Treatment. ACS nano\| PubMed ID: 37943026	2023
Facile Synthesis of a Multifunctional Porous Organic Polymer Nanosonosensitizer (mHM@HMME) for Enhanced Cancer Sonodynamic Therapy. ACS applied materials & interfaces\| PubMed ID: 38769350	2024
Endoperoxide-enhanced self-assembled ROS producer as intracellular prodrugs for tumor chemotherapy and chemodynamic therapy. Exploration (Beijing, China)\| PubMed ID: 39175885	2024
Revolutionizing pressure ulcer regeneration: Unleashing the potential of extracellular matrix-derived temperature-sensitive injectable antioxidant hydrogel for superior stem cell therapy. Biomaterials\| PubMed ID: 39383777	2024

Junjie Tang

Biography

JoVE Journal Publications

Other Publications