Zwitterionic Injectable Hydrogel-Combined Chemo- and Immunotherapy Medicated by Monomolecular Micelles to Effectively Prevent the Recurrence of Tumor Post Operation.

Surgical resection remains the most common method of tumor treatment; however, the high recurrence and metastasis after surgery need to be solved urgently. Herein, we report an injectable zwitterionic hydrogel based on "thiol-ene" click chemistry containing doxorubicin (DOX) and a macrophage membrane (MM)-coated 1-methyl-tryptophan (1-MT)-loaded polyamide-amine dendrimer (P-DOX/1MT) for preventing the postoperative recurrence of tumors. The results indicated that P-DOX/1MT@MM exhibited enhanced recognition and uptake of the dendrimer by tumor cells and induced the immunogenic cell death. In the mice tumor model, the P-DOX/1MT@MM-Gel exhibited high therapeutic efficiency, which could significantly reduce the recurrence of the tumor, including suppressing tumor growth, promoting dendritic cell maturation, and increasing tumor-infiltrating cytotoxic T lymphocytes. The mechanism analysis revealed that the hydrogel greatly reduces the side effects to normal tissues and significantly improves its therapeutic effect. 1MT in the hydrogel is released more rapidly, improving the tumor suppressor microenvironment and increasing the tumor cell sensitivity to DOX. Then, the DOX in the P-DOX/1MT@MM effectively eliminatedo the residual tumor cells and exerted enhanced toxicity. In conclusion, this novel injectable hydrogel that combines chemotherapy and immunotherapy has the property of sequential drug release and is a promising strategy for preventing the postoperative recurrence of tumors.

Injectable Zwitterionic Physical Hydrogel with Enhanced Chemodynamic Therapy and Tumor Microenvironment Remodeling Properties for Synergistic Anticancer Therapy.

Surgical resection is the first-line therapy for breast cancer. However, residual tumor cells and the highly immunosuppressive tumor microenvironment (TME) continue to have a serious impact on tumor recurrence and metastasis postresection. Implantation of an in situ hydrogel system postresection has shown to be an effective treatment with great clinical potential. Herein, an injectable zwitterionic hydrogel system was developed for local drug delivery with enhanced immune activation and prevention of tumor recurrence. Driven by electrostatic interactions, poly(sulfobetaine methacrylate) (PSBMA) self-assembles into a hydrogel in saline, achieving low protein adsorption and tunable biodegradability. The chemotherapy drug doxorubicin (DOX) was loaded into copper peroxide nanoparticles (CuO2/DOX), which were coated with macrophage membranes to form tumor-targeting nanoparticles (M/CuO2/DOX). Next, M/CuO2/DOX and the stimulator of interferon genes (STING) agonist 2',3'-cGAMP were coloaded into PSBMA hydrogel (Gel@M/CuO2/DOX/STING). The hydrophilic STING agonist was first released by diffusion from hydrogel to activate the STING pathway and upregulate interferon (IFN) signaling related genes, remodeling the immunosuppressive TME. Then, M/CuO2/DOX targeted the residual tumor cells, combining with DOX-induced DNA damage, immunogenic tumor cell death, and copper death. Hence, this work combines chemodynamic therapy with STING pathway activation in TME, encouraging residual tumor cell death, promoting the maturation of dendritic cells, enhancing tumor-specific CD8+ T cell infiltration, and preventing postoperative recurrence and metastasis.

Salt sensitive purely zwitterionic physical hydrogel for prevention of postoperative tissue adhesion.

Abdominal adhesions are a class of serious complications following abdominal surgery, resulting in a complicated and severe syndrome and sometimes leading to a Gordian knot. Traditional therapies employ hydrogels synthesized using complicated chemical formulations-often with click chemistry or thermal responsive hydrogel. The complicated synthesis process and severe conditions limit the extent of the hydrogels' applications. In this work, poly 3-[2-(methacryloyloxy)ethyl](dimethyl)-ammonio]-1-propanesulfonate (PSBMA) polymer was synthesized to self-assemble into physical hydrogels due to the inter- and intramolecular ion interactions. The strong static interaction bonding density has a substantial impact on the gelation and physicochemical properties, which is beneficial to clinical applications and offers a novel way to obtain the desired hydrogel for a specific biomedical application. Intriguingly, this PSBMA polymer can be customized into a transient network with outstanding antifouling capability depending on the ion concentration. As ion concentration increases, the PSBMA hydrogel dissociated completely, endowing it as a candidate for adhesion prevention. In the cecum-sidewall model, the PSBMA hydrogel demonstrated superior anti-adhesion properties than commercial HA hydrogel. Furthermore, we have demonstrated that this PSBMA hydrogel could inhibit the inflammatory response and encourage anti-fibrosis resulting in adhesion prevention. Most surprisingly, the recovered skins of cecum and sidewall are as smooth as the control skin without any scar and damage. In conclusion, a practical hydrogel was synthesized using a facile method based on purely zwitterionic materials, and this ion-sensitive, antifouling adjustable supramolecular hydrogel with great clinic transform potential is a promising barrier for preventing postoperative tissue adhesion. STATEMENT OF SIGNIFICANCE: The development of hydrogels with satisfactory coverage, long retention time, facile synthetic method, and good biocompatibility is vital for preventing peritoneal adhesions. Herein, we developed a salt sensitive purely zwitterionic physical hydrogel poly 3-[2-(methacryloyloxy)ethyl](dimethyl)-ammonio]-1-propanesulfonate (PSBMA) hydrogel to effectively prevent postoperative and recurrent abdominal adhesions. The hydrogel was simple to synthesize and easy to use. In the cecum-sidewall model, PSBMA hydrogel could instantaneously adhere and fix on irregular surfaces and stay in the wound for more than 10 days. The PSBMA hydrogel could inhibit the inflammatory response, encourage anti-fibrosis, and restore smoothness to damaged surfaces resulting in adhesion prevention. Overall, the PSBMA hydrogel is a promising candidate for the next generation of anti-adhesion materials to meet clinical needs.

Chlorin e6-loaded sonosensitive magnetic nanoliposomes conjugated with the magnetic field for enhancing anti-tumor effect of sonodynamic therapy.

In sonodynamic therapy (SDT), when Chlorin e6 (Ce6) accumulates in tumor tissues, its anti-tumor effect can be achieved by ultrasound activation. To increase the local drug concentration of Ce6 in tumor cells, we had established a novel drug delivery system, Ce6-loaded sonosensitive magnetic nanoliposome (Ce6/SML), which realized the targeting delivery by the external magnetic field. It was worth mentioning that the targeting release of Ce6/SML and the activation on Ce6 could be achieved simultaneously by ultrasound of SDT. In our study, after Ce6 was loaded into the sonosensitive magnetic nanoliposome (SML), the values of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) in vitro and in vivo were determined, indicating the activation on Ce6 of ultrasound. The delivery system also displayed the tumor-targeting ability and anti-tumor activity, which associated with the determined tumor growth and expression levels of angiogenin (ANG), vascular endothelial growth factor (VEGF) and tumor necrosis factor-alpha (TNF-α). In conclusion, the Ce6/SML-SDT-Targeted delivery system could effectively enhance the anti-tumor activity of SDT and had a great potential application for the treatment of malignant tumors located in deep tissues.

Atorvastatin and whisker stimulation synergistically enhance angiogenesis in the barrel cortex of rats following focal ischemia.

Physical therapy can promote neurovascular plasticity and functional recovery after CNS disorders such as ischemic stroke. We have previously demonstrated that whisker stimulation promotes angiogenesis in the penumbra of the ischemic barrel cortex. The aim of this study was to examine whether atorvastatin and whisker stimulation can act synergistically in enhancing angiogenesis in the barrel cortex following ischemia. Rats were divided into sham-operation, control, atorvastatin-treatment, whisker stimulation and combination therapy groups. And they were trained continuously for 10 trials per half day until the rat fulfilled 80% correct choices for continuous thirty trials, which were considered to reach the criteria. The number was significantly less in the combination therapy group than that in the whisker stimulation group (P<0.01). Immunofluorescence was used to detect angiogenesis 14 d following focal ischemia. These data showed that the combination therapy was more effective in enhancing VEGF and BDNF expression than whisker stimulation (P<0.01). Our study indicated that atorvastatin can improve the discrimination ability of whisker stimulation in rats and amplify post-ischemic angiogenesis induced by whisker stimulation, potentially via enhanced expression of VEGF and BDNF in the peri-infarct region.

DL-3-n-Butylphthalide protects rat bone marrow stem cells against hydrogen peroxide-induced cell death through antioxidation and activation of PI3K-Akt pathway.

Bone marrow stem cells (BMSCs) have been one of the most important cell sources for cell replacement therapy (CRT) in cerebral infarction. However, long-lasting oxidative stress during stroke, which plays an important role in neuron damage, deteriorates the microenvironment for cell survival, differentiation and removal. Thus the outcome of CRT in ischemic diseases was poor. DL-3-n-Butylphthalide (NBP) has protective effects on ischemic brain tissue through multiple mechanisms and has been used for stroke treatment in China for several years. In this study, hydrogen peroxide (H(2)O(2)) was used to induce oxidative stress injury to rat bone marrow stem cells (rBMSCs), imitating the microenvironment surrounding transplanted cells in the ischemic brain in vitro. The protective effects of NBP on rBMSCs against apoptosis induced by oxidative stress were investigated. Our results indicated that NBP could protect rBMSCs against apoptosis due to antioxidative properties and modulation of PI3K/Akt pathway. NBP could be used in combination with BMSCs for the treatment of cerebral infarction by improving the oxidative stress microenvironments and cell survival, however, further studies remain warranted.