Gastrodin Liposomes Block Crosstalk between Astrocytes and Glioma Cells via Downregulating Cx43 to Improve Antiglioblastoma Efficacy of Temozolomide.

The crosstalk between glioma cells and astrocytes plays a crucial role in developing temozolomide (TMZ) resistance of glioblastomas, together with the existence of the BBB contributing to the unsatisfactory clinical treatment of glioblastomas. Herein, we developed a borneol-modified and gastrodin-loaded liposome (Bo-Gas-LP), with the intent of enhancing the efficacy of TMZ therapy after intranasal administration. The results showed that Bo-Gas-LP improved GL261 cells' sensitivity to TMZ and prolonged survival of GL261-bearing mice by blocking the crosstalk between astrocytes and glioblastoma cells with the decrease of Cx43. Our study showed that intranasal Bo-Gas-LP targeting the crosstalk in glioblastoma microenvironments proposed a promising targeted therapy idea to overcome the current therapeutic limitations of TMZ-resistant glioblastomas.

Biomimetic "nano-spears" for CAFs-targeting: splintered three "shields" with enhanced cisplatin anti-TNBC efficiency.

The treatment dilemma of triple-negative breast cancer (TNBC) revolves around drug resistance and metastasis. Cancer-associated fibroblasts (CAFs) contribute to cisplatin (Cis) resistance and further metastasis in TNBC, making TNBC a difficult-to-treat disease. The dense stromal barrier which restricts drug delivery, invasive phenotype of tumor cells, and immunosuppressive tumor microenvironment (TME) induced by CAFs serve as three "shields" for TNBC against Cis therapy. Here, we designed a silybin-loaded biomimetic nanoparticle coated with anisamide-modified red blood cell membrane (ARm@SNP) as a "nanospear" for CAFs-targeting, which could shatter the "shields" and significantly exhibit inhibitory effect on 4T1 cells in combination with Cis both in vitro and in vivo. The ARm@SNP/Cis elicited 4T1 tumor growth arrest and destroyed three "shields" as follows: disintegrating the stromal barrier by inhibiting blood vessels growth and the expression of fibronectin; decreasing 4T1 cell invasion and metastasis by affecting the TGF-ß/Twist/EMT pathway which impeded EMT activation; reversing the immunosuppressive microenvironment by increasing the activity and infiltration of immunocompetent cells. Based on CAFs-targeting, ARm@SNP reversed the resistance of Cis, remodeled the TME and inhibited invasion and metastasis while significantly improving the therapeutic effect of Cis on 4T1 tumor-bearing mice, providing a promising approach for treating intractable TNBC.

Enhancing Tai Chi Training System: Towards Group-Based and Hyper-Realistic Training Experiences.

In this article, we propose a lightweight and flexible enhanced Tai Chi training system composed of multiple standalone virtual reality (VR) devices. The system aims to enable a hyper-realistic multi-user action training platform at low cost by displaying real-time action guidance trajectories, providing real-world impossible visual effects and functions, and rapidly enhancing movement precision and communication interest for learners. We objectively evaluate participants' action quality at different levels of immersion, including traditional coach guidance (TCG), VR, and mixed reality (MR), along with subjective measures like motion sickness, quality of interaction, social meaning, presence/immersion to comprehensively explore the system's feasibility. The results indicate VR performs the best in training accuracy, but MR provides superior social experience and relatively high accuracy. Unlike TCG, MR offers hyper-realistic hand movement trajectories and Tai Chi social references. Compared with VR, MR provides more realistic avatar companions and a safer environment. In summary, MR balances accuracy and social experience.

Nanomedicines for reversing immunosuppressive microenvironment of hepatocellular carcinoma.

Although immunotherapeutic strategies such as immune checkpoint inhibitors (ICIs) have gained promising advances, their limited efficacy and significant toxicity remain great challenges for hepatocellular carcinoma (HCC) immunotherapy. The tumor immunosuppressive microenvironment (TIME) with insufficient T-cell infiltration and low immunogenicity accounts for most HCC patients' poor response to ICIs. Worse still, the current immunotherapeutics without precise delivery may elicit enormous autoimmune side effects and systemic toxicity in the clinic. With a better understanding of the TIME in HCC, nanomedicines have emerged as an efficient strategy to achieve remodeling of the TIME and superadditive antitumor effects via targeted delivery of immunotherapeutics or multimodal synergistic therapy. Based on the typical characteristics of the TIME in HCC, this review summarizes the recent advancements in nanomedicine-based strategies for TIME-reversing HCC treatment. Additionally, perspectives on the awaiting challenges and opportunities of nanomedicines in modulating the TIME of HCC are presented. Acquisition of knowledge of nanomedicine-mediated TIME reversal will provide researchers with a better opportunity for clinical translation of HCC immunotherapy.

Nose to brain delivery of Astragaloside IV by ß-Asarone modified chitosan nanoparticles for multiple sclerosis therapy.

Multiple sclerosis (MS), an autoimmune disease, has been considered an inflammatory disorder of the central nervous system (CNS) with demyelination and axonal damage. Although there are certain first-line therapies to treat MS, their unsatisfactory efficacy is partly due to the limited CNS access after systemic administration. Besides, there is an urgent need to treat MS by enhancing remyelination or neuroprotection, or dampen the activity of microglia. Astragaloside IV (ASI) bears anti-inflammatory, antioxidant, remyelination and neuroprotective activity. While its poor permeability, relatively high molecular weight and low lipophilicity restrict it to reach the brain. Therefore, ß-asarone modified ASI loaded chitosan nanoparticles (ASI-ßCS-NP) were prepared to enhance the nose-to-brain delivery and therapeutic effects of ASI on EAE mice. The prepared ASI-ßCS-NP showed mean size of about 120 nm, and zeta potential from +19 to +25 mV. DiR-ßCS-NP was confirmed with good nose-to-brain targeting ability. After intranasal administration, the ASI-ßCS-NP significantly reduced behavioral scores, decreased weight loss, suppressed inflammatory infiltration and astrocyte/microglial activation, reduced demyelination and increased remyelination on a mice EAE model. Our findings indicate that ASI-ßCS-NP may be a potent treatment for MS after nose-to-brain drug delivery.

Intranasal delivery of Borneol/R8dGR peptide modified PLGA nanoparticles co-loaded with curcumin and cisplatin alleviate hypoxia in pediatric brainstem glioma which improves the synergistic therapy.

Cisplatin (cis) is a first-line chemotherapeutic used for the treatment of intractable pediatric brainstem glioma (PBSG). Its therapeutic effect in PBSG is, however, critically challenged by the hypoxic microenvironment of the tumor and the presence of the blood brain barrier (BBB). Herein, we report on the intranasal administration of borneol (Bo)/R8dGR peptide modified PLGA based nanoparticles (NP) co-loaded with curcumin and cisplatin (cur/cis). We observed that borneol modification improved the brain penetration of the nanoparticles by reduction of the expression of ZO-1 and occludin in nasal mucosa, while the R8dGR peptide modification allowed the targeting of the NP through the binding on integrin αvß3 receptors which are present on PBSG cells. Following intranasal administration, BoR-cur/cis-NP attenuated hypoxia in the PBSG microenvironment and reduced angiogenesis, which prolonged survival of GL261-bearing PBSG mice. Therefore, intranasal administration of BoR-cur/cis-NP, which deeply penetrate PBSG, is an encouraging strategy to attenuate hypoxia which potentiates the efficacy of cisplatin in the treatment of PBSG.

Experimental murine models of brainstem gliomas.

As an intractable central nervous system (CNS) tumor, brainstem glioma (BG) is one of the leading causes of pediatric death by brain tumors. Owing to the risk of surgical resection and the little improvement in survival time after radiotherapy and chemotherapy, there is an urgent need to find reliable model systems to better understand the regional pathogenesis of the brainstem and improve treatment strategies. In this review, we outline the evolution of BG murine models, and discuss both their advantages and limitations in drug discovery.

Improved Anti-Triple Negative Breast Cancer Effects of Docetaxel by RGD-Modified Lipid-Core Micelles.

PURPOSE: A novel RGD-modified PEGylated lipid-core micelle delivery system was designed to improve the anti-cancer effect of docetaxel on triple negative breast cancer (TNBC). METHODS: The tumor-targeted lipid-core micelles loaded with docetaxel were prepared and characterized. Their morphology, particle size, zeta potential, entrapment efficiency, release profiles, and targeting effects were studied. The antitumor effects of the docetaxel-loaded nano-micelles were investigated in a MDA-MB-231 cell model in vitro and a MDA-MB-231 xenograft model in vivo. RESULTS: The prepared RGD-modified docetaxel-loaded lipid-core micelles were spherical with a particle size of 16.44±1.35 nm, zeta potential of -19.24±1.24 mV, and an encapsulation efficiency of 96.52±0.43%. The drug delivery system showed sustained release properties and could significantly enhance docetaxel uptake by MDA-MB-231 tumor cells in vitro, which was proved to be a caveolae pathway mediated process requiring ATP, Golgi apparatus, and acid lysosomes. The results of the pharmacokinetic study displayed that the area under the curve of the targeted micelles was 3.2-times higher than that of docetaxel commercial injections. Furthermore, in a MDA-MB-231 tumor-bearing mice model, a higher antitumor efficacy than docetaxel commercial injections was displayed, and the safety experiments showed that the micellar material did not cause major organ damage after intravenous administration in mice. CONCLUSION: The novel RGD-modified PEGylated lipid-core micelle delivery system significantly improved the antitumor effects and reduced the side-effects of docetaxel, providing a promising therapeutics for the treatment of TNBC.