The Combination of Sinusoidal Perfusion Enhancement and Apoptosis Inhibition by Riociguat Plus a Galactose-PEGylated Bilirubin Multiplexing Nanomedicine Ameliorates Liver Fibrosis Progression.

Chronic liver injury and continuous wound healing lead to extracellular matrix (ECM) deposition and liver fibrosis. The elevated production of reactive oxygen species (ROS) in the liver leads to the apoptosis of hepatocytes and the activation of hepatic stellate cells (HSCs). In the current study, we describe a combination strategy of sinusoidal perfusion enhancement and apoptosis inhibition enabled by riociguat together with a tailor-designed galactose-PEGylated bilirubin nanomedicine (Sel@GBRNPs). Riociguat enhanced sinusoidal perfusion and decreased the associated ROS accumulation and inflammatory state of the fibrotic liver. Concurrently, hepatocyte-targeting galactose-PEGylated bilirubin scavenged excessive ROS and released encapsulated selonsertib. The released selonsertib inhibited apoptosis signal-regulating kinase 1 (ASK1) phosphorylation to alleviate apoptosis in hepatocytes. The combined effects on ROS and hepatocyte apoptosis attenuated the stimulation of HSC activation and ECM deposition in a mouse model of liver fibrosis. This work provides a novel strategy for liver fibrosis treatment based on sinusoidal perfusion enhancement and apoptosis inhibition.

Platelet-Membrane-Coated Nanoparticles Enable Vascular Disrupting Agent Combining Anti-Angiogenic Drug for Improved Tumor Vessel Impairment.

Compared with traditional chemotherapeutics, vascular disruption agents (VDAs) have the advantages of rapidly blocking the supply of nutrients and starving tumors to death. Although the VDAs are effective under certain scenarios, this treatment triggers angiogenesis in the later stage of therapy that frequently leads to tumor recurrence and treatment failure. Additionally, the nonspecific tumor targeting and considerable side effects also impede the clinical applications of VDAs. Here we develop a customized strategy that combines a VDA with an anti-angiogenic drug (AAD) using mesoporous silica nanoparticles (MSNs) coated with platelet membrane for the self-assembled tumor targeting accumulation. The tailor-made nanoparticles accumulate in tumor tissues through the targeted adhesion of platelet membrane surface to damaged vessel sites, resulting in significant vascular disruption and efficient anti-angiogenesis in animal models. This study demonstrates the promising potential of combining VDA and AAD in a single nanoplatform for tumor eradication.

Reversal of the immunosuppressive tumor microenvironment by nanoparticle-based activation of immune-associated cells.

Immunotherapy that activates the host immune system to reverse immunosuppression has emerged as a new generation of cancer treatment in both preclinical studies and clinical trials. Although immunotherapy has shown significant achievements in the treatment of various cancers, it faces challenges that limit its further evolution such as poor permeation and modest responsiveness. The development of nanoparticle drug delivery system has provided an opportunity to overcome these drawbacks and to achieve optimized immunotherapy. Based on the research of our group, we here introduce the new strategies being employed using nanoscale intelligent drug delivery systems to enhance the effects of cancer immunotherapy. We also provide a perspective on the further possible application of nanoparticles in more effective antitumor immunotherapy.

The dynamic role of platelets in cancer progression and their therapeutic implications.

Systemic antiplatelet treatment represents a promising option to improve the therapeutic outcomes and therapeutic efficacy of chemotherapy and immunotherapy due to the critical contribution of platelets to tumour progression. However, until recently, targeting platelets as a cancer therapeutic has been hampered by the elevated risk of haemorrhagic and thrombocytopenic (low platelet count) complications owing to the lack of specificity for tumour-associated platelets. Recent work has advanced our understanding of the molecular mechanisms responsible for the contribution of platelets to tumour progression and metastasis. This has led to the identification of the biological changes in platelets in the presence of tumours, the complex interactions between platelets and tumour cells during tumour progression, and the effects of platelets on antitumour therapeutic response. In this Review, we present a detailed picture of the dynamic roles of platelets in tumour development and progression as well as their use in diagnosis, prognosis and monitoring response to therapy. We also provide our view on how to overcome challenges faced by the development of precise antiplatelet strategies for safe and efficient clinical cancer therapy.

Monitoring circulating platelet activity to predict cancer-associated thrombosis.

A characteristic clinical complication in cancer patients is the frequent incidence of thrombotic events. Numerous studies have shown hyperactive/activated platelets to be a critical earlier trigger for cancer-associated thrombus formation. However, there currently is no viable approach to monitor specific changes in tumor-associated platelet activity. Here, we describe a chromatograph-like microfluidic device that is highly sensitive to the activity status of peripheral circulating platelets in both tumor-bearing mice and clinical cancer patients. Our results show a strongly positive correlation between platelet activation status and tumor progression. Six-month follow-up data from advanced cancer patients reveal positive links between platelet activity level and thrombus occurrence rate, with a high predictive capacity of thrombotic events (AUC = 0.842). Our findings suggest that circulating platelet activity status determined by this microfluidic device exhibits sensitive, predictive potential for thrombotic events in cancer patients for directing well-timed antithrombosis treatment.

Nanoparticle-Based Combination Therapy Enhances Fulvestrant Efficacy and Overcomes Tumor Resistance in ER-Positive Breast Cancer.

Nanoparticles (NP) spanning diverse materials and properties have the potential to encapsulate and to protect a wide range of therapeutic cargos to increase bioavailability, to prevent undesired degradation, and to mitigate toxicity. Fulvestrant, a selective estrogen receptor degrader, is commonly used for treating patients with estrogen receptor (ER)-positive breast cancer, but its broad and continual application is limited by poor solubility, invasive muscle administration, and drug resistance. Here, we developed an active targeting motif-modified, intravenously injectable, hydrophilic NP that encapsulates fulvestrant to facilitate its delivery via the bloodstream to tumors, improving bioavailability and systemic tolerability. In addition, the NP was coloaded with abemaciclib, an inhibitor of cyclin-dependent kinases 4 and 6 (CDK4/6), to prevent the development of drug resistance associated with long-term fulvestrant treatment. Targeting peptide modifications on the NP surface assisted in the site-specific release of the drugs to ensure specific toxicity in the tumor tissues and to spare normal tissue. The NP formulation (PPFA-cRGD) exhibited efficient tumor cell killing in both in vitro organoid models and in vivo orthotopic ER-positive breast cancer models without apparent adverse effects, as verified in mouse and Bama miniature pig models. This NP-based therapeutic provides an opportunity for continual and extensive clinical application of fulvestrant, thus indicating its promise as a treatment option for patients with ER-positive breast cancer. SIGNIFICANCE: A smart nanomedicine encapsulating fulvestrant to improve its half-life, bioavailability, and tumor-targeting and coloaded with CDK4/6 inhibitor abemaciclib to block resistance is a safe and effective therapy for ER-positive breast cancer.

Reducing Postoperative Recurrence of Early-Stage Hepatocellular Carcinoma by a Wound-Targeted Nanodrug.

New strategies to decrease risk of relapse after surgery are needed for improving 5-year survival rate of hepatocellular carcinoma (HCC). To address this need, a wound-targeted nanodrug is developed, that contains an immune checkpoint inhibitor (anti-PD-L1)and an angiogenesis inhibitor (sorafenib)). These nanoparticles consist of highly biocompatible mesoporous silica (MSNP) that is surface-coated with platelet membrane (PM) to achieve surgical site targeting in a self-amplified accumulation manner. Sorafenib is introduced into the MSNP pores while covalently attaching anti-PD-L1 antibody on the PM surface. The resulting nano-formulation, abbreviated as a-PM-S-MSNP, can effectively target the surgical margin when intraperitoneally (IP) administered into an immune competent murine orthotopic HCC model. Multiple administrations of a-PM-S-MSNP generate potent anti-HCC effect and significantly prolong overall mice survival. Immunophenotyping and immunochemistry staining reveal the signatures of favorable anti-HCC immunity and anti-angiogenesis effect at tumor sites. More importantly, microscopic inspection of a-PM-S-MSNP treated mice shows that 2 out 6 are histologically tumor-free, which is in sharp contrast to the control mice where tumor foci can be easily identified. The data suggest that a-PM-S-MSNP can efficiently inhibit post-surgical HCC relapse without obvious side effects and holds considerable promise for clinical translation as a novel nanodrug.

An Activatable Host-Guest Conjugate as a Nanocarrier for Effective Drug Release through Self-Inclusion.

There is a challenge in supramolecular chemotherapy for constructing a system equipped with both sufficient protection and high-efficiency release of drugs. To this end, a new strategy of an activatable host-guest conjugate with self-inclusion property is proposed. Based on the binding affinity gain of intramolecular host-guest self-inclusion, an activatable host-guest conjugate was designed, bearing cucurbit[7]uril as the host, an alkyl ammonium moiety as the guest, and the redox-responsive disulfide linkage. Oxaliplatin, a clinical antitumor drug, could be firmly encapsulated by the activatable host-guest conjugate to form the supramolecular drug with high stability. Moreover, oxaliplatin loaded in the activatable host-guest conjugate could be almost completely released by self-inclusion triggered by glutathione in a tumor microenvironment, thus exhibiting comparable antitumor bioactivity with naked oxaliplatin through in vitro cell experiments. It is highly anticipated that this line of research may open new horizons for programmable and on-demand supramolecular chemotherapy with high antitumor efficiency.

Molecularly engineered truncated tissue factor with therapeutic aptamers for tumor-targeted delivery and vascular infarction.

Selective occlusion of tumor vasculature has proven to be an effective strategy for cancer therapy. Among vascular coagulation agents, the extracellular domain of coagulation-inducing protein tissue factor, truncated tissue factor (tTF), is the most widely used. Since the truncated protein exhibits no coagulation activity and is rapidly cleared in the circulation, free tTF cannot be used for cancer treatment on its own but must be combined with other moieties. We here developed a novel, tumor-specific tTF delivery system through coupling tTF with the DNA aptamer, AS1411, which selectively binds to nucleolin receptors overexpressing on the surface of tumor vascular endothelial cells and is specifically cytotoxic to target cells. Systemic administration of the tTF-AS1411 conjugates into tumor-bearing animals induced intravascular thrombosis solely in tumors, thus reducing tumor blood supply and inducing tumor necrosis without apparent side effects. This conjugate represents a uniquely attractive candidate for the clinical translation of vessel occlusion agent for cancer therapy.

Colonic electrical stimulation promotes colonic motility through regeneration of myenteric plexus neurons in slow transit constipation beagles.

Slow transit constipation (STC) is a common disease characterized by markedly delayed colonic transit time as a result of colonic motility dysfunction. It is well established that STC is mostly caused by disorders of relevant nerves, especially the enteric nervous system (ENS). Colonic electrical stimulation (CES) has been regarded as a valuable alternative for the treatment of STC. However, little report focuses on the underlying nervous mechanism to normalize the delayed colonic emptying and relieve symptoms. In the present study, the therapeutic effect and the influence on ENS triggered by CES were investigated in STC beagles. The STC beagle model was established by oral administration of diphenoxylate/atropine and alosetron. Histopathology, electron microscopy, immunohistochemistry, Western blot analysis and immunofluorescence were used to evaluate the influence of pulse train CES on myenteric plexus neurons. After 5 weeks of treatment, CES could enhance the colonic electromyogram (EMG) signal to promote colonic motility, thereby improving the colonic content emptying of STC beagles. HE staining and transmission electron microscopy confirmed that CES could regenerate ganglia and synaptic vesicles in the myenteric plexus. Immunohistochemical staining showed that synaptophysin (SYP), protein gene product 9.5 (PGP9.5), cathepsin D (CAD) and S-100B in the colonic intramuscular layer were up-regulated by CES. Western blot analysis and immunofluorescence further proved that CES induced the protein expression of SYP and PGP9.5. Taken together, pulse train CES could induce the regeneration of myenteric plexus neurons, thereby promoting the colonic motility in STC beagles.

S-ethyl ethanethiosulfinate, a derivative of allicin, induces metacaspase-dependent apoptosis through ROS generation in Penicillium chrysogenum.

Allicin can be used as fumigant to protect food and cultural relics from fungal contamination because of its strong antifungal activity and the characteristics of high volatility and no residues. However, the obvious disadvantages such as high minimal inhibitory concentration and instability prevent it from wide application. In this study, a stable derivative of allicin, S-ethyl ethanethiosulfinate (ALE), was synthesized. We further explored its antifungal activity and apoptosis-inducing effect, as well as the underlying mechanism. ALE had an excellent capability of inhibiting spore germination and mycelial growth of Penicillium chrysogenum observed by inverted microscope and scanning electron microscopy. XTT colorimetric assay indicated ALE could reduce the cell viability obviously and IC50 was 0.92 µg/ml, only 1/42 of allicin (38.68 µg/ml). DHR 123 ROS Assay Kit, flow cytometry assay and confocal immunofluorescence revealed intercellular ROS generation and metacaspase-dependent apoptosis triggered by ALE, while antioxidant tocopherol could reverse ALE-induced cytotoxicity effect and metacaspase activation. These results indicate that ALE induces metacaspase-dependent apoptosis through ROS generation, thus possesses an effective antifungal activity. This new derivative of allicin might be developed as a high efficient alternative to the conventional fungicides for food storage and cultural relic protection.

Diosgenin promotes antitumor immunity and PD-1 antibody efficacy against melanoma by regulating intestinal microbiota.

Diosgenin, a natural steroidal saponin, can exert antitumor effect by regulating immune function and improving intestinal microbiota. The response to anti-PD-1 immunotherapy is associated with intestinal microbiota and effector T cells in tumor microenvironment. We hypothesize that the modulation of diosgenin on intestinal microbiota can facilitate antitumor immunity and the therapeutic efficacy of PD-1 antibody. In melanoma-bearing C57BL/6 mice, we observed that the anti-melanoma effect of diosgenin relied more on antitumor immunity than direct tumor inhibition activity evidenced by obvious CD4+/CD8+ T-cell infiltration and IFN-γ expression in tumor tissues, and it could improve the compositions of intestinal microbiota. Antibiotics impaired the therapeutic efficacy and immunity responses of diosgenin through disturbing intestinal microbiota, indicating the importance of intestinal microbiota in diosgenin's in vivo antitumor activity. More importantly, the combined administration of PD-1 antibody with diosgenin aggravated the tumor necrosis and apoptosis by eliciting augmented T-cell responses. Taken together, diosgenin can be used as a microecological regulator to induce antitumor immunity and improve the efficacy of immune checkpoint antibody, making it more suitable for the treatment of malignant tumors.