Search

Polysialic acid (PSA) is a straight-chain homoglycan linked by N-acetylneuraminic acid monomers via α-2, 8- or α-2, 9-glycosidic bonds. As a negatively charged non-glycosaminoglycan, PSA has the remarkable characteristics of non-immunogenicity and biodegradation. Although different in class, PSA is similar to poly(ethylene glycol), and was originally used to increase the stability of the delivery system in circulation to prolong the half-life. As research continues, PSA's application potential in the pharmaceutical field becomes increasingly prominent. It can be used as a biomaterial for protein polysialylation and tissue engineering, and it can be used alone or with other materials to develop multifunctional drug delivery systems. In this article, the results of the bioproduction and biofunction of PSA are introduced, the common strategies for chemical modification of PSA are summarized, and the application progress of PSA-based drug delivery systems is reviewed.

Pancreatitis is an inflammatory reaction of pancreatic tissue digestion, edema, bleeding and even necrosis caused by activation of pancreatin due to various causes. In particular, patients with severe acute pancreatitis (SAP) often suffer from secondary infection, peritonitis and shock, and have a high mortality rate. Chronic pancreatitis (CP) can cause permanent damage to the pancreas. Due to the innate characteristics, structure and location of the pancreas, there is no effective treatment, only relief of symptoms. Especially, AP is an unpredictable and potentially fatal disease, and the timely diagnosis and treatment remains a major challenge. With the rapid development of nanomedicine technology, many potential tools can be used to address this problem. In this review, we have introduced the pathophysiological processes of pancreatitis to understanding its etiology and severity. Most importantly, the current progress in the diagnosis and treatment tools of pancreatitis based on nanomedicine is summarized and prospected.

In this paper we investigate a semi-linear degenerate elliptic equation Δ L u + h ( ξ ) u p + g ( ξ ) u q = 0 related to the generalized Baouendi-Grushin vector fields, where p and q satisfy certain conditions. The idea is to extend the Obata method applying elliptic equations to the degenerate elliptic equation. In consideration of noncommutative relations of the generalized Baouendi-Grushin vector fields, an identity corresponding to the degenerate elliptic equation is established. By using a special truncated function, the identity deformation and accurate estimates, we derive Liouville theorems which show that all nonnegative solutions to the equation are trivial.

Aromatized thioketal (ATK) linked the immunoregulatory molecule (budesonide, Bud) and the cytotoxic molecule (gemcitabine, Gem) to construct a ROS-activated Janus-prodrug, termed as BAG. Benefiting from the hydrogen bonding, π-π stacking, and other intermolecular interactions, BAG could self-assemble into nanoaggregates (BAG NA) with a well-defined spherical shape and uniform size distribution. Compared to the carrier-based drug delivery system, BAG NA have ultrahigh drug loading content and ROS concentration-dependent drug release. Colitis-associated colorectal cancer (CAC) is a typical disease in which chronic inflammation transforms into tumors. BAG NA can be internalized by colon cancer C26 cells and then triggered by excessive intracellular ROS to release nearly 100% of the drugs. Based on this, BAG NA showed a stronger pro-apoptotic effect than free Bud combined with free Gem. What is gratifying is that orally administered BAG NA can precisely accumulate in the diseased colon tissues of CAC mice induced by AOM/DSS and simultaneously release Bud and Gem. Bud can regulate the tumor immune microenvironment to restore and enhance the cytotoxicity of Gem. Therefore, BAG NA maximizes the synergistic therapeutic effect through co-delivery of Bud and Gem. This work provided a cutting-edge method for constructing self-delivery Janus-prodrug based on ATK and confirmed its potential application in inflammation-related carcinogenesis.

B-cell lymphoma is one of the most common types of lymphoma, and chemotherapy is still the current first-line treatment. However, due to the systemic side effects caused by chemotherapy drugs, traditional regimens have limitations and are difficult to achieve ideal efficacy. Recent studies have found that CD22 (also known as Siglec-2), as a specific marker of B-cells, is significantly up-regulated on B-cell lymphomas. Inspired by the specific recognition and binding of sialic acid residues by CD22, a polysialic acid (PSA)-modified PLGA nanocarrier (SAPC NP) designed to target B-cell lymphoma was fabricated. Mitoxantrone (MTO) was further loaded into SAPC NP through hydrophobic interactions to obtain polysialylated immunogenic cell death (ICD) nanoinducer (MTO@SAPC NP). Cellular experiments confirmed that MTO@SAPC NP could be specifically taken up by two types of CD22

Due to its complexity, diversity and heterogeneity, melanoma is a kind of malignant tumor. It has been proved that the enhancement of anti-tumor immune response such as immunogenic cell death (ICD) is an important therapeutic strategy. In previous studies, we confirmed that dermatan sulfate (DS) from skin tissue could specifically homing to melanoma B16F10 cells. In this study, we propose a nanoinducer (DOX/ADS NP) based on a functional DS for melanoma. This nanosystem is composed of DS as framework, aromatic thioketal derivative (ATK) as functional grafting unit and doxorubicin (DOX) designed as an ICD inducer. Through the intermolecular interaction between DOX and ATK, DOX/ADS NP with specific-homing, high-loading and ROS-triggering release was obtained via self-assemble. Compared with free DOX and non-functionalized nanomedicine, DOX/ADS NP could release DOX into B16F10 cells better, and strongly induce the translocation of calreticulin (CRT) to the cell membrane. CRT is a marker of ICD, also as a "eat me" signal to stimulate the maturation and antigen presentation of dendritic cells. Therefore, a series of subsequent immune responses were activated: maturation of dendritic cells, T cells proliferation, increased tumor-infiltrating CTLs and the ratio of CTLs to Tregs, and up-regulated cytotoxic cytokine expression. In conclusion, DOX/ADS NP promoted ICD-associated immune response through more specific targeting effect and sensitive responsive DOX release, achieving better inhibitory effect on melanoma than free DOX and other nanoformulation. This biomimetic ICD nanoinducer based on DS is expected to provide new strategies and references for the treatment of melanoma.

Numerous cutting-edge studies have confirmed that the slow accumulation of cell cycle arrested and secretory cells, called senescent cells (SCs), in tissues is an important negative factor, or even the culprit, in age- associated diseases such as non-alcoholic fatty liver, Alzheimer's disease, type 2 diabetes, atherosclerosis, and malignant tumors. With further understanding of cellular senescence, SCs are important effective targets for the treatment of senescence-related diseases, called the Senotherapy. However, existing therapies, including Senolytics (which lyse SCs) and Senostatic (which regulate senescence-associated secretory phenotype), do not have the properties to target SCs, and side effects due to non-specific distribution are one of the hindrances to clinical use of Senotherapy. In the past few decades, targeted delivery has attracted much attention and been developed as a recognized diagnostic and therapeutic novel tool, due to the advantages of visualization of targets, more accurate drug/gene delivery, and ultimately "reduced toxicity and enhanced efficacy". Despite considerable advances in achieving targeted delivery, it has not yet been widely used in Senotherapy. In this review, we clarify the challenge for Senotherapy, then discuss how different targeted strategies contribute to imaging or therapy for SCs in terms of different biomarkers of SCs. Finally, the emerging nano-Senotherapy is prospected.

A self-assembled and oxidation-degradable Janus-prodrug, termed as Bud-ATK-Tem (B-ATK-T), was fabricated by ROS-responsive aromatized thioketal (ATK) linked anti-inflammatory drug budesonide (Bud) and antioxidant tempol (Tem). Benefiting from the hydrophobic interactions and π-π stacking interactions of ATK, prodrug B-ATK-T could self-assemble into nanoparticles (NP) in water containing lecithin and DSPE-PEG2K. The morphology of B-ATK-T NP (approximate 100-120nm) was confirmed to be regular spherical by transmission electron microscope. B-ATK-T NP was endowed high drug loading content with 41.23% for Bud and 15.55% for Tem. The rapid drug release from B-ATK-T NP proceeded in an extensive reactive oxygen species (ROS)-dependent manner. More than 98% of Bud and Tem in B-ATK-T NP could release in the mimic inflammation microenvironment or phorbol-12-myristate-13-acetate (PMA)-stimulated macrophages within short time. The release of drugs in a simultaneous and proportional manner ensures that B-ATK-T NP can increase the combined efficacy of anti-inflammation and anti-oxidation. It is worth noting that B-ATK-T NP could be passively accumulated and dramatically increasing the maximum drugs concentration in the inflamed colon of mice with inflammatory bowel disease (IBD) by oral route, and avoiding potential systemic side effects. B-ATK-T NP could not only relieve colitis via inhibiting the expression of oxidative and proinflammatory mediators more than combination of free drugs, but also significantly reduce colitis-caused death. Taken together, the self-assembled, Janus-prodrug B-ATK-T NP is a promising candidate therapies for IBD, even for other inflammatory diseases.

Drug-induced hepatitis (DIH), which seriously interferes with disease treatment, is one of the most common reasons for termination of new drugs during preclinical studies or post-marketing surveillance. Although antioxidants and anti-inflammatory agents are promising, their nonspecific distribution and insolubility limit their application. Therefore, precise drug release at the disease site is an important way to alleviate DIH and avoid side effects. Methods: A gripper-like hydrophilic cyclic phenylboronic acid (cPBA) was synthesized and a nanoprodrug (cPBA-BE) was established by coupling cPBA with hydrophobic baicalein (BE). The stimuli-responsive release properties and therapeutic effect of cPBA-BE on drug-injured hepatocyte were investigated. The biodistribution and therapeutic effect of cPBA-BE both in acetaminophen-induced acute hepatitis model and rifampicin-induced chronic hepatitis model were further evaluated. Results: cPBA-BE conjugate could self-assemble into nanoprodrug with cPBA as the hydrophilic external layer and BE as the hydrophobic core. In HepaRG cells, cPBA-BE showed stronger cellular uptake. Due to the H2O2- and acid-sensitivity, cPBA-BE could achieve adequate BE release, significantly resist the depletion of GSH, mitochondrial dysfunction, downregulation of inflammation and cell apoptosis in the acetaminophen injured HepaRG cells. Biodistribution showed that cPBA-BE specifically increased the concentration of BE in the liver of DIH mice. cPBA-BE could alleviate acetaminophen-induced acute hepatitis or rifampicin-induced chronic hepatitis more effectively through relieving the oxidative stress, inflammation and block the neutrophil infiltration in liver. Conclusions: cPBA is expected to be a good platform for constructing injectable nanoprodrug with both H2O2 and pH-responsive properties by coupling a wide range of drugs containing o-diol. In this study, the nanoprodrug cPBA-BE was determined to be effective for alleviating the DIH.

Inflammatory bowel disease (IBD), including Crohn's disease and ulcerative colitis, is characterized by a complex and dysfunctional immune response. Currently, IBD is incurable, and patients with IBD often need to take drugs for life. However, as the traditional systemic treatment strategies for IBD do not target the site of inflammation, only limited efficacy can be obtained from them. Moreover, the possibility of serious side effects stemming from the systemic administration or redistribution of drugs in the body is high when conventional drug formulations are used. Therefore, a targeted drug-delivery system for IBD should be considered. Based on the pathological features related to IBD, the new targeted drug-delivery strategy can directly transfer the drug to the inflammatory site, thus enhancing the accumulation of the drugs and reducing side effects. This article reviews the pathological features of IBD and the application of the IBD-targeted delivery system based on different pathological features, and discusses the challenges and new prospects in this field.

Although plant diseases generally cause more severe symptoms under conditions of high temperature and high humidity(HTHH), how plant respond to pathogen attack under this condition remains elusive.As an example, we herein comparatively studied pepper(Capsicum annuum) immunity against Ralstonia solanacearum under HTHH and ambient temperature by approaches of reverse genetics. We found that pepper respond to R.solanacearum infection by activating salicylic-acid- and jasmonic-acid-mediated immunity at ambient temperature. Under HTHH, However, it no longer activates JA-mediated immunity and activates only transient SA signaling at the early stage of R.solanacearum infection, but instead induces cytokinin mediated immunity.These two immune systems are positively regulated by CaWRKY40 via binding the WT-box and a novel W-box like (WL) box, respectively, in an environment-dependent manner: CaWRKY40 is activated upon R. solanacearum infection under HTHH, thereby upregulating ISOPENTENYLTRANSFERASE5(IPT5). The resulting cytokinin then works synergistically with CaWRKY40 in activating a subset of glutathione S-transferase genes via chromatin activation and WL-box binding, but prevent CaWRKY40 from activating ISOCHORISMATE SYNTHASE1 (ICS1) or SA-/JA-dependent pathogenesis-related genes by chromatin inactivation or by blocking WT-box binding.These results highlight the specific pepper immune response to R. solanacearum infection under HTHH and its synergistic activation by CaWRKY40 and cytokinins.

A novel exopolysaccharide (EPS) with high molecular weight (3.65 × 105 Da) and film-forming ability was produced by the strain Kosakonia sp. CCTCC M2018092. Partially acid hydrolyzed EPS (AH-EPS) with high content of fucose was prepared and exhaustively characterized. The molecular weight of AH-EPS was determined to be 3.47 × 104 Da. GC–MS and HPLC analyses indicated that AH-EPS is composed of L-fucose, d -glucose, D-galactose, D-glucuronic acid and pyruvic acid in the molar ratio of 2.03:1.00:1.18:0.64:0.67. Chemical and NMR analyses revealed that AH-EPS is an anionic heteropolysaccharide, with a major linkage structural motif as follows. Utilizing AH-EPS as reducing and stabilizing agent, silver nanoparticles (AH-EPS@Ag NPs) with uniform size (diameter about 20 nm) were synthesized through a green method. A hybrid film containing EPS and AH-EPS@Ag NPs was further prepared, and its antibacterial effectiveness to Staphylococcus aureus was confirmed. Taken together, this work revealed the structural characteristics of a novel fucose-rich polysaccharide, with good potential in developing new biodegradable antibacterial film.

There has been increasing interest in constructing affinity-based drug delivery systems via different non-covalent interactions. Herein we report a host-guest interaction-based strategy to develop effective drug delivery systems using cyclodextrin-containing copolymers. Hydrophilic copolymers with one polyethylene glycol block and another block containing either α-cyclodextrin or β-cyclodextrin were synthesized. Using poly(β-benzyl l-aspartate) and pyrene as model guest compounds, we demonstrated the nanoparticle formation by host-guest interaction-mediated self-assembly. When an antioxidant and anti-inflammatory drug Tempol was used, the formation of well-defined spherical nanoparticles and therapeutic loading can be simultaneously realized. The obtained nanotherapy showed affinity-controlled drug release. In vitro cell culture experiments suggested that the host-guest nanotherapy exhibited desirable antioxidant and anti-inflammatory effects in macrophages. In a mouse model of an inflammatory disease ulcerative colitis, the orally administered host-guest nanoparticle can be effectively accumulated in the inflamed colonic tissue. Oral treatment of mice bearing colitis with the nanotherapy led to significantly improved efficacy in comparison with free drugs. A good in vivo safety profile was also observed for the developed host-guest nanotherapy. Accordingly, these types of affinity nanoparticles based on CD-containing copolymers can function as effective nanoplatforms for targeted treatment of a plethora of diseases.

We report the synthesis and characterization of a myeloperoxidase (MPO)-responsive, biodegradable, and luminescent material derived from functionalized cyclodextrin. The nanoparticle based on this functional material shows notably high and sustainable luminescent signals upon triggering by inflammatory conditions with abnormally elevated reactive oxygen species and MPO. Activated neutrophils during inflammatory responses can be selectively imaged using this nanoprobe, with luminescent signals positively correlated to neutrophil counts. This nanoprobe enables in vivo precise quantification and tracking of the number and dynamics of neutrophils in both superficial and deep tissues in various mouse models of inflammatory diseases, including peritonitis, paw edema, colitis, and acute lung injury. In vitro and in vivo evaluations also demonstrate the safety and biocompatibility of this newly engineered material in its native and nanoparticle forms.

To develop reactive oxygen species (ROS)-responsive anti-inflammatory materials and establish their structure–property correlations, a series of H2O2-eliminating materials (OxbCDs) were designed and synthesized by conjugating different phenylboronic acid pinacol ester (PBAP) groups onto a biocompatible scaffold compound β-cyclodextrin via varied linker groups. Both the H2O2-triggered hydrolysis profiles and H2O2-eliminating capacities of these materials were dependent on the chemical structure of the PBAP moieties. Together with the elucidation of hydrolysis mechanisms, we established structure–property correlations of these OxbCD materials. Extensive in vitro experiments revealed nanoparticles (NPs) based on OxbCDs showed no adverse biological effects on normal cells. OxbCD NPs could effectively inhibit inflammatory responses and oxidative stress in stimulated macrophages. Consistently, OxbCD NPs efficaciously alleviated the symptoms of peritonitis in mice, with respect to reducing the counts of neutroph...

Oxidative stress, resulting from excessive generation of reactive oxygen species (ROS), plays a pivotal role in the initiation and progression of inflammatory bowel disease (IBD). To develop an efficacious and safe nanotherapy against IBD, we designed and developed a superoxide dismutase/catalase mimetic nanomedicine comprising a hydrogen peroxide-eliminating nanomatrix and a free radical scavenger Tempol (Tpl). To this end, an oxidation-responsive β-cyclodextrin material (OxbCD) was synthesized, and a Tpl-loaded OxbCD nanoparticle (Tpl/OxbCD NP) was produced. Hydrolysis of OxbCD NP could be triggered by hydrogen peroxide, leading to on-demand release of loaded Tpl molecules from Tpl/OxbCD NP. OxbCD NP was able to efficiently accumulate in the inflamed colon in mice, thereby dramatically reducing nonspecific distribution after oral delivery. In three mouse colitis models, oral administration of Tpl/OxbCD NP notably mitigated manifestations relevant to colitis, and significantly suppressed expression of proinflammatory mediators, with the efficacy superior over free Tpl or a control nanomedicine based on poly(lactide-co-glycolide) (PLGA). Accordingly, by scavenging multiple components of ROS, Tpl/OxbCD NP may effectively reduce ulcerative colitis in mice, and it can be intensively developed as a translational nanomedicine for the management of IBD and other inflammatory diseases.

Melanoma is a malignant tumor of melanocytes that is a serious threat to human health. Dermatan sulfate (DS) is a natural glycosaminoglycan. Inspired by the origin of DS, we report a DS-functionalized biomimetic chitosan nanocarrier (DCNP) for melanoma targeted chemotherapy. DS can anchor to the surface of the chitosan nanocarrier (CNP) by forming amide bond. The SN38/DCNP can rapidly release the anti-tumor drug under acidic conditions. The functionalization of DS not only promoted the specific uptake behavior of melanoma cells, but also up-regulated cleaved caspase-3 and PARP promote tumor cell apoptosis. In vivo model, DCNP reduced the non-specific distribution of SN38 in the circulation and other tissues, while shows superior tumor targeting ability. SN38/DCNP significantly inhibit tumor growth and improved the survival rate. Moreover, SN38/DCNP has a milder myelosuppressive effect. The above results indicated that DS could be used as an excellent targeting unit for the treatment of melanoma.

Self-assembly provides a powerful approach for generating complex materials with advanced functionalities. Currently it remains a great challenge to create hierarchically structured assemblies from materials with simple molecular structure. Further, successful clinical translation of polymer assemblies-based therapeutics requires facile yet effective strategies for their fabrication and cargo loading based on structurally simple and cost-effective starting materials. Herein we partly addressed these issues by an all-in-one strategy involving host–guest assembly via molecular recognition, in which carboxyl-bearing compounds serve as guest molecules, while N-substituted acrylamide homopolymers or their various copolymers are host materials. Assembly and therapeutic loading can be simultaneously realized by this one-pot approach, leading to superstructures across length scales and with multiple morphologies, such as micelle-like nanoparticles, vesicles, nano- and microspheres, microtubes, and onion-like multilayer structures. In addition to biomedical applications, superstructures generated by this simple and robust strategy have potential uses in templated synthesis, catalysis, optics, and microelectronics.

Coronary arterial disease (CAD) remains the leading cause of death globally. Percutaneous coronary interventions are frequently used nonsurgical techniques for treating CAD, which may unfortunately lead to arterial restenosis. Currently, there are no effective drugs that can thoroughly prevent restenosis. We hypothesize inflammation-triggerable nanomedicines may function as effective therapeutics for targeted therapy of restenosis, by preferentially releasing their payload at the diseased site. To demonstrate our hypothesis and develop targeted nanotherapies for restenosis, this study was designed to examine effectiveness of nanomedicines responsive to the inflammatory microenvironment with mild acidity and high reactive oxygen species (ROS). To this end, an acetalated β-cyclodextrin (β-CD) material (Ac-bCD) was synthesized as a pH-responsive carrier material, while a ROS-responsive material (Ox-bCD) was produced by hydrophobic functionalization of β-CD with an oxidation-labile group. Based on these two responsive materials, either pH- or ROS-responsive nanoparticles (NPs) were produced by a nanoprecipitation technique and fully characterized. Using rapamycin (RAP) as a candidate drug, responsive nanotherapies were fabricated. In vitro hydrolysis and release studies confirmed these nanovehicles and nanotherapies exhibited desirable responsive behaviors. Both in vitro cell culture and in vivo evaluations revealed their good safety profile. These responsive NPs could be effectively internalized by rat vascular smooth muscle cells, which in turn notably potentiated anti-proliferation and anti-migration activities of RAP. After intravenous (i.v.) injection, NPs may be accumulated at the injured site in the carotid artery of rats subjected to balloon angioplasty injury. Compared with a non-responsive nanotherapy based on poly(lactide-co-glycolide), treatment with either pH- or ROS-responsive nanotherapy by i.v. injection more effectively attenuated neointimal hyperplasia in a rat model of arterial restenosis. Accordingly, nanotherapeutics responsive to the inflammatory microenvironment hold great potential for the management of vascular restenosis by selectively releasing drug molecules at the inflamed sites.

The flavonoid-metal complexes showed obviously stronger bioactivities such as antibiosis, antivirus, anti-inflammatory, anti-tumor and anti-free-radical, possibly because of the stronger binding force caused by the change in complex structure and accessibility to target spots, or the synergy effect between flavonoids and metallic ions. This essay summarizes studies on bioactivity and mechanism of flavonoid-metal complexes, in order to provide reference for in-depth study and development on effective constituents contained in flavonoid traditional Chinese medicines.