Search

Activation of signal transducer and activator of transcription 3 (STAT3) under conditions of inflammation plays a crucial role in the pathogenesis of life-threatening pulmonary fibrosis (PF), initiating pro-fibrotic signaling following its phosphorylation. While there have been attempts to interfere with STAT3 activation and associated signaling as a strategy for ameliorating PF, potent inhibitors with minimal systemic toxicity have yet to be developed. Here, we assessed the in vitro and in vivo therapeutic effectiveness of a cell-permeable peptide inhibitor of STAT3 phosphorylation, designated APTstat3-9R, for ameliorating the indications of pulmonary fibrosis. Our results demonstrate that APTstat3-9R formulated with biomimetic disc-shaped lipid nanoparticles (DLNPs) markedly enhanced the penetration of pulmonary surfactant barrier and alleviated clinical symptoms of PF while causing negligible systemic cytotoxicity. Taken together, our findings suggest that biomimetic lipid nanoparticle-assisted pulmonary delivery of APTstat3-9R may be a feasible therapeutic option for PF in the clinic, and could be applied to treat other fibrotic diseases.

Rosmarinic acid (RA), one of the most important polyphenol-based antioxidants, has received growing interest because of its bioactive properties, including anti-inflammatory, anticancer, and antibacterial activities. Despite the high therapeutic potential of RA, its intrinsic properties of poor water solubility and low bioavailability have limited its translation into the clinic. Here, we report on the synthesis and preparation of PEGylated RA-derived nanoparticles (RANPs) and their use as a therapeutic nanomedicine for treatment of inflammatory bowel disease (IBD) in a dextran sulfate sodium (DSS)-induced acute colitis mouse model. PEGylated RA, synthesized via a one-step process from RA and a PEG-containing amine, self-assembled in buffer to form nanoparticles (RANPs) with a diameter of 63.5 ± 4.0 nm. The resulting RANPs showed high colloidal stability in physiological medium up to 2 weeks. RANPs were capable of efficiently scavenging H2O2, thereby protecting cells from H2O2-induced damage. Furthermore, the corticosteroid drug, dexamethasone (DEX), could be loaded into RANPs and released in response to a reactive oxygen species stimulus. Intravenously administered RANPs exhibited significantly improved pharmacokinetic parameters compared with those of the parent RA and were preferentially localized to the inflamed colon. Intravenous administration of RANPs in DSS-induced colitis mice substantially mitigated colonic inflammation in a dose-dependent manner compared with the parent RA, as evidenced by significantly reduced disease activity index scores, body weight loss, and colonic inflammatory damage. In addition, RANPs suppressed expression and production of typical pro-inflammatory cytokines in the inflamed colon. Furthermore, DEX-loaded RANPs showed enhanced therapeutic efficacy in the colitis model compared with bare RANPs at the equivalent dose, indicating synergy with a conventional medication. These findings suggest that RANPs deserve further consideration as a potential therapeutic nanomedicine for the treatment of various inflammatory diseases, including IBD.

Patients with BRAF

Peptide-based therapeutics have suffered from a short plasma half-life. On the other hand, antibodies suffer from poor penetration into solid tumors owing to their large size. Herein, we present a new molecular form, namely a hybrid complex between a hapten-labeled bispecific peptide and an anti-hapten antibody ("HyPEP-body"), that may be able to overcome the aforementioned limitation. The bispecific peptide containing a cotinine tag was synthesized by linking a peptide specific to fibronectin extra domain B (EDB) and a peptide able to bind and inhibit vascular endothelial growth factor (VEGF), yielding cot-biPEPEDB-VEGF . Simple mixing of cot-biPEPEDB-VEGF and anti-cotinine antibody (Abcot ) yielded the hybrid complex, HyPEPEDB-VEGF . HyPEPEDB-VEGF retained the characteristics of the included peptides, and showed improved pharmacokinetic behavior. Moreover, HyPEPEDB-VEGF showed tumor growth inhibition with excellent tumor accumulation and penetration. These findings suggest that the hybrid platform described here offers a solution for most peptide therapeutics that suffer from a short circulation half-life in blood.

Pulmonary fibrosis is an irreparable and life-threatening disease with only limited therapeutic options. The recent outbreak of COVID-19 has caused a sharp rise in the incidence of pulmonary fibrosis owing to SARS-CoV-2 infection-mediated acute respiratory distress syndrome (ARDS). The considerable oxidative damage caused by locally infiltrated immune cells plays a crucial role in ARDS, suggesting the potential use of antioxidative therapeutics. Here, we report the therapeutic potential of nanoparticles derived from the endogenous antioxidant and anti-inflammatory bile acid, bilirubin (BRNPs), in treating pulmonary fibrosis in a bleomycin-induced mouse model of the disease. Our results demonstrate that BRNPs can effectively reduce clinical signs in mice, as shown by histological, disease index evaluations, and detection of biomarkers. Our findings suggest that BRNPs, with their potent antioxidant and anti-inflammatory effects, long blood circulation half-life, and preferential accumulation at the inflamed site, are potentially a viable clinical option for preventing Covid-19 infection-associated pulmonary fibrosis.

Cancer-targeting ligands used for nanomedicines have been limited mostly to antibodies, peptides, aptamers, and small molecules thus far. Here, a library of glycocalyx-mimicking nanoparticles as a platform to enable screening and identification of cancer-targeting nanomedicines is reported. Specifically, a library of 31 artificial glycopolymers composed of either homogeneous or heterogeneous display of five different sugar moieties (β-glucose, β-galactose, α-mannose, β-N-acetyl glucosamine, and β-N-acetyl galactosamine) is converted to a library of glyconanoparticles (GlyNPs). GlyNPs optimal for targeting CT26, DU145, A549, and PC3 tumors are systematically screened and identified. The cypate-conjugated GlyNP displaying α-mannose and β-N-acetyl glucosamine show selective targeting and potent photothermal therapeutic efficacy against A549 human lung tumors. The docetaxel-contained GlyNP displaying β-glucose, β-galactose, and α-mannose demonstrate targeted chemotherapy against DU145 human prostate tumors. The results presented herein collectively demonstrate that the GlyNP library is a versatile platform enabling the identification of cancer-targeting glyconanoparticles and suggest its potential applicability for targeting various diseased cells beyond cancer.

Although the cause of multiple sclerosis (MS) is unclear, an autoimmune attack on myelin-based coating layers of nerve cells in the brain and spinal cord is the main feature of the disease, highlighting modulation of the immune response to myelin as a feasible therapeutic approach. Here, we report the potential of bilirubin nanoparticles (BRNPs) based on the endogenous antioxidant and anti-inflammatory agent, bilirubin, as a therapeutic nanomedicine for MS. In a mouse model of experimental autoimmune encephalomyelitis (EAE), multiple intravenous injections of BRNPs significantly delayed disease onset and suppressed disease progression and severity as well as disease incidence rate without systemic immunosuppression. Following intravenous injection, BRNPs accumulated more extensively and were retained longer in secondary lymphoid organs of EAE-induced mice compared with non-immunized control mice, including in inguinal lymph nodes (iLNs) and spleens, where antigen presenting cells (APCs) activated by the myelin antigen are abundant. Studies of the underlying mechanism of action further revealed that BRNPs negatively regulated the differentiation of naive CD4+ T cells into T helper 17 (Th17) cells by inhibiting maturation of APCs through scavenging of reactive oxygen species (ROS) overproduced in both dendritic cells (DCs) and macrophages upon antigen uptake. These findings indicate that BRNPs have the potential to be used as a new therapeutic nanomedicine for treatment of various CD4+ T cell-associated autoimmune diseases.

Psoriasis is a prevalent chronic inflammatory skin disease characterized by thickening of the epidermis accompanied by lesional erythema, scaling, and induration as a result of abnormal proliferation of keratinocytes. During the development of psoriasis, levels of intracellular reactive oxygen species (ROS) within psoriatic lesions are elevated, activating a pro-inflammatory signaling cascade. Here, we evaluated the therapeutic efficacy and mode of action of bilirubin nanoparticles (BRNPs), based on the potent, endogenous antioxidant bilirubin, in a preclinical psoriasis model. We found that topical treatment of psoriatic lesions with BRNPs effectively attenuated upregulation of intracellular ROS levels within keratinocytes and ameliorated the symptoms of psoriasis. A subsequent mechanistic study showed that preventing oxidative stress in activated keratinocytes suppressed the secretion of inflammatory mediators and recruitment of immune cells. Subsequent expression of the antigen-presenting cell (APC) maturation markers, class II major histocompatibility complex (MHC class II), cluster of differentiation (CD) 80 and CD86, was significantly decreased, resulting in a reduction in the differentiation of naive CD4+ T cells into interleukin (IL)-17–producing T-helper (Th) 17 cells. Unlike the commercial corticosteroid drug, clobetasol propionate (CLQ), BRNPs, composed of the endogenous antioxidant bilirubin and the approved polymer polyethylene glycol (PEG), did not exert systemic cytotoxicity. Collectively, these findings highlight the potential of BRNPs as a novel nanomedicine for ameliorating psoriasis-like skin inflammation through topical treatment and suggest that their use could be further expanded to treat other chronic skin inflammation diseases, including atopic dermatitis.

Tubulin-based nanotubes (TNTs) to deliver microtubule-targeting agents (MTAs) for clinical oncology are reported. Three MTAs, docetaxel (DTX), laulimalide (LMD), and monomethyl auristatin E (MMAE), which attach to different binding sites in a tubulin, are loaded onto TNTs and cause structural changes in them, including shape anisotropy and tubulin layering. This drug-driven carrier transformation leads to changes in the drug-loading efficiency and stability characteristics of the carrier. TNTs coloaded with DTX and LMD efficiently deliver dual drug cargoes to cellular tubulins by the endolysosomal pathway, and results in synergistic anticancer and antiangiogenic action of the drugs in vitro. In in vivo tests, TNTs loaded with a microtubule-destabilizing agent MMAE suppress the growth of tumors with much higher efficacy than free MMAE did. This work suggests a new concept of using a drug's target protein as a carrier. The findings demonstrate that the TNTs developed here can be used universally as a delivery platform for many MTAs.

Despite the wide utility of gold nanorods (GNRs) in biomedical fields, only a few methods for modifying or coating the surface of GNRs suitable for biomedical applications are available. In this study, we report a new facile method that enables formation of an ultra-thin (nanometre-thickness) siloxane layer on GNRs with anti-biofouling properties and ligand functionalisation ability. A triblock random copolymer, poly(TMSMA-r-PEGMA-r-NAS), was used to coat GNRs. An ultrathin polymeric shell was formed surrounding GNRs through acid-catalysed crosslinking of silicates of TMSMA. The polymer-coated GNRs (p-GNRs) exhibited high colloidal stability in biological solutions of high ionic strength and long-term stability superior to that of PEG2k-S-GNRs. The functionalities of NAS were demonstrated using two methods for conjugating targeting ligands and loading doxorubicin via electrostatic interactions. The ligand-specific cancer-targeting ability and combinatorial chemo-photothermal anticancer effects were validated in vitro and in vivo, suggesting their potential utility in various fields.

Photoimaging and phototherapy have become major platforms for the diagnosis and treatment of various health complications. These applications require a photosensitizer (PS) that is capable of absorbing light from a source and converting it into other energy forms for detection and therapy. While synthetic inorganic materials such as quantum dots and gold nanorods have been widely explored for their medical diagnosis and photodynamic (PDT) and photothermal (PTT) therapy capabilities, translation of these technologies has lagged, primarily owing to potential cytotoxicity and immunogenicity issues. Of the various photoreactive molecules, the naturally occurring endogenous compound heme, a constituent of red blood cells, and its derivatives, porphyrin, biliverdin and bilirubin, have shown immense potential as noteworthy candidates for clinically translatable photoreactive agents, as evidenced by previous reports. While porphyrin-based photomedicines have attracted significant attention and are well documented, research on photomedicines based on two other heme-derived compounds, biliverdin and bilirubin, has been relatively lacking. In this review, we summarize the unique photoproperties of heme-derived compounds and outline recent efforts to use them in biomedical imaging and phototherapy applications.

As reports of multidrug resistant pathogens have increased, patients with implanted medical catheters increasingly need alternative solutions to antibiotic treatments. As most catheter-related infections are directly associated with biofilm formation on the catheter surface, which, once formed, is difficult to eliminate, a promising approach to biofilm prevention involves inhibiting the initial adhesion of bacteria to the surface. In this study, we report an amphiphilic, antifouling polymer, poly(DMA-mPEGMA-AA) that can facilely coat the surfaces of commercially available catheter materials in water and prevent bacterial adhesion to and subsequent colonization of the surface, giving rise to an antibiofilm surface. The antifouling coating layer was formed simply by dipping a model substrate (polystyrene, PET, PDMS, or silicon-based urinary catheter) in water containing poly(DMA-mPEGMA-AA), followed by characterization by X-ray photoelectron spectroscopy (XPS). The antibacterial adhesion properties of the polymer-coated surface were assessed for Staphylococcus aureus (S. aureus) and Escherichia coli (E. coli) growth under static (incubation in the presence of a bacterial suspension) and dynamic (bacteria suspended in a solution under flow) conditions. Regardless of the conditions, the polymer-coated surface displayed significantly reduced attachment of the bacteria (antiadhesion effect∼8-fold) compared to the bare noncoated substrates. Treatment of the implanted catheters with S. aureus in vivo further confirmed that the polymer-coated silicon urinary catheters could significantly reduce bacterial adhesion and biofilm formation in a bacterial infection animal model. Furthermore, the polymer-coated catheters did not induce hemolysis and were resistant to the adhesion of blood-circulating cells, indicative of high biocompatibility. Collectively, the present amphiphilic antifouling polymer is potentially useful as a coating platform that renders existing medical devices resistant to biofilm formation.