ROS-responsive celastrol-nanomedicine alleviates inflammation for dry eye disease.

Dry eye disease (DED) is a major global eye disease leading to severe eye discomfort and even vision impairment. The incidence of DED has been gradually increasing with the high frequency of use of electronic devices. It has been demonstrated that celastrol (Cel) has excellent therapeutic efficacy in ocular disorders. However, the poor water solubility and short half-life of Cel limit its further therapeutic applications. In this work, a reactive oxygen species (ROS) sensitive polymeric micelle was fabricated for Cel delivery. The micelles improve the solubility of Cel, and the resulting Cel loaded micelles exhibit an enhanced intervention effect for DED. Thein vitroresults demonstrated that Cel-nanomedicine had a marked ROS responsive release behavior. The results ofin vitroandin vivoexperiments demonstrated that Cel has excellent biological activities to alleviate inflammation in DED by inhibiting TLR4 signaling activation and reducing pro-inflammatory cytokine expression. Therefore, the Cel nanomedicine can effectively eliminate ocular inflammation, promote corneal epithelial repair, and restore the number of goblet cells and tear secretion, providing a new option for the treatment of DED.

Syntheses of Polypeptides and Their Biomedical Application for Anti-Tumor Drug Delivery.

Polypeptides have attracted considerable attention in recent decades due to their inherent biodegradability and biocompatibility. This mini-review focuses on various ways to synthesize polypeptides, as well as on their biomedical applications as anti-tumor drug carriers over the past five years. Various approaches to preparing polypeptides are summarized, including solid phase peptide synthesis, recombinant DNA techniques, and the polymerization of activated amino acid monomers. More details on the polymerization of specifically activated amino acid monomers, such as amino acid N-carboxyanhydrides (NCAs), amino acid N-thiocarboxyanhydrides (NTAs), and N-phenoxycarbonyl amino acids (NPCs), are introduced. Some stimuli-responsive polypeptide-based drug delivery systems that can undergo different transitions, including stability, surface, and size transition, to realize a better anti-tumor effect, are elaborated upon. Finally, the challenges and opportunities in this field are briefly discussed.

Micro- and Nanocapsules Based on Artificial Peptides.

The encapsulation of active ingredients into solid capsules from biodegradable materials has received significant attention over the last decades. In this short review, we focus on the formation of micro- and nano-sized capsules and emulsions based on artificial peptides as a fully degradable material. It deals with various approaches for the preparation of peptide-based capsules as well as with their crucial properties such as size and stability. We categorize all preparation procedures into three basic approaches: self-assembly, polymerization and crosslinking, and layer-by-layer technology. This article is meant to offer a short overview over all successful methods suitable for obtaining access to these very promising carrier systems.

Capsules from synthetic diblock-peptides as potential artificial oxygen carriers.

The design of an encapsulation system consisting of a synthetic peptide which is fully biodegradable into non-toxic constituents. This system should be capable of encapsulating perfluorinated hydrocarbons and should be a promising basis for oxygen carriers to be used as artificial blood replacement. A diblock-peptide is synthesised following a phosgene-free method and characterised by 1H-NMR. Subsequently, this diblock-peptide is self-assembled with perfluorodecalin (PFD) to form PFD-filled capsules as potential artificial oxygen carriers allowing for rapid oxygen uptake and release. The diblock-peptide Bu-PAsp10-PPhe10 is successfully synthesised and used to encapsulate PFD. The capsules have a spherical shape with an average diameter of 360 nm in stable aqueous dispersion. NMR measurements prove their physical capability for reversible uptake and release of oxygen. The resulting capsules are expected to be fully biodegradable and possibly could act as oxygen carriers for artificial blood replacement.

A comparison of the efficacy and safety of endoscopic full-thickness resection and laparoscopic-assisted surgery for small gastrointestinal stromal tumors.

BACKGROUND AND AIM: Laparoscopic-assisted surgery (LAC) is an alternative to open surgery for gastrointestinal stromal tumors (GISTs). Endoscopic full-thickness resection (EFTR), a recently developed procedure, is increasingly used to resect GISTs originated from the muscularis propria. In this retrospective study, we aimed to compare EFTR with LAC as minimally invasive treatments for GISTs, especially those with a diameter <2 cm, originating from the muscularis propria. Moreover, we evaluated the clinical efficacy, safety, and feasibility of EFTR for GISTs. METHODS: The study included 68 patients with GISTs originating from the muscularis propria (35 patients who underwent EFTR, and 33 who underwent LAC) who were treated at the Affiliated Hospital of Guangdong Medical University (Zhanjiang, China) between January 2011 and December 2013. The therapeutic outcomes of EFTR and LAC were reviewed retrospectively. RESULTS: In the EFTR group, the mean tumor size was 13 ± 5 mm, the mean procedure time was 91 ± 63 min, and the complete resection rate was 100 %. There were 35 "artificial" perforations and four cases of intraoperative bleeding; all complications were successfully managed endoscopically without emergency surgery. In the LAC group, the mean tumor size was 16 ± 4 mm, the mean operation time was 155 ± 37 min, and complications included three wound infections and one anastomotic leakage. CONCLUSIONS: EFTR was associated with a lower complication rate than LAC, with favorable en bloc and sufficient tumor tissue for histological diagnosis. EFTR seems to be an efficacious, relatively safe, and minimally invasive treatment for GISTs and could replace LAC surgical resection in cases where the tumor is smaller than 2 cm in diameter.

Cross-linked Triblock Peptide Capsules as Potential Oxygen Carriers.

Perfluorodecalin (PFD)-filled capsules have been studied for over 15 years as artificial oxygen carriers. However, none of these capsules combines good biocompatibility, good mechanical stability and dispersion stability. Here we propose to use synthetic triblock peptides containing a central block of cysteine units as a cross-linking shell material for capsules with both good biocompatibility and stability. Together with outer aspartate units and inner phenylalanine units, the resulting amphiphilic triblock peptides can encapsulate PFD efficiently to prepare capsules with a suitable diameter, a certain mechanical strength, a large diffusion constant, fast gas exchange rates, and little cytotoxicity. Given the above advantages, these PFD-filled peptide capsules are very promising as potential artificial oxygen carriers.

Co-Delivery of Paclitaxel and siRNA with pH-Responsive Polymeric Micelles for Synergistic Cancer Therapy.

Due to the complex physiological characteristics of tumors, chemotherapy or gene therapy alone cannot completely kill tumor cells. Therefore, combining chemotherapy with gene therapy for combination therapy is the key to solving this problem. However, there are still significant challenges in how to simultaneously deliver and rapidly release the drugs and siRNA into cancer cells. In this work, a triblock copolymer was synthesized to co-deliver siRNA and paclitaxel to tumor cells. This system has an acid-sensitive subsurface layer, which can not only load siRNA to prevent premature drug release but also has good controlled release performance. In vitro experiments showed that polymeric vectors can efficiently deliver siRNA and paclitaxel simultaneously into tumor cells for rapid release within the tumor cells. This study reveals that this novel polymeric micelle is a suitable vector for the codelivery of chemotherapeutic drugs and siRNA to cancer cells, representing an important advance in nanotechnology, nanomedicine, drug delivery, and cancer therapy.

Effectively suppressed angiogenesis-mediated retinoblastoma growth using celastrol nanomicelles.

Celastrol, a Chinese herbal medicine, has already shown an inhibition effect on retinoblastoma growth activity in our previous research, but its mechanism is not well understood. Angiogenesis is a main driving force in many tumors. Here, we studied whether celastrol could inhibit angiogenesis-mediated retinoblastoma growth, if so, through what mechanism. In this work, we developed celastrol-loaded polymeric nanomicelles to improve the poor water solubility of celastrol. When given an intraperitoneal injection to mice bearing human retinoblastoma xenografts, celastrol nanomicelles (CNMs, 27.2 mg/kg/2 days) significantly reduced the weight and the volume of tumors and decreased tumor angiogenesis. We found that CNMs suppressed hypoxia-induced proliferation, migration, and invasion by human umbilical vascular endothelial cells (EA.hy 926) in a dose-dependent manner. Furthermore, CNMs inhibited SO-Rb 50 cells-induced sprouting of the vessels and vascular formation in chick embryo chorioallantoic membrane assay in vitro. To understand the molecular mechanism of these activities, we assessed the signaling pathways in CoCl2 treated EA.hy 926. CNMs inhibited the hypoxia-induced HIF-1α and VEGF. In conclusion, our results reveal that CNMs target the HIF-1α/VEGF pathway, which may be an important reason for the suppression of retinoblastoma growth and angiogenesis.

Hypoxia-Responsive Polymeric Micelles for Enhancing Cancer Treatment.

Polymeric drug vectors have shown great potentials in cancer therapy. However, intelligent controlled release of drugs has become a major challenge in nanomedicine research. Hypoxia-responsive polymeric micelles have received widespread attention in recent years due to the inherent hypoxic state of tumor tissue. In this study, a novel diblock polymer consisting of polyethylene glycol and poly[glutamic acid (3-(2-nitro-imidazolyl)-propyl)] was synthesized and self-assembled into hypoxia-responsive polymeric micelles for the controlled release of doxorubicin (DOX). The cell experiments demonstrated that DOX-loaded micelles had a stronger killing capacity on tumor cells under hypoxic conditions, while the blank micelles had good biocompatibility. All the experiments indicate that our hypoxia-responsive polymeric micelles have a great potential for enhanced cancer treatment.

Multifunctional Polymeric Carrier for Co-Delivery of MRI Contrast Agents and siRNA to Tumors.

Gene therapy holds tremendous promise in the treatment of tumors, in which an effective delivery system plays a crucial role. Herein, a nanoscale polymeric micelle is developed to co-deliver superparamagnetic iron oxide nanoparticles (SPIONs) and siRNA targeting luciferase gene (siLuc) into tumors. In vitro studies showed that SPIO and siRNA-loaded micelles could enter cancer cells easily and they have no cytotoxicity. And in vivo studies indicated that polymeric micelle could deliver SPIO and siRNA into tumors efficiently. Our results strongly demonstrated that the novel polymeric micelle is a promising carrier for delivery of siRNA and SPIO to enable noninvasive imaging-assisted therapy in vivo.

PiggyBac transposon system with polymeric gene carrier transfected into human T cells.

CAR-T cell-based immunotherapy has shown great promise in clinical trials for the treatment of hematological malignancies. The majority of these trials utilize retroviral and lentiviral vectors to introduce CAR transgene. In spite of its satisfactory efficiency, the concerns about the potential carcinogenicity and complicated synthesis procedure restrict widespread clinical applications of viral vectors. Recent studies show that transposon-based gene transfer is a safer and simpler non-viral approach for stable transgene expression. Here, we developed an in house made polymeric nanomicelles carrier for piggyBac (PB) transposon delivery to primary T lymphocytes. The properties, transfection efficiency and toxicity of this carrier was analyzed. Results indicated that nanomicelles produced in our study were stable and reduction-sensitive. These micelles can completely condense DNA and mediate transfection with efficiency of average 30.2% with high cell viability (> 80%). Furthermore, incorporating piggyBac transposase elements into polyplexes promoted persistent expression of the transgene (up to 55%). At the end of culture, CAR-T cells mainly exhibited memory phenotype and consisted of CD3+CD8+ T cells. The cytotoxicity of these CAR-T cells was average 17% at 20:1 ratio. In conclusion, polymeric nanomicelles provide a flexible and safe method for gene delivery to T lymphocytes.

Fabrication of a drug delivery system that enhances antifungal drug corneal penetration.

Fungal keratitis (FK) remains a severe eye disease, and effective therapies are limited by drug shortages and critical ocular barriers. Despite the high antifungal potency and broad spectrum of econazole, its strong irritant and insolubility in water hinder its ocular application. We designed and fabricated a new drug delivery system based on a polymeric vector for the ocular antifungal application of econazole. This novel system integrates the advantages of its constituent units and exhibits superior comprehensive performance. Using the new system, drug content was significantly increased more than 600 folds. The results of in vivo and in vitro experiments demonstrated that the econazole-loaded formulation exhibited significantly enhanced corneal penetration after a single topical ocular administration, excellent antifungal activity, and good tolerance in rabbits. Drug concentrations and ocular relative bioavailability in the cornea were 59- and 29-time greater than those in the control group, respectively. Following the topical administration of one eye drop (50 µL of 0.3% w/v econazole) in fungus-infected rabbits, a high concentration of antimycotic drugs in the cornea and aqueous humor was sustained and effective for 4 h. The mechanism of corneal penetration was also explored using dual fluorescent labeling. This novel drug delivery system is a promising therapeutic approach for oculomycosis and could serve as a candidate strategy for use with various hydrophobic drugs to overcome barriers in the treatment of many other ocular diseases.

A DOX-loaded polymer micelle for effectively inhibiting cancer cells.

A novel triblock polymer is synthesized and self-assembled with doxorubicin to form DOX-loaded micelles. The synthetic process involves the ring-opening polymerization, carboxylation and amidation reactions, and the structures are characterized. The drug release test indicated that the micelles have the ability to control the release of drugs. The cell uptake results indicated that the DOX-loaded micelles could enter cancer cells easily, and the cytotoxicity and apoptosis test confirmed that DOX-loaded micelles have a strong killing effect on tumor cells, while the blank micelles do not have cytotoxicity. Therefore, the novel polymer micelles are a promising carrier for delivery of anticancer drugs to enhance cancer treatment.