Fabrication of pH-Responsive Nanoparticles with an AIE Feature for Imaging Intracellular Drug Delivery.

Here we have demonstrated a facile method for construction of self-assembled nanoparticles with excellent fluorescent properties by the synergetic combination of unique AIE effects and tadpole-shaped polymers. The introduction of acid-sensitive Schiff base bonds furnished the polymeric vesicles and micelles with unique pH responsiveness that can possess maximal drug-release controllability inside tumor cells upon changes in physical and chemical environments, but present good stability under physiological conditions. Having benefited from the efficient fluorescence resonance energy transfer (FRET), the DOX-loaded fluorescent aggregates were employed for intracellular imaging and self-localization in surveillance of systemic DOX delivery. Cytotoxicity assay of the DOX-loaded aggregates indicated a fast internalization and a high cellular proliferation inhibition to MCF-7 cells while the PEG-POSS-(TPE)7 nanoparticles displayed no cytotoxicity, exhibiting excellent biocompatibility and biological imaging properties. These results indicated that these biodegradable nanoparticles, as a class of effective pH-responsive and visible nanocarriers, have the potential to improve smart drug delivery and enhance the antitumor efficacy for biomedical applications.

Prevented Cell Clusters' Migration Via Microdot Biomaterials for Inhibiting Scar Adhesion.

Cluster-like collective cell migration of fibroblasts is one of the main factors of adhesion in injured tissues. In this research, a microdot biomaterial system is constructed using α-helical polypeptide nanoparticles and anti-inflammatory micelles, which are prepared by ring-opening polymerization of α-amino acids-N-carboxylic anhydrides (NCAs) and lactide, respectively. The microdot biomaterial system slowly releases functionalized polypeptides targeting mitochondria and promoting the influx of extracellular calcium ions under the inflammatory environment, thus inhibiting the expression of N-cadherin mediating cell-cell interaction, and promoting apoptosis of cluster fibroblasts, synergistically inhibiting the migration of fibroblast clusters at the site of tendon injury. Meanwhile, the anti-inflammatory micelles are celecoxib (Cex) solubilized by PEG/polyester, which can improve the inflammatory microenvironment at the injury site for a long time. In vitro, the microdot biomaterial system can effectively inhibit the migration of the cluster fibroblasts by inhibiting the expression of N-cadherin between cell-cell and promoting apoptosis. In vivo, the microdot biomaterial system can promote apoptosis while achieving long-acting anti-inflammation effects, and reduce the expression of vimentin and α-smooth muscle actin (α-SMA) in fibroblasts. Thus, this microdot biomaterial system provides new ideas for the prevention and treatment of tendon adhesion by inhibiting the cluster migration of fibroblasts.

Motion lubrication suppressed mechanical activation via hydrated fibrous gene patch for tendon healing.

Mechanical activation of fibroblasts, caused by friction and transforming growth factor-ß1 recognition, is one of the main causes of tissue adhesions. In this study, we developed a lubricated gene-hydrogel patch, which provides both a motion lubrication microenvironment and gene therapy. The patch's outer layer is composed of polyethylene glycol polyester hydrogel. The hydrogel forms hydrogen bonds with water molecules to create the motion lubrication layer, and it also serves as a gene delivery library for long-term gene silencing. Under the motion lubricated microenvironment, extracellular signal-regulated kinase-small interfering RNA can silence fibroblasts and enhance the blocking effect against fibroblast activation. In vitro, the proposed patch effectively inhibits fibroblast activation and reduces the coefficient of friction. In vivo, this patch reduces the expression of vimentin and α-smooth muscle actin in fibroblasts. Therefore, the lubricated gene-hydrogel patch can inhibit the mechanical activation of fibroblasts to promote tendon healing.

Biomaterial-based delivery of nucleic acids for tissue regeneration.

Gene therapy is a promising novel method of tissue regeneration by stimulating or inhibiting key signaling pathways. However, their therapeutic applications in vivo are largely limited by several physiological obstacles, such as degradation of nucleases, impermeability of cell membranes, and transport to the desired intracellular compartments. Biomaterial-based gene delivery systems can overcome the problems of stability and local drug delivery, and can temporarily control the overexpression of therapeutic genes, leading to the local production of physiologically relevant levels of regulatory factors. But the gene delivery of biomaterials for tissue regeneration relies on multi-factor design. This review aims to outline the impact of gene delivery methods, therapeutic genes and biomaterials selection on this strategy, emphatically introduce the latest developments in the design of gene delivery vehicles based on biomaterials, summarize the mechanism of nucleic acid for tissue regeneration, and explore the strategies of nucleic acid delivery vehicles for various tissue regeneration.

Injectable Thermogel Generated by the "Block Blend" Strategy as a Biomaterial for Endoscopic Submucosal Dissection.

Endoscopic submucosal dissection is an established method for the removal of early cancers and large lesions from the gastrointestinal tract but is faced with the risk of perforation. To decrease this risk, a submucosal fluid cushion (SFC) is needed clinically by submucosal injection of saline and so on to lift and separate the lesion from the muscular layer. Some materials have been tried as the SFC so far with disadvantages. Here, we proposed a thermogel generated by the "block blend" strategy as an SFC. This system was composed of two amphiphilic block copolymers in water, so it was called a "block blend". We synthesized two non-thermogellable copolymers poly(d,l-lactide-co-glycolide)-b-poly(ethylene glycol)-b-poly(d,l-lactide-co-glycolide) and blended them in water to achieve a sol-gel transition upon heating in both pure water and physiological saline. We explored the internal structure of the resultant thermogel with transmission electron microscopy, three-dimensional light scattering, 13C NMR, fluorescence resonance energy transfer, and rheological measurements, which indicated a percolated micelle network. The biosafety of the synthesized copolymer was preliminarily confirmed in vitro. The main necessary functions as an SFC, namely, injectability of a sol and the maintained mucosal elevation as a gel after injection, were verified ex vivo. This study has revealed the internal structure of the block blend thermogel and illustrated its potential application as a biomaterial. This work might be stimulating for investigations and applications of intelligent materials with both injectability and thermogellability of tunable phase-transition temperatures.

Acetal-linked PEGylated paclitaxel prodrugs forming free-paclitaxel-loaded pH-responsive micelles with high drug loading capacity and improved drug delivery.

Endosomal pH-responsive micellar nanoparticles were prepared by self-assembly of an amphiphilic poly(ethylene glycol)-acetal-paclitaxel (PEG-acetal-PTX) prodrug, and free PTX could be encapsulated in the hydrophobic core of the nanoparticles. These nanoparticles exhibited excellent storage stability for over 6months under normal conditions, but disassembled quickly in response to faintly acidic environment. Incorporating physical encapsulation and chemical conjugation, the PTX concentration in the nanoparticles solution could reach as high as 3665µg/mL, accompanying with a high drug loading capacity of 60.3%. Additionally, benefitting from the difference in drug release mechanism and rate between encapsulated PTX and conjugated PTX, a programmed drug release behavior was observed, which may result in higher intracellular drug concentration and longer action time. CCK-8 assays showed that the nanoparticles demonstrated superior antitumor activity than free PTX against both HeLa and MDA-MB-231 cells. These prodrug-based nanomedicines have a great potential in developing translational PTX formulations for cancer therapy.

Dopamine-assisted fixation of drug-loaded polymeric multilayers to osteoarticular implants for tuberculosis therapy.

Currently, the major issues in the treatment of osteoarticular tuberculosis (TB) after implant placement are low drug concentration at the infected focus and drug resistance resulting from the long-term chemotherapy. The application of drug-loaded polymeric multilayers on implantable devices offers a promising solution to the problems. Herein, a poly(ethylene glycol)-based hydrogel film embedded with isoniazid (INH)-loaded alginate microparticles was fixed to Ti implants via adhesive polydopamine, subsequently capped by poly(lactic-co-glycolic acid) membranes for the sustained and localized delivery of the anti-TB drug. The antibacterial efficacy of the released INH was confirmed by a 4.5 ± 0.8 cm inhibition zone formed in the fourth week after inoculation of Mycobacterium tuberculosis. The INH-loaded Ti implants showed no toxicity to the osteoblast cell and provided a consistent drug release for nearly one week in vitro. The release profile in vivo showed a high local concentration and low systemic exposure. The local INH concentration could be kept higher than its minimum inhibitory concentration over a period of 8 weeks, which proves that it is a promising strategy to improve the severe osteoarticular TB treatment.

Uniform PEGylated PLGA Microcapsules with Embedded Fe3O4 Nanoparticles for US/MR Dual-Modality Imaging.

Well-designed agents for enhanced multimodal imaging have attracted great interests in recent years. In this work, we adopted a premix membrane emulsification (PME) method to prepare uniform PEGylated poly(lactic-co-glycolic acid) (PLGA) microcapsules (MCs) with superparamagnetic Fe3O4 nanoparticles (NPs) embedded in the shell (Fe3O4@PEG-PLGA MCs) for ultrasound (US)/magnetic resonance (MR) bimodal imaging. Compared to Fe3O4@PLGA MCs without PEGylation, Fe3O4@PEG-PLGA MCs could more stably and homogeneously disperse in physiological solutions. In vitro and in vivo trials demonstrated that Fe3O4@PEG-PLGA MCs (∼3.7 µm) with very narrow size distribution (PDI=0.03) could function as efficient dual-modality contrast agents to simultaneously enhance US and MR imaging performance greatly. In vitro cell toxicity and careful histological examinations illustrated no appreciable cytotoxicity and embolism of Fe3O4@PEG-PLGA MCs to mice even at high dose. The uniform composite MCs developed here can act as clinical bimodal contrast agents to improve hybrid US/MR imaging contrast, which is promising for accurate diagnosis and real-time monitoring of difficult and complicated diseases.