Research Progress on Nanoplatforms and Nanotherapeutic Strategies in Treating Glioma.

Glioma is the most common and aggressive primary intracranial tumor within the central nervous system. The blood-brain barrier (BBB) has been a great hurdle for an effective glioma treatment. To effectively treat glioma, various strategies have been applied to deliver drugs to the brain by crossing the BBB. Nanocarrier-mediated drug delivery is emerging as an effective and noninvasive system to treat glioma, showing great potential in glioma therapy. In this review, we will provide a comprehensive overview on nanocarrier-mediated drug delivery and related glioma therapy. Following an initial overview of the BBB and blood-brain-tumor barrier (BBTB) structure and characteristics, nanocarrier-mediated drug delivery strategies (liposomes, micelles, inorganic systems, polymeric nanoparticles, nanogel system, biomimetic nanoparticles, and exosomes) for crossing the BBB are discussed. Finally, nanotherapeutic techniques (imaging-mediated chemotherapy, photothermal therapy, photodynamic therapy, gene therapy, immunotherapy, ferroptosis therapy, sonodynamic therapy, chemodynamic therapy, and combination therapy) in treating glioma are summarized. In addition, this review provides some perspectives on the clinical applications of nanomedicines.

Cascade enzymatic preparation of carboxymethyl chitosan-based multifunctional hydrogels for promoting cutaneous wound healing.

Designing wound dressings with inherent multifunctional therapeutic effects is desirable for clinical applications. Herein, a series of multifunctional carboxymethyl chitosan (CMCS)-based hydrogels were fabricated by the facile urate oxidase (UOX)-horseradish peroxidase (HRP) cascade enzymatic crosslinking system. For the first time, the cascade enzymatic crosslinking system was not only used for preparing hydrogel wound dressings but also for accelerating wound healing due to the activity retention of the self-compartmental enzymes. A CMCS derivative (HCMCS-mF) synthesized by successively grafting 4-hydroxybenzaldehyde (H) and 5-methylfurfural (mF) on CMCS and a quaternary ammonium crosslinker (QMal) with terminal grafting maleimide (Mal) groups were combined with enzymatic system for the facile preparation of hydrogels. The mild Diels-Alder (DA) crosslinking reaction between mF and Mal groups constructed the first network of hydrogels. The cascade UOX-HRP system mediated the oxidative crosslinking of phenols thus forming the second gel network. Self-entrapped UOX maintained its enzymatic activity and could continuously catalyze the oxidation of uric acid, generating therapeutic allantoin. These porous, degradable, mechanically stable hydrogels with excellent antioxidant performance and enhanced antibacterial capacity could effectively accelerate skin wound repair by simultaneously reducing oxidative stress, relieving inflammation, promoting collagen deposition and upregulating the expression level of CD31.

Mimic enzymatic preparation of conductive supramolecular-polymeric hydrogels with antibacterial and antioxidant properties for accelerating wound healing.

Supramolecular-polymeric hydrogels by combining low-molecular-weight gelators (LMWGs) with polymers have attracted great attention due to their unique double networks. Polymers are generally introduced into an LMWG matrix, thus enhancing the mechanical performance and broadening of the application fields of supramolecular hydrogels. Herein, a series of supramolecular-polymer hydrogels with inherent multiple properties were fabricated as wound dressings. An enzyme-like supramolecular H/G4 hydrogel co-assembled by hemin and guanosine-quartet motifs was successively integrated with hyaluronic acid (HA) and polyaniline (PANI), yielding a supramolecular-polymeric composite hydrogel (namely H/G4-HA(Cu)/PANI). The introduction of Cu2+-crosslinked hydrazide-grafted HA polymeric networks not only enhanced the viscoelasticity of the H/G4 supramolecular hydrogel but also endowed composite hydrogels with bioactive properties as wound healing dressings. The enzyme-like nanofibril H/G4 hydrogel could catalyse the oxidative polymerization of aniline, thus introducing PANI into gel networks. The porous H/G4-HA(Cu)/PANI exhibited a certain degree of swelling ratio under physiological conditions. H/G4-HA(Cu)/PANI also showed degradability, conductivity and appropriate mechanical properties. Through a full-thickness skin defect model of mice, this haemostatic, antioxidant, antibacterial and drug-free H/G4-HA(Cu)/PANI could accelerate wound healing processes by promoting wound closure, collagen deposition and upregulation of the CD31 expression level, which indicates that H/G4-HA(Cu)/PANI could be a promising wound dressing material.

Photo-induced adhesive carboxymethyl chitosan-based hydrogels with antibacterial and antioxidant properties for accelerating wound healing.

Designing adhesive hydrogel wound dressings with inherent antibacterial and antioxidant properties is desirable to treat cutaneous full-thickness injuries in clinical care. Herein, a series of photo-induced Schiff base crosslinking-based adhesive hydrogels with promising traits are designed and prepared through Diels-Alder (DA) reactions between functional groups-grafted carboxymethyl chitosan (CMCS) and a photo-responsive polyethylene glycol (PEG) crosslinker. The quaternary ammonium and phenol groups in modified CMCS endows hydrogels excellent antibacterial and antioxidant properties. Upon UV (365 nm) irradiation, the generated o-nitrosobenzaldehyde from the photo-isomerization of o-nitrobenzyl in PEG derivative can subsequently crosslink with amino groups on tissue interfaces via Schiff base, endowing the hydrogel with well adhesiveness. Additionally, the hydrogel exhibits good BSA adsorption capacity, cytocompatibility and hemostatic property. The in vivo full-thickness skin defect study on mice indicates that the multi-functional hydrogel with considerable collagen deposition and vascularization capacities can be an effective and promising adhesive dressing for improving wound healing.

Photo-induced programmable degradation of carboxymethyl chitosan-based hydrogels.

Hydrogels are widely used in the biomedical field, due to their high similarity to native extracellular matrix (ECM). Most responsive hydrogels could only passively receive stimuli and independently change their properties. In this study, a photosensitive o-nitrobenzyl (NB) ester linker of polyethylene glycol (PEG) with maleimido (Mal) as terminal groups (PEG-NB-Mal) and a 5-methylfurfuryl (mF) grafted carboxymethyl chitosan (CMCS) derivative (CMCS-mF) were synthesized and used to prepare functional hydrogels via Diels-Alder (DA) reactions. The hydrogel exhibited programmable degradation properties after sequential exposure to UV light and acid treatments. It can maintain high integrity upon the single stimuli, the cascade acid and UV light treatments or the cascade UV light and alkaline treatments. Moreover, the hydrogel exhibited well controlled release profile of rhodamine B (RB). In summary, such CMCS-based hydrogels show great potential in biomedical applications. In addition, the usage of photo-induced cascade reaction in sequential degradation hydrogels can be extended to design other types of programmable smart materials.

One-pot preparation of double network hydrogels via enzyme-mediated polymerization and post-self-assembly for wound healing.

Hybrid hydrogels combining polymers and low-molecular-weight gelators (LMWGs) are promising soft materials. Self-assembled LMWG-based supramolecular networks via noncovalent interactions exhibit excellent reversible thixotropy, which are usually incorporated into polymer gel networks generating functional double network hybrid hydrogels. In this study, we used enzyme-mediated polymerization and post-self-assembly for the one-pot preparation of LMWG-based hybrid hydrogels which consist of a covalently cross-linked polyacrylamide as the first chemical network and post-self-assembled DBS-COOH as the second supramolecular network. The gelation processes are monitored by the EPR measurement and 1H NMR characterization. The DBS-COOH gel network endows the hybrid gel with a well-controlled release behaviour of an anti-inflammatory drug-diclofenac sodium (DCF). Further in vivo wound healing experiments elucidated that the hybrid gel is a promising candidate material for biomedical applications. The enzymatic one-pot preparation principle will provide a unique viewpoint for fabricating functional LMWG/polymer hybrid hydrogels.

Controllable Growth of Core-Shell Nanogels via Esterase-Induced Self-Assembly of Peptides for Drug Delivery.

In this work, we developed an unexplored enzyme-responsive core-shell nanogel via the assembly of hydrogelators at the surface of silicon nanoparticles. The immobilized carboxylesterase at the surface of silicon nanoparticles can catalyse precursors into hydrogelators, self-assembling around the surface of silicon nanoparticles owing to its surface confinement effect. These novel phenomena can be confirmed by observation of their morphology and increased diameters through scanning electron microscopy, transmission electron microscopy and dynamic light scattering. Moreover, these resulting core-shell nanogels can achieve controlled growth of the gel layer by means of changing the concentrations of precursors. Because of their good biocompatibility, these nanogels can realize applications in enzyme-specific drug delivery as nanocarriers.

d-Serine enzymatic metabolism induced formation of a powder-remoldable PAAM-CS hydrogel.

The metabolism of d-serine by d-amino acid oxidase was developed to induce radical polymerization and formation of a powder-remoldable PAAM-CS hydrogel.