A cyclic brush zwitterionic polymer based pH-responsive nanocarrier-mediated dual drug delivery system with lubrication maintenance for osteoarthritis treatment.

Enhanced joint synergistic lubrication combined with anti-inflammatory therapy is an effective strategy to delay the progression of early osteoarthritis (OA) but has been rarely reported. The hydration lubrication of zwitterions and inherent super-lubrication properties of the cyclic brush, as well as the enhancement of the steric stability of the cyclic topology, can effectively improve the drug loading and utilization; herein we report a pH-responsive cyclic brush zwitterionic polymer (CB) with SBMA and DMAEMA as brushes and a cyclic polymer (c-P(HEMA)) as the core template, possessing a low coefficient of friction (0.017). After loading with hydrophobic curcumin and hydrophilic loxoprofen sodium it demonstrates high drug-loading efficiency. In vitro and in vivo experiments confirmed the triple function of the CB on superlubrication, sequence controlled release and anti-inflammatory effects demonstrated by Micro CT, histological analysis and qRT-PCR. Overall, the CB is a promising long-acting lubricating therapeutic agent, with potential for OA treatment or other diseases.

Ratiometric singlet oxygen self-detecting and oxygen self-supplying nanosensor for real-time photodynamic therapy feedback and therapeutic effect enhancement.

Integration of singlet oxygen (1O2) detection that provides necessary therapeutic feedback into nanotheranostics for hypoxic tumor photodynamic therapy (PDT) is desirable but still challenging. Herein, we report a nanosensor (denominated PAPD) by combining dual-channel ratiometric sensing and oxygen-augmenting strategies, which synergistically realizes real-time 1O2 self-detection, O2 self-supply and enhanced phototherapy. PAPD nanosensor is constructed by encapsulating anthracene-based 1O2 sensitive fluorophore (DPA) into porphyrin metal-organic frameworks (PCN-224), decorating gold nanoparticles (AuNPs) as nanoenzymes, and coating polyethylene glycol thiol (PEG-SH) by the Au-S bond. PCN-224 serves as 1O2 reference fluorescence (FL) agent and photosensitizer. Once PCN-224-induced 1O2 is synthesized, the dual-channel ratiometric FL signal of PAPD actualizes sensitive, accurate and dynamic 1O2 visualization and gives real-time therapeutic information correlated with the therapeutic progression. Additionally, the catalase-like activity of PAPD possesses in situ O2 production via intracellular H2O2 decomposition and accelerates 1O2 yields for amplifying the tumor cell killing efficiency. Moreover, the ratiometric 1O2 self-detection affords the capacity to evaluate the O2 self-supplying effect in tumor 4T1 cells. Consequently, the rational-designed nanosensor PAPD provides a paradigm for real-time therapeutic evaluation and precise hypoxic tumor treatment clinically.

Hexapeptide decorated ß-cyclodextrin delivery system for targeted therapy of bone infection.

Successfully treating bone infections is a major orthopedic challenge. Clinically, oral, intravenous, or intramuscular injections of drugs are usually used for direct or complementary treatment. However, once the drug enters the system, it circulates throughout the body, leading to an insufficient local dose and limiting the therapeutic effect because of the lack of targeting in the drug system. In this study, ß-cyclodextrin, modified with poly (ethylene glycol) [PEG] and aspartic acid hexapeptide (Asp6-ß-CD), was used to specifically target the hydroxyapatite (HA) component of the bone. It was then loaded with norfloxacin (NFX) to treat bone infections. The antibacterial ability of NFX was enhanced by loading it into Asp6-ß-CD, because the solubility of Asp6-ß-CD@NFX increased significantly. Moreover, Asp6-ß-CD could target bone tissue in nude mice and showed significantly enhanced accumulation (10 times) than the unmodified ß-CD. In addition, in a rat model of osteomyelitis, Asp6-ß-CD@NFX targeted HA well and exerted its antibacterial activity, which reduced inflammation and promoted bone tissue repair. This study indicates that the Asp6-ß-CD based drug delivery system can efficiently target bone tissue to enable potential applications for treating bone-related diseases.

Chloroplast-inspired Scaffold for Infected Bone Defect Therapy: Towards Stable Photothermal Properties and Self-Defensive Functionality.

Bone implant-associated infections induced by bacteria frequently result in repair failure and threaten the health of patients. Although black phosphorus (BP) material with superior photothermal conversion ability is booming in the treatment of bone disease, the development of BP-based bone scaffolds with excellent photothermal stability and antibacterial properties simultaneously remains a challenge. In nature, chloroplasts cannot only convert light into chemical energy, but also hold a protective and defensive envelope membrane. Inspired by this, a self-defensive bone scaffold with stable photothermal property is developed for infected bone defect therapy. Similar to thylakoid and stroma lamella in chloroplasts, BP is integrated with chitosan and polycaprolactone fiber networks. The mussel-inspired polydopamine multifunctional "envelope membrane" wrapped above not only strengthens the photothermal stability of BP-based scaffolds, but also realizes the in situ anchoring of silver nanoparticles. Bacteria-triggered infection of femur defects in vivo can be commendably inhibited at the early stage via these chloroplast-inspired implants, which then effectively promotes endogenous repair of the defect area under mild hyperthermia induced by near-infrared irradiation. This chloroplast-inspired strategy shows outstanding performance for infected bone defect therapy and provides a reference for the functionality of other biomedical materials.

Polyvinyl alcohol/chitosan composite hydrogels with sustained release of traditional Tibetan medicine for promoting chronic diabetic wound healing.

The Tibetan eighteen flavor dangshen pills (TEP) are composed of 18 traditional Tibetan medicines, which are commonly used in the treatment of skin diseases in the Tibetan medical system. They have anti-inflammatory and analgesic effects, and healing properties. However, TEP contain large doses and have strong side effects and low bioavailability. To improve the utilization rate of TEP in skin treatment, we prepared TEP powder and then introduced it into polyvinyl alcohol/chitosan (PVA/CS) hydrogels to treat diabetic wounds by slowly releasing the active ingredients of TEP. In vitro studies showed that TEP-loaded hydrogels can effectively and continuously release the active ingredients of TEP and have antibacterial and antioxidant properties. In addition, the hydrogel system was not cytotoxic to L929 cells, and significantly promoted the proliferation of HUVECs. Moreover, when the TEP-loaded hydrogel was applied to diabetic wounds in rats, it reduced the inflammatory response and improved collagen deposition, which in turn promoted skin healing. Our results indicate that TEP-loaded hydrogels may be a new formulation for the application of traditional Tibetan medicines for the treatment of chronic wounds.

Programmed antibacterial and mineralization therapy for dental caries based on zinc-substituted hydroxyapatite/ alendronate-grafted polyacrylic acid hybrid material.

The domination of cariogenic bacteria in dental plaque biofilms is the primary cause of dental caries. In view of this, for the purpose of an effective treatment of dental caries, it is of great importance to inhibit the activity of acidogenic bacteria and promote the remineralization of damaged teeth simultaneously. However, the expensive antibacterial agents and poor mineralization ability of materials limit the practical applications. Biomineralization regulated by non-collagenous proteins (NCPs) gives hints to combine the remineralization ability of NCPs with accessible antibacterial property effectively. In this work, we propose a programmed antibacterial and remineralization strategy for the therapy of dental caries based on zinc-substituted hydroxyapatite/ alendronate-grafted polyacrylic acid hybrid nanoneedles (ZHA@ALN-PAA). This hybrid material dissolves in the acidic caries environment and regulate the pH to nearly neutral (6.5). Abundant calcium/ phosphate ions are supplemented and the ALN-PAA embedded in it has also been released, which assists the biomineralization on tooth defect. It has been revealed that the inhibition ratio of ZHA@ALN-PAA against Streptococcus mutans is the highest (11.25 folds that of HA), which originates from the highest zinc ions released (132.9 mg/L). Besides, the interspace of etched enamel is fully filled with regenerated nanorods and the surface microhardness (SMH) is significantly improved (3.68 folds that of etched enamel) after only 3 days of mineralization in vitro. This strategy developed here is simple and cost-effective, which can be referred to design the effective anti-caries materials applied for clinic treatment and daily oral care.

Zwitterionic PMCP-Modified Polycaprolactone Surface for Tissue Engineering: Antifouling, Cell Adhesion Promotion, and Osteogenic Differentiation Properties.

Biodegradable polycaprolactone (PCL) has been widely applied as a scaffold material in tissue engineering. However, the PCL surface is hydrophobic and adsorbs nonspecific proteins. Some traditional antifouling modifications using hydrophilic moieties have been successful but inhibit cell adhesion, which is not ideal for tissue engineering. The PCL surface is modified with bioinspired zwitterionic poly[2-(methacryloyloxy)ethyl choline phosphate] (PMCP) via surface-initiated atom transfer radical polymerization to improve cell adhesion through the unique interaction between choline phosphate (CP, on PMCP) and phosphate choline (PC, on cell membranes). The hydrophilicity of the PCL surface is significantly enhanced after surface modification. The PCL-PMCP surface reduces nonspecific protein adsorption (e.g., up to 91.7% for bovine serum albumin) due to the zwitterionic property of PMCP. The adhesion and proliferation of bone marrow mesenchymal stem cells on the modified surface is remarkably improved, and osteogenic differentiation signs are detected, even without adding any osteogenesis-inducing supplements. Moreover, the PCL-PMCP films are more stable at the early stage of degradation. Therefore, the PMCP-functionalized PCL surface promotes cell adhesion and osteogenic differentiation, with an antifouling background, and exhibits great potential in tissue engineering.