Injective Programmable Proanthocyanidin-Coordinated Zinc-Based Composite Hydrogel for Infected Bone Repair.

Effectively integrating infection control and osteogenesis to promote infected bone repair is challenging. Herein, injective programmable proanthocyanidin (PC)-coordinated zinc-based composite hydrogels (ipPZCHs) are developed by compositing antimicrobial and antioxidant PC-coordinated zinc oxide (ZnO) microspheres with thioether-grafted sodium alginate (TSA), followed by calcium chloride (CaCl ) crosslinking. Responsive to the high endogenous reactive oxygen species (ROS) microenvironment in infected bone defects, the hydrophilicity of TSA can be significantly improved, to trigger the disintegration of ipPZCHs and the fast release of PC-coordinated ZnOs.

Versatile Polymer-Initiating Biomineralization for Tumor Blockade Therapy.

Tumor blockade therapy is a promising penetration-independent antitumor modality, which effectively inhibits the exchange of nutrients, oxygen, and information between the tumor and surrounding microenvironments. However, the current blockade therapy strategies have limited antitumor efficacy due to defects of inadequate tumor obstruction, possible side effects, and short duration. For these reasons, a facilely synthesized versatile polymer 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-poly(ethylene glycol)-alendronate (DSPE-PEG-ALN, DPA) is developed to initiate the formation of biomineral shell around osteosarcoma as a potent physical barrier.

3D-printing magnesium-polycaprolactone loaded with melatonin inhibits the development of osteosarcoma by regulating cell-in-cell structures.

Melatonin has been proposed as a potent anticarcinogen presents a short half-life for osteosarcoma (OS). Cell-in-cell (CIC) structures play a role in the development of malignant tumors by changing the tumor cell energy metabolism. This study developed a melatonin-loaded 3D printed magnesium-polycaprolactone (Mg-PCL) scaffold and investigated its effect and molecular mechanism on CIC in OS.

Poly(l-glutamic acid)-cisplatin nanoformulations with detachable PEGylation for prolonged circulation half-life and enhanced cell internalization.

PEGylation has been widely applied to prolong the circulation times of nanomedicines the steric shielding effect, which consequently improves the intratumoral accumulation. However, cell uptake of PEGylated nanoformulations is always blocked by the steric repulsion of PEG, which limits their therapeutic effect. To this end, we designed and prepared two kinds of poly(l-glutamic acid)-cisplatin (PLG-CDDP) nanoformulations with detachable PEG, which is responsive to specific tumor tissue microenvironments for prolonged circulation time and enhanced cell internalization.

Poly(lactic--glycolic acid)-based composite bone-substitute materials.

Research and development of the ideal artificial bone-substitute materials to replace autologous and allogeneic bones for repairing bone defects is still a challenge in clinical orthopedics. Recently, poly(lactic--glycolic acid) (PLGA)-based artificial bone-substitute materials are attracting increasing attention as the benefit of their suitable biocompatibility, degradability, mechanical properties, and capabilities to promote bone regeneration. In this article, we comprehensively review the artificial bone-substitute materials made from PLGA or the composites of PLGA and other organic and inorganic substances, elaborate on their applications for bone regeneration with or without bioactive factors, and prospect the challenges and opportunities in clinical bone regeneration.

Mesenchymal stem cells for cartilage regeneration.

Cartilage injuries are typically caused by trauma, chronic overload, and autoimmune diseases. Owing to the avascular structure and low metabolic activities of chondrocytes, cartilage generally does not self-repair following an injury. Currently, clinical interventions for cartilage injuries include chondrocyte implantation, microfracture, and osteochondral transplantation.

Spatiotemporally Targeted Nanomedicine Overcomes Hypoxia-Induced Drug Resistance of Tumor Cells after Disrupting Neovasculature.

Vascular disrupting agents (VDAs) are emerging anticancer agents, which show rising demand for combination with cytostatic drugs (CSDs), owing to inadequate tumor inhibition when applied singly. Nevertheless, the combination remains a challenge due to the different working sites of VDAs and CSDs and hypoxia-induced drug resistance after disrupting neovasculature by VDAs. Herein, we developed a shell-stacked nanoparticle (SNP) for coencapsulation of a VDA combretastatin A-4 phosphate (CA4P) and a proteasome inhibitor bortezomib (BTZ).

Electroactive composite scaffold with locally expressed osteoinductive factor for synergistic bone repair upon electrical stimulation.

Tissue engineering is a promising strategy for the repair of large-scale bone defects, in which scaffolds and growth factors are two critical issues influencing the efficacy of bone regeneration. Unfortunately, the broad application of growth factors is limited by their poor stability in the scaffolds. In the present study, the strictly controlled expression of human bone morphogenetic protein-4 (hBMP-4) in the presence of doxycycline is achieved by adding an hBMP-4 gene fragment into a non-viral artificial restructuring plasmid vector (pSTAR) to form the pSTAR-hBMP-4 plasmid (phBMP-4).

Polymer-Mediated Penetration-Independent Cancer Therapy.

The development of polymer-based drug delivery systems provides efficient modalities for cancer therapy. Most of the polymer pharmaceuticals target cancer cells directly, but the insufficient penetration always results in unsatisfactory anticancer efficacy. To break the above bottleneck, strategies of penetration-independent cancer therapy have been developed as advanced treatments for various cancers in the past decade.

Chiral Polypeptide Thermogels Induce Controlled Inflammatory Response as Potential Immunoadjuvants.

The in vivo implanted biomaterials are known to induce inflammatory response and recruit immune cells, which could be used as robust adjuvants for immunotherapy. However, the degree of inflammatory response induced by the implanted biomaterials is hard to control. In this work, we reported the application of three kinds of thermogels from the polypeptide methoxy poly(ethylene glycol)-polyalanine (mPEG-PAla) with various chiralities to regulate the levels of inflammatory responses in vivo.

Gradiently degraded electrospun polyester scaffolds with cytostatic for urothelial carcinoma therapy.

Kidney-sparing surgery is the preferred treatment strategy for low-risk upper tract urothelial carcinoma (UTUC). However, after this procedure, prevention of the carcinoma recurrence in the ureter and supporting the ureter with a ureteral stent are necessary. Biodegradable drug-loaded ureteral scaffolds are able to maintain their long-term effective drug concentrations in the lesion sites without the defects of traditional ureteral stents, which may address both issues simultaneously.

Injectable Enzymatically Cross-linked Hydrogels with Light-Controlled Degradation Profile.

An advanced hydrogel that features facile formation and injectability as well as light-controlled degradation profile is reported here. By modifying 4-arm poly(ethylene glycol) (4-arm PEG) with 2-nitrobenzyl (NB) and phenol, the 4-arm PEG precursor solutions could form enzymatically cross-linked hydrogels in the presence of horseradish peroxidase (HRP) and hydrogen peroxide (H O ). The gelation time, mechanical strength, and porous structure could be simply tuned by the concentration of HRP and H O .

Receptor and Microenvironment Dual-Recognizable Nanogel for Targeted Chemotherapy of Highly Metastatic Malignancy.

Targeted delivery of chemotherapeutic drugs to the desired lesion sites is the main objective in malignancy treatment, especially in highly metastatic malignancies. However, extensive studies around the world on traditional targeting strategies of recognizing either overexpressed receptors or microenvironments in tumors show great limitations, owing to the off-target effect and tumor homogeneity. Integration of both receptor-mediated targeting (RMT) and environment-mediated targeting (EMT) enhances the tumor accumulation and subsequent cell uptake at the same time, which may avoid these limitations.

Sequentially Responsive Shell-Stacked Nanoparticles for Deep Penetration into Solid Tumors.

Nanomedicine to overcome both systemic and tumor tissue barriers ideally should have a transformable size and surface, maintaining a certain size and negative surface charge for prolonged circulation, while reducing to a smaller size and switching to a positive surface charge for efficient penetration to and retention in the interstitial space throughout the tumor tissue. However, the design of such size and charge dual-transformable nanomedicine is rarely reported. Here, the design of a shell-stacked nanoparticle (SNP) is reported, which can undergo remarkable size reduction from about 145 to 40 nm, and surface charge reversal from -7.

Schiff base bond-linked polysaccharide-doxorubicin conjugate for upregulated cancer therapy.

The pH-responsive polymer prodrugs were designed to maintain sufficient stability in the bloodstream and promptly release the active drugs when entering the acidic microenvironments, such as tumor tissue and cells. This kind of polymer-drug conjugates has become increasingly intriguing given the specific advantages over traditional drug delivery system. In our work, dextran (Dex) was oxidized into aldehyde-functionalized Dex-CHO before conjugating with doxorubicin (DOX) via efficient Schiff base reaction.

Core cross-linked poly(ethylene glycol)-graft-Dextran nanoparticles for reduction and pH dual responsive intracellular drug delivery.

A kind of core cross-linked poly(ethylene glycol)-graft-Dextran nanoparticles (CPD NPs) was prepared by a simple chemical cross-linking method for reduction and pH dual response drug delivery. The resultant CPD NPs are of homogeneous spherical structure with sizes from 69±11 to 107±18nm. Doxorubicin (DOX) was then loaded into the CPD NPs in high efficiency, and showing typical reduction and pH dual responsive release profiles.

Scavenger Receptor-Mediated Targeted Treatment of Collagen-Induced Arthritis by Dextran Sulfate-Methotrexate Prodrug.

Rheumatoid arthritis (RA) is a chronic autoimmune disorder implicated in multiple joint affection and even disability. The activated macrophages perform a predominant role in onset and persistence of RA. Scavenger receptor (SR), one of several receptors overexpressed on the activated macrophages, is a specific biomarker for targeted therapy of numerous chronic inflammation diseases like RA.

High-Pressure Compression-Molded Porous Resorbable Polymer/Hydroxyapatite Composite Scaffold for Cranial Bone Regeneration.

Fabricating porous scaffolds with sufficient mechanical properties is a challenge for healing bone defects. High-pressure compression-molded (HPCM) porous composite scaffold comprising poly(l-lactide) (PLLA), poly(lactide--glycolide) (PLGA), and hydroxyapatite (HA) was prepared and showed upregulated mechanical properties due to a solid network structure and a highly ordered crystalline architecture. The compressive yield strength and modulus of the HPCM scaffold molded at 1000 MPa and 180 °C were 0.

Drug binding rate regulates the properties of polysaccharide prodrugs.

Three intracellular acid-degradable hydroxyethyl starch-doxorubicin (HES[double bond, length as m-dash]DOX) prodrugs with different drug binding rates (DBRs) were synthesized through the conjugation of oxidized HES and DOX with a pH-responsive Schiff base bond. The DBRs of HES[double bond, length as m-dash]DOX conjugates were determined to be 1.7, 3.

One-Step "Click Chemistry"-Synthesized Cross-Linked Prodrug Nanogel for Highly Selective Intracellular Drug Delivery and Upregulated Antitumor Efficacy.

Polymeric prodrugs formed by the conjugation of drugs onto polymers have shown great promise in cancer therapy because of the enhancement of water solubility, elimination of premature drug release, and the improvement of pharmacokinetics. To integrate the two advantages of upregulated stability during circulation and selective release of drug in cancer cells, a pH and reduction dual-sensitive prodrug nanogel (CLP) was synthesized via a simple one step "click chemistry". CLP was spherically shaped with a uniform diameter of 60.

A comparative study of linear, Y-shaped and linear-dendritic methoxy poly(ethylene glycol)-block-polyamidoamine-block-poly(l-glutamic acid) block copolymers for doxorubicin delivery in vitro and in vivo.

Unlabelled: The linear, Y-shaped, and linear-dendritic block copolymers of methoxy poly(ethylene glycol)-block-polyamidoamine-block-poly(l-glutamic acid) (MPEG-b-PAMAM-b-PGA) with one, two, four, and eight PGA arms but similar MPEG/PGA weight ratios (W/W) (named as P1PA, P2PA, P4PA and P8PA, respectively) were synthesized and comparatively investigated for doxorubicin hydrochloride (DOX) delivery. All the obtained block copolymers were highly biocompatible and could efficiently load DOX into nanoparticles (NPs) through electrostatic interaction. The NPs formed by linear (P1PA) or Y-shaped (P2PA) block copolymers and DOX were spherically shaped with smaller sizes, while the NPs formed from linear-dendritic block copolymers (P4PA and P8PA) were irregular in shape and larger in size.

Activated macrophage-targeted dextran-methotrexate/folate conjugate prevents deterioration of collagen-induced arthritis in mice.

Rheumatoid arthritis (RA) is an autoimmune inflammatory disease, leading to articular synovial hyperplasia, cartilage destruction, and bone erosion. In RA pathophysiology, the activated macrophages contribute to the initiation and maintenance of the disease. Folate receptor, an overexpressed receptor on the activated macrophages, becomes a promising target site for RA treatment.