Synthesis of Paclitaxel Derivatives for Remote Loading into Liposomes and Improved Therapeutic Effect.

A series of novel paclitaxel derivatives modified by boronic acid according to the characteristics of the interaction between RB(OH)2 and different strapping agents of intraliposomal aqueous phase were designed and synthesized, which were then used to develop remote poorly water-soluble drugs loading into liposomes. Meanwhile, we screened nineteen paclitaxel boronic acid derivatives for their cytotoxic activities against three cancer cell lines (A549, HCT-116 and 4T1) and one normal cell line (LO2), and performed liposome formulation screening of active compounds. Among all the compounds, the liposome of 4d, with excellent drug-encapsulated efficiency (>95% for drug-to-lipid ratio of 0.1 w/w), was the most stable. Furthermore, the liposomes of compound 4d (8 mg/kg, 4 times) and higher dose of compound 4d (24 mg/kg, 4 times) showed better therapeutic effect than paclitaxel (8 mg/kg, 4 times) in the 4T1 tumor model in vivo, and the rates of tumor inhibition were 74.3%, 81.9% and 58.5%, respectively. This study provided a reasonable design strategy for the insoluble drugs to improve their drug loading into liposomes and anti-tumor effect in vivo.

Multifunctionalized Micelles Facilitate Intracellular Doxorubicin Delivery for Reversing Multidrug Resistance of Breast Cancer.

Intracellular doxorubicin (DOX) pumping out of cells through the P-glycoprotein (P-gp) transporter leads to the reduction of intracellular DOX levels and induces multidrug resistance (MDR). A hyaluronic acid-deoxycholic acid-histidine and Pluronic F127 (PF127) mixed micellar system, named HA-DOCA-His-PF micelles, functionalized with active targeted endocytosis mediated via CD44 receptor, intracellular triggered DOX release under endosome-pH, and combined with PF127-mediated P-gp efflux inhibition was developed for sufficient intracellular DOX delivery and MDR reversion. The DOX/HA-DOCA-His-PF drug-loaded micelles displayed endosomal pH-mediated self-assembly/disassembly characteristics, triggered DOX release under an endosomal (pH 5.5) environment, and demonstrated enhanced cytotoxicity and superior MDR reversion performance against drug-resistant MCF-7/Adr tumor cells. Importantly, superior antitumor activity of DOX/HA-DOCA-His-PF micelles was presented on the growth inhibition of MCF-7/Adr tumor cells, by further inhibiting the P-gp activity on intracellular DOX efflux through the depletion of intracellular adenosine triphosphate content. This multifunctional micellar system could be facilitated by the intracellular DOX delivery for reversing MDR of breast cancer.

Co-Delivery of Paclitaxel by a Capsaicin Prodrug Micelle Facilitating for Combination Therapy on Breast Cancer.

Poor anticancer ability, serious adverse reaction, and drug resistance against paclitaxel (PTX) have limited its clinical applications. When a mouse breast carcinoma cell line (4T1) was treated with both PTX and capsaicin (CAP), there was a synergistic anti-proliferative effect demonstrated with a combination index of 0.28. Therefore, a novel polyethylene glycol-derivatized CAP (PEG-Fmoc-CAP2) polymeric prodrug micellar carrier was developed and further encapsulated with PTX for antitumor combination treatment. The PEG-Fmoc-CAP2 polymeric micelles co-delivered with PTX achieved a 62.3% fraction of apoptotic cells in comparison to 45.4% fraction of apoptotic cells to that upon treatment with PTX alone. Comparable CAP amounts were found in the cell lysate treatment with PEG-Fmoc-CAP2-conjugated micelles to that of free CAP-treated 4T1 cells after 12 h treatment. Pharmacokinetic and biodistribution studies showed that the micelles possessed much longer circulation time in blood and preferential tumor tissue accumulation compared to the Taxol solution. Importantly, PTX/CAP-loaded micelles exhibited superior in vivo antitumor activity on the inhibition rate of tumor growth than other treatments (70.5% tumor growth reduction in PTX/CAP micelle-treated mice vs 57.8, 43.3, and 23.8% of tumor growth inhibition rate in PTX/PEG-Fmoc-OA2 micelles, Taxol, and PEG-Fmoc-CAP2 micelle-treated mice, respectively). Thus, the dual-functional PEG-Fmoc-CAP2 polymeric prodrug micelles are a promising co-delivery nanosystem for achieving synergistic antitumor efficacy of PTX and CAP.

Lymphoma Immunochemotherapy: Targeted Delivery of Doxorubicin via a Dual Functional Nanocarrier.

Chemotherapy drug (paclitaxel, PTX) incorporated in a dual functional polymeric nanocarrier, PEG-Fmoc-NLG, has shown promise as an immunochemotherapy in a murine breast cancer model, 4T1.2. The formulation is composed of an amphiphilic polymer with a built-in immunotherapy drug NLG919 that exhibits the immunostimulatory ability through the inhibition of indoleamine 2,3-dioxygenase 1 (IDO-1) in cancer cells. This work evaluates whether the PEG-derivatized NLG polymer can also be used for delivery of doxorubicin (Dox) in treatment of leukemia. The Dox-loaded micelles were self-assembled from PEG-Fmoc-NLG conjugate, which have a spherical shape with a uniform size of ∼120 nm. In cultured murine lymphocytic leukemia cells (A20), Dox-loaded PEG-Fmoc-NLG micelles showed a cytotoxicity that was comparable to that of free Dox. For in vivo studies, significantly improved antitumor activity was observed for the Dox/PEG-Fmoc-NLG group compared to Doxil or the free Dox group in an A20 lymphoma mouse model. Flow cytometric analysis showed that treatment with Dox/PEG-Fmoc-NLG micelles led to significant increases in the numbers of both total CD4+/CD8+ T cells and the functional CD4+/CD8+ T cells with concomitant decreases in the numbers of myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Treg). Dox/PEG-Fmoc-NLG may represent a promising immunochemotherapy for lymphoma, which warrants more studies in the future.

Programmable co-delivery of the immune checkpoint inhibitor NLG919 and chemotherapeutic doxorubicin via a redox-responsive immunostimulatory polymeric prodrug carrier.

To achieve synergistic therapeutic efficacy and prevent cancer relapse, chemotherapy and immunotherapy have been combined as a new modality for tumor treatment. In this work, we designed a redox-responsive immunostimulatory polymeric prodrug carrier, PSSN10, for programmable co-delivery of an immune checkpoint inhibitor NLG919 (NLG) and a chemotherapeutic doxorubicin (DOX). NLG-containing PSSN10 prodrug polymers were self-assembled into nano-sized micelles that served as a carrier to load DOX (DOX/PSSN10 micelles). DOX/PSSN10 micelles displayed spherical morphology with a size of ∼170 nm. DOX was effectively loaded into PSSN10 micelles with a loading efficiency of 84.0%. In vitro DOX release studies showed that rapid drug release could be achieved in the highly redox environment after intracellular uptake by tumor cells. In 4T1.2 tumor-bearing mice, DOX/PSSN10 micelles exhibited greater accumulation of DOX and NLG in the tumor tissues compared with other organs. The PSSN10 carrier dose-dependently enhanced T-cell immune responses in the lymphocyte-Panc02 co-culture experiments, and significantly inhibited tumor growth in vivo. DOX/PSSN10 micelles showed potent cytotoxicity in vitro against 4T1.2 mouse breast cancer cells and PC-3 human prostate cancer cells comparable to that of DOX. In 4T1.2 tumor-bearing mice, DOX/PSSN10 mixed micelles (5 mg DOX/kg, iv) was more effective than DOXIL (a clinical formulation of liposomal DOX) or free DOX in inhibiting the tumor growth and prolonging the survival of the treated mice. In addition, a more immunoactive tumor microenvironment was observed in the mice treated with PSSN10 or DOX/PSSN10 micelles compared with the other treatment groups. In conclusion, systemic delivery of DOX via PSSN10 nanocarrier results in synergistic anti-tumor activity.

One-pot synthesis of fluorescent nitrogen-doped carbon dots with good biocompatibility for cell labeling.

Here we report an easy and economical hydrothermal carbonization approach to synthesize the fluorescent nitrogen-doped carbon dots (N-CDs) that was developed using citric acid and triethanolamine as the precursors. The synthesis conditions were optimized to obtain the N-CDs with superior fluorescence performances. The as-prepared N-CDs are monodispersed sphere nanoparticles with good water solubility, and exhibited strong fluorescence, favourable photostability and excitation wavelength-dependent behavior. Furthermore, the in vitro cytotoxicity and cellular labeling of N-CDs were investigated using the rat glomerular mesangial cells. The results showed the N-CDs have more inconspicuous cytotoxicity and better biosafety in comparison with ZnSe quantum dots, although both targeted the cells successfully. Considering their admirable photostability, low toxicity and good compatibility, the as-obtained N-CDs could have potential applications in biosensors, cellular imaging, and other fields.

One-step modification of fabrics with bioinspired polydopamine@octadecylamine nanocapsules for robust and healable self-cleaning performance.

An in-situ polymerization to coat fabrics with polydopamine-encapsulated octadecylamine endows the fabrics with self-cleaning and self-healing abilities. The treated fabric exhibits self-healing after losing its hydrophobicity. It is durable against washing and mechanical abrasion without changing the hydrophobicity. Thanks to the versatile adhesive property of polydopamine, the approach is compatibile with a variety of substrates, such as fabrics, glass, sponge, paper, and polymeric materials.

Identification of the antibacterial action mechanism of curcumin on Streptococcus mutans through transcriptome profiling.

OBJECTIVE: The purpose of this study was to explore the effect and mechanism responsible for how curcumin affects the biofilm formation by Streptococcus mutans (S. mutans). DESIGN: The antibacterial activity of curcumin was evaluated by measuring the minimum inhibitory concentration (MIC) and the minimum bactericidal concentration (MBC). The mass of the biofilm was measured by crystal violet staining. Transcriptome sequencing was used to obtain all the transcript information associated with the biological activity of curcumin-treated S. mutans. Real-time quantitative PCR (qRT-PCR) was performed to examine the expression levels of related biofilm formation genes. RESULTS: The MIC value for curcumin was 64 µM. Curcumin inhibited the formation of a biofilm by S. mutans and degraded mature biofilms. A gene ontology enrichment analysis showed that the DEGs were significantly relevant to biofilm formation. In addition, 17 significantly enriched Kyoto Encyclopedia of Genes and Genomes pathways (p ≤ 0.01) were identified and were potentially associated with the biochemical metabolic processes of S. mutans. DEGs associated with the biofilm formation of S. mutants, including gtfB, gtfC, rgpG, spaP, spxA1, spxA2, bacA, lrgB, and gshAB. The qRT-PCR results were consistent with transcriptome sequencing that the expression levels of gtfB, gtfC, rgpG, and spaP significantly decreased in the curcumin-treated group, whereas the expression levels of spx1, spx2, bacA, lrgB, and gshAB were up-regulated. CONCLUSIONS: Curcumin showed marked inhibitory effects against the formation of biofilms by S. mutans and degradation of formed biofilms.

Reaction kinetics of chitosan nanogels crosslinked by genipin.

Crosslinking of chitosan chains in dilute solution by natural crosslinker genipin leads to biocompatible nanogels. Here we investigated the reaction kinetics between chitosan and genipin in a 200 mM acetate buffer at 37 °C, and the structural and conformational evolutions of the nanogels during the crosslinking reaction by multi detection asymmetric flow field-flow fractionation (AF4). Upon crosslinking by genipin, the z-average hydrodynamic radius Rhz of the chitosan chains increased from 26 nm to 130 nm, while the weight average molar mass Mw increased from 2.0 × 105 g/mol to 1.8 × 107 g/mol. The crosslinking reaction appeared to be first-order and size-dependent. In particular, the intrachain crosslinking reaction was preferentially for nanogels having the larger size, leading to formation of branched chains/nanogels having a wide range of molar masses between 106 and 108 g/mol but a similar radius of gyration Rg ∼ 40 nm. For the largest nanogel fractions with M > 2.0 × 108 g/mol, both Rg and Rh showed a scaling relation with exponent 1/3 and a structure parameter Rg/Rh = 0.74, as expected for the hard sphere particle. The reaction was accompanied by a reduction of charge density and an increase in hydrophobicity of chitosan nanogels, which plays a key role in the formation of uniform size nanogels with chain density ρ(Rh) up to 0.45 g/cm3.

Blue-ringed octopus-inspired microneedle patch for robust tissue surface adhesion and active injection drug delivery.

Intratissue topical medication is important for the treatment of cutaneous, mucosal or splanchnic diseases. However, penetrating surface barriers to providing adequate and controllable drug delivery while guaranteeing adhesion in bodily fluids remains challenging. Here, the predatory behavior of the blue-ringed octopus inspired us with a strategy to improve topical medication. For effective intratissue drug delivery, the active injection microneedles were prepared in a manner inspired by the teeth and venom secretion of blue-ringed octopus. With on demand release function guided by temperature-sensitive hydrophobic and shrinkage variations, these microneedles can supply adequate drug delivery at an early stage and then achieve the long-term release stage. Meanwhile, the bionic suction cups were developed to facilitate microneedles to stay firmly in place (>10 kilopascal) when wet. With wet bonding ability and multiple delivery mode, this microneedle patch achieved satisfactory efficacy, such as accelerating the ulcers' healing speed or halting early tumor progression.

Association between Periodontitis and Aortic Calcification: A Cohort Study.

The present study investigated the association between the presence of periodontitis and aortic calcification (AC) risk among Chinese adults. A total of 6059 individuals who underwent regular health check-ups and received a diagnosis of periodontitis between 2009 and 2016 were included. The outcome was AC, assessed by a chest low-dose spiral CT scan. Cox proportional hazards regression analysis was used to assess the association between periodontitis and AC risk after adjusting for several confounders. After a median follow-up period of 2.3 years (interquartile range: 1.03-4.97 years), 843 cases of AC were identified, with 532 (12.13%) and 311 (18.59%) patients in the non-periodontitis group and periodontitis group, respectively. Multivariate analyses demonstrated that, compared with those without periodontitis, the hazard ratio and 95% confidence interval for AC risk in participants with periodontitis was 1.18 (1.02-1.36) (P = .025) in the fully adjusted model. Stratified analyses showed that the positive relationship between periodontitis and AC was more evident in males and participants <65 years of age (pinteraction = .005 and .004, respectively). Our results show that the presence of periodontitis was positively associated with AC among Chinese adults, especially among males and younger participants.

Purification of Egg White Lysozyme Determines the Downstream Fibrillation of Protein and Co-assembly with Phytochemicals to Form Edible Hydrogels Regulating the Lipid Metabolism.

Although the synthetic chemistry or synthetic biological systems have already shown the power of biomaterials engineering, natural bioresource matter is still a valuable library of raw ingredients for the production of biomaterials, in particular, the edible ones. However, the influence of upstream isolation and purification of the raw materials on their performance in the downstream processing procedures is still unexplored, which is essential for the engineering of biomaterials. Based on the comparison of conventional techniques, heating-induced precipitation combined with resin-blending ion exchange was developed as a simple and cheap method for the utilization of egg whites to produce the lysozyme that is found to be exclusively feasible for fibrillation. Even with similar purities, only the lysozyme prepared by this method could be utilized to form ordered linear aggregate fibrils. Fibrillation was recently pursued as a new approach to utilize bioresource mass for high-tech end-products. Phytochemicals, totally replacing salts, induced the lysozyme fibrils to form hydrogels spontaneously, which was further demonstrated in an in vivo study to prevent obesity induced by a high-fat diet (HFD) by reducing lipid absorption and lipogenesis, promoting energy expenditure, and inhibiting inflammation. The agri-food bioresource was successfully employed as a proof of concept in edible biomedical materials for the regulation of lipid metabolism.

Gas-Sensitive Cellulosic Triboelectric Materials for Self-Powered Ammonia Sensing.

Gas-sensitive materials are capable of dynamic identification and content monitoring of specific gases in the environment, and their applications in the field of gas sensing are promising. However, weak adsorption properties are the main challenge limiting the application of gas-sensitive materials. A highly adsorbent gas-sensitive cellulose nanofibril (CNF)-based triboelectric material with a layered structure is prepared here and it is applied to self-powered gas sensing. The layered structure of the triethoxy-1H,1H,2H,2H-tridecafluoro-n-octylsilane cellulose nanofiber (PFOTES-CNF)-based gas-sensitive material further enhances the adsorption of the material due to electrostatic adsorption in the electrostatic field induced by triboelectricity. It is found that the ammonia-sensitive material obtained by loading Ti3 C2 Tx in PFOTES-CNF has a fast response/recovery (12/14 s), high sensitivity response (Vair /Vgas  = 2.1), high selectivity response (37.6%), and low detection limit (10 ppm) for 100 ppm of ammonia gas. In addition, the ammonia-sensitive CNF-based triboelectric material can accurately identify NH3 concentration changes in the range of 10-120 ppm and transmit the signal wirelessly to the user interface, facilitating real-time online monitoring of NH3 in the environment. A novel strategy is provided here for designing and preparing high-performance gas-sensitive composites and the analysis of self-powered gas sensing is guided.

Hierarchical Porous Cellulosic Triboelectric Materials for Extreme Environmental Conditions.

Synthetic polymer materials such as paraformaldehyde and polyamides are widely used in the field of energy engineering. However, they pose a challenge to environmental sustainability because they are derived from petrochemicals that are non-renewable and difficult to degrade in the natural environment. The development of high-performance natural alternatives is clearly emerging as a promising mitigation option. Inspired by natural bamboo, this research reports a "three-step" strategy for the large-scale production of triboelectric materials with special nanostructures from natural bamboo. Benefiting from the special hierarchical porous structure of the material, Bamboo/polyaniline triboelectric materials can reach short-circuit current of 2.9 µA and output power of 1.1 W m-2 at a working area of only 1 cm2 , which exceeds most wood fiber-based triboelectric materials. More importantly, it maintains 85% energy harvesting after an extreme environment of high temperature (200 °C), low temperature (-196 °C), combustion environment, and multiple thermal shocks (ΔT = 396 °C). This is unmatched by current synthetic polymer materials. This work provides new research ideas for the construction and application of biomass structural materials under extreme environmental conditions.

Structural-Functional Pluralistic Modification of Silk Fibroin via MOF Bridging for Advanced Wound Care.

Silk fibroin (SF) is widely used to fabricate biomaterials for skin related wound caring or monitoring, and its hydrogel state are preferred for their adaptability and easy to use. However, in-depth development of SF hydrogel is restricted by their limited mechanical strength, increased risk of infection, and inability to accelerate tissue healing. Therefore, a structure-function pluralistic modification strategy using composite system of metal organic framework (MOF) as bridge expanding SF's biomedical application is proposed. After developing the photocuring and bonding SF hydrogel, a MOF drug-loading system is utilized to enhance hydrogel's structural strength while endowing its antibacterial and angiogenic properties, yielding a multifunctional SF hydrogel. The synergy between the MOF and SF proteins at the secondary structure level gives this hydrogel reliable mechanical strength, making it suitable for conventional wound treatment, whether for closing incisions quickly or acting as adhesive dressings (five times the bonding strength of ordinary fibrin glue). Additionally, with the antibacterial and angiogenic functions getting from MOF system, this modified SF hydrogel can even treat ischemic trauma with cartilage exposure. This multiple modification should contribute to the improvement of advanced wound care, by promoting SF application in the production of tissue engineering materials.

Revealing the roles of polymers in supersaturation stabilization from the perspective of crystallization behaviors: A case of nimodipine.

Formulating drugs into amorphous solid dispersions (ASDs) represents an attractive means to enhance the aqueous solubility of drugs. Furthermore, water-soluble polymers have proven highly advantageous for stabilizing supersaturated solutions of ASDs. However, the performance and mechanism of various polymers in stabilizing supersaturated drug solutions have not been well-studied. The aim of this study was to investigate the effects of different commercial polymers on the dissolution behaviors and supersaturation stabilization of the ASDs and to further explore the mechanism of polymer mediated supersaturation maintenance by studying the crystallization behaviors of the ASDs. In this study, nimodipine (NMD) was used as a model drug because of its poor water-solubility and fast crystallization rate in aqueous solution, and three polymers polyvinylpyrrolidone (PVP), vinylpyrrolidone-vinyl acetate copolymer (PVP VA), and polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft co-polymer (Soluplus) was selected as the drug carriers to form the ASDs with NMD. Solid-state characterizations of the ASDs confirmed the amorphous state of the ASD systems. ASDPVP VA demonstrated superior supersaturation maintenance in dissolution experiments compared to the other two ASD systems. Among the polymers tested, PVP VA most efficiently maintained dissolution of NMD and prevented its crystallization from the supersaturated solution. The ability of PVP VA to most-effectively maintain supersaturation of the drug was manifested by inhibition of crystal nucleation rather than inhibition of crystal growth following nucleation. These results suggest that nucleation inhibition was instrumental in enabling the polymer-mediated supersaturation maintenance, at least with NMD.

A mussel-inspired film for adhesion to wet buccal tissue and efficient buccal drug delivery.

Administration of drugs via the buccal route has attracted much attention in recent years. However, developing systems with satisfactory adhesion under wet conditions and adequate drug bioavailability still remains a challenge. Here, we propose a mussel-inspired mucoadhesive film. Ex vivo models show that this film can achieve strong adhesion to wet buccal tissues (up to 38.72 ± 10.94 kPa). We also demonstrate that the adhesion mechanism of this film relies on both physical association and covalent bonding between the film and mucus. Additionally, the film with incorporated polydopamine nanoparticles shows superior advantages for transport across the mucosal barrier, with improved drug bioavailability (~3.5-fold greater than observed with oral delivery) and therapeutic efficacy in oral mucositis models (~6.0-fold improvement in wound closure at day 5 compared with that observed with no treatment). We anticipate that this platform might aid the development of tissue adhesives and inspire the design of nanoparticle-based buccal delivery systems.

Codelivered Chemotherapeutic Doxorubicin via a Dual-Functional Immunostimulatory Polymeric Prodrug for Breast Cancer Immunochemotherapy.

Immunochemotherapy is viewed as a promising approach for cancer therapy via combination treatment with immune-modulating drugs and chemotherapeutic drugs. A novel dual-functional immunostimulatory polymeric prodrug carrier PEG2k-Fmoc-1-MT was developed for simultaneously delivering 1-methyl tryptophan (1-MT) of an indoleamine 2,3-dioxygenase (IDO) inhibitor and chemotherapeutic doxorubicin (DOX) for breast cancer immunochemotherapy. DOX/PEG2k-Fmoc-1-MT micelles were more effective in cell proliferation inhibition and apoptosis induction in 4T1 cells. PEG2k-Fmoc-1-MT prodrug micelles presented enhanced inhibition ability of IDO with decreased kynurenine production and increased the proliferation in dose-dependent manners of effector CD4+ and CD8+ T cells. DOX/PEG2k-Fmoc-1-MT micelles exhibited prolonged blood circulation time and superior accumulation of DOX and 1-MT in tumors compared to that of DOX and 1-MT solutions. A significantly enhanced immune response of the DOX/PEG2k-Fmoc-1-MT micelles was observed with the decreasing tryptophan/kynurenine ratio in blood and tumor tissue, promoting effector CD4+ and CD8+ T cells while reducing regulatory T cell (Tregs) expression. Meanwhile, the coreleased DOX-triggered immunogenic cell death action combined with the cleaved 1-MT promoted the related cytokine secretion of tumor necrosis factor-α, interleukin-2, and interferon-γ, further facilitating the T cell-mediated immune responses. More importantly, the DOX-loaded micelles led to a significantly improved inhibition on tumor growth and prolonged animal survival rate in a 4T1 murine breast cancer model. In conclusion, DOX codelivered by a PEG2k-Fmoc-1-MT immunostimulatory polymeric prodrug showed a maximum immunochemotherapy efficacy against breast cancer.

ZIF-8-Modified Multifunctional Bone-Adhesive Hydrogels Promoting Angiogenesis and Osteogenesis for Bone Regeneration.

Designing bone adhesives with adhesiveness, antideformation, biocompatibility, and biofunctional effects has great practical significance for bone defect reconstructive treatment, especially for bone graft repair surgery. Here, we designed zeolitic imidazolate framework-8 nanoparticle (ZIF-8 NP)-modified catechol-chitosan (CA-CS) multifunctional hydrogels (CA-CS/Z) to stabilize the bone graft environment, ensure blood supply, promote osteogenic differentiation, and accelerate bone reconstruction. Characterizations confirmed the successful synthesis of CA-CS/Z hydrogels. Hydrogels exhibited advanced rheological properties, reliable mechanical strength, and excellent adhesion for clinical applications. Based on excellent biocompatibility, it could enhance paracrine of the vascular endothelial growth factor (VEGF) in rat bone marrow mesenchymal stem cells (rBMSCs) to ensure blood supply reconstruction in bone defect areas. Furthermore, the ZIF-8 NPs released from the hydrogels could also up-regulate the production and secretion of alkaline phosphatase, collagen 1, and osteocalcin, promoting the osteogenic differentiation of rBMSCs. In addition, the antibacterial properties of CA-CS/Z could also be observed. In vivo experiments further provided a powerful proof that CA-CS/Z promoted vascularized osteogenesis in wound areas by stabilizing bone graft materials and greatly accelerated the speed and healing of bone reconstruction. These results indicate the promising potential of CA-CS/Z hydrogels with promoting implantation stability, angiogenesis, and osteogenesis for bone regeneration applications.

Tumor Microenvironment-Triggered Charge Reversal Polymetformin-Based Nanosystem Co-Delivered Doxorubicin and IL-12 Cytokine Gene for Chemo-Gene Combination Therapy on Metastatic Breast Cancer.

Cancer metastasis is the leading cause of high mortality and disease recurrence in breast cancer. In this study, a novel tumor microenvironment charge reversal polymetformin (PMet)-based nanosystem co-delivering doxorubicin (DOX) and plasmid encoding IL-12 gene (pIL-12) was developed for chemo-gene combination therapy on metastatic breast cancer. Cationic PMet was readily self-assembled into micelles for DOX physical encapsulation and pIL-12 complexation, and a hyaluronidase-sensitive thiolated hyaluronic acid (HA-SH) was then collaboratively assembled to the pIL-12/DOX-PMet micelleplexes, abbreviated as HA/pIL-12/DOX-PMet. DOX/pIL-12 loaded in HA/pIL-12/DOX-PMet micelleplexes presented prolonged circulation in blood, efficient accumulation in tumors, and internalization in tumor cells via CD44 receptor-mediated tumor specific-targeting, and DOX/pIL-12 was co-released in endo/lysosomes tumor microenvironment followed by HAase-triggered HA-SH deshielding from HA/pIL-12/DOX-PMet micelleplexes. Moreover, HA/PMet micelleplexes displayed excellent pIL-12 transfection and IL-12 expression in tumors of 4T1 tumor-bearing mice. Importantly, HA/pIL-12/DOX-PMet micelleplexes synergistically enhanced the NK cells and tumor infiltrated cytotoxic T lymphocytes and modulated the polarization from protumor M2 macrophages to activated antitumor M1 macrophages, with concomitant decreasing of the immunosuppressive regulatory T (Treg) cells, accompanied by an increase in the cytokines expression of IL-12, IFN-γ and TNF-α, consequently showing an improved antitumor and antimetastasis activity in 4T1 breast cancer lung metastasis mice model. In conclusion, the tumor microenvironment charge reversal HA/PMet nanosystem holds great promise for DOX/pIL-12 co-delivery and exploitation in chemo-gene combination therapy on metastatic breast cancer.