Cost-effective and natural-inspired lotus root/GelMA scaffolds enhanced wound healing via ROS scavenging, angiogenesis and reepithelialization.

Skin wounds, prevalent and fraught with complications, significantly impact individuals and society. Wound healing encounters numerous obstacles, such as excessive reactive oxygen species (ROS) production and impaired angiogenesis, thus promoting the development of chronic wound. Traditional clinical interventions like hemostasis, debridement, and surgery face considerable challenges, including the risk of secondary infections. While therapies designed to scavenge excess ROS and enhance proangiogenic properties have shown effectiveness in wound healing, their clinical adoption is hindered by high costs, complex manufacturing processes, and the potential for allergic reactions. Lotus root, distinguished by its natural micro and macro porous architecture, exhibits significant promise as a tissue engineering scaffold. This study introduced a novel scaffold based on hybridization of lotus root-inspired and Gelatin Methacryloyl (GelMA), verified with satisfactory physicochemical properties, biocompatibility, antioxidative capabilities and proangiogenic abilities. In vivo tests employing a full-thickness wound model revealed that these scaffolds notably enhanced micro vessel formation and collagen remodeling within the wound bed, thus accelerating the healing process. Given the straightforward accessibility of lotus roots and the cost-effective production of the scaffolds, the novel scaffolds with ROS scavenging, pro-angiogenesis and re-epithelialization abilities are anticipated to have clinical applicability for various chronic wounds.

Multi-walled carbon nanotubes exacerbate doxorubicin-induced cardiotoxicity by altering gut microbiota and pulmonary and colonic macrophage phenotype in mice.

Epidemiologic studies show that the levels of air pollutants and particulate matter are positively associated with the morbidity and mortality of cardiovascular diseases. Here we demonstrate that the intratracheal instillation of multi-walled carbon nanotubes (MWCNTs), a standard fine particle, exacerbate doxorubicin (DOX)-induced cardiotoxicity in mice through altering gut microbiota and pulmonary and colonic macrophage phenotype. MWCNTs (25 µg/kg per day, 5 days a week for 3 weeks) promoted cardiotoxicity and apoptosis in the DOX (2 mg/kg, twice a week for 5 weeks)-treated C57BL/6 mice. MWCNTs exaggerated DOX-induced gut microbiota dysbiosis characterized by the increased abundances of Helicobacteraceae and Coriobacteriaceae. In addition, MWCNTs promoted DOX-induced M1-like polarization of colonic macrophages with an increase in TNF-α, IL-1ß and CC chemokine ligand 2 in peripheral blood. Importantly, treatment with the antibiotics attenuated MWCNTs plus DOX-induced apoptosis of cardiomyocytes and M1-like polarization of colonic macrophages. The fecal microbiota transplantation demonstrated that MWCNTs exaggerated DOX-induced cardiotoxicity with M1-like polarization of colonic macrophages. The conditioned medium from MWCNTs-treated pulmonary macrophages promoted DOX-induced gut microbiota dysbiosis and colonic macrophage polarization. Furthermore, the co-culture of macrophages and fecal bacteria promoted M1-like macrophage polarization and their production of TNF-α and IL-1ß, and thereby exacerbated the effects of MWCNTs. Moreover, IL-1ß and TNF-α blockade, either alone or in combination attenuated MWCNTs-exacerbated cardiotoxicity. In summary, MWCNTs exacerbate DOX-induced cardiotoxicity in mice through gut microbiota and pulmonary and colonic macrophage interaction. Our findings identify a novel mechanism of action of inhaled particle-driven cardiotoxicity.

Enhanced osseointegration of double network hydrogels via calcium polyphosphate incorporation for bone regeneration.

To overcome the low mechanical strength and difficult bonding of hydrogels to bones which are the major limitations of hydrogels used in bone-regeneration, a new type of calcium polyphosphate incorporated into bioinspired alginate/polyacrylic acid (CPP/PAA-Alg) hybrid double network (DN) hydrogel with both high strength and enhanced osseointergration was prepared by a two-step polymerization with alginate and polyacrylic acid for bone regeneration. The morphology, mechanical properties, swelling, biocompatibility, osseointegration and osteogenic ability of this CPP/PAA-Alg DN hydrogel were investigated. The results show that CPP/PAA-Alg DN hydrogel with highly porous microstructure possesses high water absorption capacity and highly strength properties which meet the requirements of bone repairing. The results of in vitro studies revealed that the CPP/PAA-Alg DN hydrogels can support the spread of cells and promote the cell proliferation. Animal studies demonstrated that the CPP incorporated would enhance the osseointegration of DN hydrogel with host bone at an early stage after implantation to accelerate the regeneration of bone. This research may provide a new way to develop biocompatible biomaterials with high mechanical strength and good osseointegration to meet the needs of bone regeneration.

Tumor immune microenvironment modulation-based drug delivery strategies for cancer immunotherapy.

The past years have witnessed promising clinical feedback for anti-cancer immunotherapies, which have become one of the hot research topics; however, they are limited by poor delivery kinetics, narrow patient response profiles, and systemic side effects. To the best of our knowledge, the development of cancer is highly associated with the immune system, especially the tumor immune microenvironment (TIME). Based on the comprehensive understanding of the complexity and diversity of TIME, drug delivery strategies focused on the modulation of TIME can be of great significance for directing and improving cancer immunotherapy. This review highlights the TIME modulation in cancer immunotherapy and summarizes the versatile TIME modulation-based cancer immunotherapeutic strategies, medicative principles and accessory biotechniques for further clinical transformation. Remarkably, the recent advances of cancer immunotherapeutic drug delivery systems and future prospects of TIME modulation-based drug delivery systems for much more controlled and precise cancer immunotherapy will be emphatically discussed.

Double-Layer Microsphere Incorporated with Strontium Doped Calcium Polyphosphate Scaffold for Bone Regeneration.

To design and prepare a novel controlled release system for sustained release of two drugs. In this study, a double-layer microsphere was incorporated with strontium-doped calcium polyphosphate (SCPP) scaffold to facilitate bone regeneration and achieve skull repair. The double-layer microsphere combining tetracycline loaded sodium alginate and matrix metalloproteinase-2 (MMP-2) loaded chitosan was manufactured by electrospinning, which were further adhered to SCPP scaffold. The characteristics of microstructure were observed through scanning electron microscope. Loading efficiencies and the optimal ratio of microsphere of the obtained controlled release system were investigated. In addition, the cytotoxicity and the effects on osteoblast proliferation and expressions of osteogenesis-related factors were examined in vitro. Thereafter, the compound material with the controlled release system was implanted in the skull defect of rabbit to evaluate its properties of promoting bone regeneration. The results indicated that this novel controlled release system with SCPP scaffold and the double-layer microspheres loaded with tetracycline and MMP-2 could be a promising material for bones repair.

Egg white coated alginate nanoparticles with electron sprayer for potential anticancer application.

To development biomimetic strategy for enhanced cancer therapy, the paclitaxel loaded egg white/sodium alginate nanoparticles were prepared by electronic spray method. Their appearance and particle size were observed by transmission electron microscope and particle size analyzer. The drug release behavior of nanoparticles was determined by high performance liquid chromatography (HPLC). The toxicity, morphology and interaction of nanoparticles to cells were studied by means of MTT, live/dead staining and laser scanning confocal microscopy. The results show that the nanoparticles have good particle size dispersion, regular morphology, good drug release performance, good biocompatibility and in vitro effective inhibition of CT26 colorectal cancer cells. These results demonstrated that the good biocompatibility of egg white coated sodium alginate nanoparticles and PTX loaded these nanoparticles would show potential application for cancer therapy.

Modulation of intestinal microbiota by glycyrrhizic acid prevents high-fat diet-enhanced pre-metastatic niche formation and metastasis.

High-fat diet (HFD) promotes lung pre-metastatic niche formation and metastasis. Thus, there is an urgent need to identify the underlying mechanisms and develop strategies to overcome them. Here we demonstrate that glycyrrhizic acid (GA) prevents HFD-enhanced pre-metastatic niche formation and metastasis through gut microbiota. GA reduced HFD-enhanced myeloid-derived suppressor cell recruitment, pro-metastatic protein S100A8/A9 expression and metastasis burden of 4T1 breast cancer and B16F10 melanoma, accompanied by gut microbiota alteration and colonic macrophage polarization far away the M1-like phenotype. These parameters were greatly decreased by treatment with antibiotics, recolonization of Desulfovibrio vulgaris and Clostridium sordellii, and administration of lipopolysaccharide or deoxycholic acid. Macrophage depletion attenuated HFD-enhanced pre-metastatic niche formation and metastasis, but failed to further affect the effects of GA. Mechanistically, counteraction of HFD-enhanced gut microbiota dysbiosis by GA inhibited Gr-1+ myeloid cell migration and S100A8/A9 expression through decreasing the proportion of M1-like macrophages and their production of CCL2 and TNF-α in the colons via LPS/HMGB1/NF-κB signaling inactivation. Together, targeting the gut microbiota by GA to modulate colonic macrophages could be a novel strategy for the prevention of HFD-enhanced pre-metastatic niche formation and metastasis.

BAPTA-AM Nanoparticle for the Curing of Acute Kidney Injury Induced by Ischemia/Reperfusion.

Ischemia-reperfusion (I/R) is a major cause of acute kidney injury (AKI), which is associated with unacceptably high mortality rates in ICU. This research was designed to explore the therapeutic effect of BAPTA-AM (1,2-Bis(2-aminophenoxy) ethane-N,N,N,N-tetraacetic acid tetrakis(acetoxymethyl ester)) nanoparticle (BA-N) on AKI. BA-N was developed by liposome strategy and characterized by standard methods. The rat model was selected and the rats were randomly allocated into four groups: (1) Normal group; (2) Sham-operated group; (3) Model group (I/R + NS); (4) BA-N treatment group (I/R + BA-N). AKI model was established via clipping the bilateral renal artery with a microvascular clamp for 45 min. After reperfusion, serum cystatin C (Cys C), creatinine (Cr), blood urea nitrogen (BUN), lactate dehydrogenase (LDH) and caspase 3 levels were determined for the assessment of renal function. Kidney samples were then collected for the measurement of renal malondialdehyde (MDA) level and superoxide dismutase (SOD) activity. The assays of histological examination, ELISA, immunohistochemistry, western blot, TUNEL and RT-PCR were utilized for the detection of apoptosis. The results demonstrated that AKI model caused a significant decreasing in SOD activity, accompanied by a remarkable increase in Cys C, Cr, BUN, LDH, MDA, caspase 3 and cytochrome c (Cyt C) level, compared to the control group. BA-N (100 µg/kg i.v.) significantly improved renal function and histopathological appearance, restored MDA level and SOD activity, decreased Bax/Bcl-2 ratio, caspase 3 activity, Cyt C release and TUNEL positive apoptotic cells. Our studies indicated that BA-N plays a renal-protective role, probably through antiapoptotic and antioxidant mechanisms. BA-N may regulate mitochondria pathway via decreasing Bax/Bcl-2 ratio, inhibiting caspase 3 expression and Cyt C release. Overall, BA-N may have potentials as an anti-AKI drug.

CYP4X1 Inhibition by Flavonoid CH625 Normalizes Glioma Vasculature through Reprogramming TAMs via CB2 and EGFR-STAT3 Axis.

Tumor-associated macrophages (TAMs) are pivotal effector cells in angiogenesis. Here, we tested whether CYP4X1 inhibition in TAMs by flavonoid CH625 prolongs survival and normalizes glioma vasculature. CH625 was selected against the CYP4X1 3D model by virtual screening and showed inhibitory activity on the CYP4X1 catalytic production of 14,15-EET-EA in the M2-polarized human peripheral blood mononuclear cells (IC50 = 16.5 µM). CH625 improved survival and reduced tumor burden in the C6 and GL261 glioma intracranial and subcutaneous model. In addition, CH625 normalized vasculature (evidenced by a decrease in microvessel density and HIF-1α expression and an increase in tumor perfusion, pericyte coverage, and efficacy of temozolomide therapy) accompanied with the decreased secretion of 14,15-EET-EA, VEGF, and TGF-ß in the TAMs. Furthermore, CH625 attenuated vascular abnormalization and immunosuppression induced by coimplantation of GL261 cells with CYP4X1high macrophages. In vitro TAM polarization away from the M2 phenotype by CH625 inhibited proliferation and migration of endothelial cells, enhanced pericyte migration and T cell proliferation, and decreased VEGF and TGF-ß production accompanied with the downregulation of CB2 and EGFR-dependent downstream STAT3 expression. These effects were reversed by overexpression of CYP4X1 and STAT3 or exogenous addition of 14,15-EET-EA, VEGF, TGF-ß, EGF, and CB2 inhibitor AM630. These results suggest that CYP4X1 inhibition in TAMs by CH625 prolongs survival and normalizes tumor vasculature in glioma via CB2 and EGFR-STAT3 axis and may serve as a novel therapeutic strategy for human glioma.

Screening of novel RGD peptides to modify nanoparticles for targeted cancer therapy.

New targeted RGD peptides obtained by solid phase peptide synthesis (SPPS) were successfully screened by Molecular Operating Environment (MOE) and used for the building of the 6-O-carboxymethyl chitosan based carrier with an active target on the surface. CRGDYC-6-O-carboxymethyl chitosan based nanoparticles (NPs) loaded with doxorubicin hydrochloride (DOX) were successfully prepared by an ionic gelation method with the carrier synthesized before. Synthesis conditions and formulation parameters were optimized by determining the characteristics of nanoparticles including the particle size and drug encapsulation efficiency. 6-O-Carboxymethyl chitosan concentration, calcium chloride concentration and calcium chloride/6-O-carboxymethyl chitosan ratio all had effects on the particle size and drug encapsulation efficiency. Nanoparticles with an average diameter of 193.4 nm, an average drug loading efficiency of up to 69.5% and an average drug loading of up to 0.395% were prepared successfully with the optimal formulation. Flow cytometry and confocal microscopy analyses showed that the cellular uptake of DOX in human breast cancer cell lines (MCF-7) was higher in the CRGDYC-modified nanoparticles compared with the unmodified nanoparticles. In vivo imaging showed that the distribution of CRGDYC-modified nanoparticles in the tumor site was higher compared with the unmodified nanoparticles. These results suggest that CRGDYC-6-O-carboxymethyl chitosan may be a promising cancer targeting carrier which can enhance the intracellular uptake and cytotoxicity of the drug-loaded nanoparticles.

Self-assembly of peptide amphiphiles for drug delivery: the role of peptide primary and secondary structures.

Peptide amphiphiles (PAs), functionalized with alkyl chains, are capable of self-assembling into various nanostructures. Recently, PAs have been considered as ideal drug carriers due to their good biocompatibility, specific biological functions, and hypotoxicity to normal cells and tissues. Meanwhile, the nanocarriers formed by PAs are able to achieve controlled drug release and enhanced cell uptake in response to the stimulus of the physiological environment or specific biological factors in the location of the lesion. However, the underlying detailed drug delivery mechanism, especially from the aspect of primary and secondary structures of PAs, has not been systematically summarized or discussed. Focusing on the relationship between the primary and secondary structures of PAs and stimuli-responsive drug delivery applications, this review highlights the recent advances, challenges, and opportunities of PA-based functional drug nanocarriers, and their potential pharmaceutical applications are discussed.