Exposure to chlorpyrifos interferes with intercellular communication in cumulus-oocyte complexes during porcine oocyte maturation.

Chlorpyrifos (CPF), a widely used organophosphorus pesticide (OP) to control pests has been verified reproductive toxicity on mammalian oocytes. However, limited information exists on its correlation with the dysfunction of the intercellular communication in cumulus-oocyte complexes (COCs). Herein, our study utilized porcine COCs as models to directly address the latent impact of CPF on the communication between cumulus cells (CCs) and oocytes during in vitro maturation. The results demonstrated that CPF exposure decreased the rate of the first polar body (PB1) extrusion and blocked meiosis progression. Notably, the cumulus expansion of CPF-exposed COCs was suppressed significantly, accompanied by the down-regulated mRNA levels of cumulus expansion-related genes. Furthermore, the early apoptotic level was raised and the expression of BAX/BCL2 and cleaved caspase 3 was up-regulated in the CCs of CPF-exposed COCs (p < 0.05). Moreover, CPF exposure impaired mRNA levels of antioxidant enzyme-related genes, induced higher levels of reactive oxygen species (ROS) and reduced the levels of mitochondrial membrane potential (MMP) in CCs (p < 0.05). Additionally, the integrated optical density (IOD) rate (cumulus/oocyte) of calcein and the expression of connexin 43 (CX43) was increased in CPF treatment groups (p < 0.05). As well, CPF exposure reduced the expression levels of FSCN1, DAAM1 and MYO10, which resulted in a significant decrease in the number and fluorescence intensity of transzonal projections (TZPs). In conclusion, CPF inhibited the expansion of cumulus and caused oxidative stress and apoptosis as well as disturbed the function of gap junctions (GJs) and TZPs, which eventually resulted in the failure of oocyte maturation.

A dual network cross-linked hydrogel with multifunctional Bletilla striata polysaccharide/gelatin/tea polyphenol for wound healing promotion.

Wound healing is a dynamic and complex biological process, and traditional biological excipients cannot meet the needs of the wound healing process, and there is an urgent need for a biological dressing with multifunctionality and the ability to participate in all stages of wound healing. This study developed tea polyphenol (TP) incorporated multifunctional hydrogel based on oxidized Bletilla striata polysaccharide (OBSP) and adipic acid dihydrazide modified gelatin (Gel-ADH) with antimicrobial, antioxidant hemostatic, and anti-inflammatory properties to promote wound healing. The composite OBSP, Gel-ADH, TP (OBGTP) hydrogels prepared by double crosslinking between OBSP, TP and Gel-ADH via Schiff base bonding and hydrogen bonding had good rheological and swelling properties. The introduction of TP provided the composite hydrogel with excellent antioxidant antibacterial activities against Staphylococcus aureus (S. aureus) and Escherichia coli (E. coil). In the rat liver hemorrhage model and skin injury model, the OBGTP composite hydrogel had significant (p < 0.001) hemostatic ability, and had the ability to accelerate collagen deposition, reduce the expression of inflammatory factors, and promote rapid wound healing. In addition, OBGTP hydrogels had adhesive properties and good biocompatibility. In conclusion, OBGTP multifunctional composite hydrogels have great potential for wound healing applications.

Nanoparticles exhibiting virus-mimic surface topology for enhanced oral delivery.

The oral delivery of nano-drug delivery systems (Nano-DDS) remains a challenge. Taking inspirations from viruses, here we construct core-shell mesoporous silica nanoparticles (NPs, ~80 nm) with virus-like nanospikes (VSN) to simulate viral morphology, and further modified VSN with L-alanine (CVSN) to enable chiral recognition for functional bionics. By comparing with the solid silica NPs, mesoporous silica NPs and VSN, we demonstrate the delivery advantages of CVSN on overcoming intestinal sequential barriers in both animals and human via multiple biological processes. Subsequently, we encapsulate indomethacin (IMC) into the nanopores of NPs to mimic gene package, wherein the payloads are isolated from bio-environments and exist in an amorphous form to increase their stability and solubility, while the chiral nanospikes multi-sited anchor and chiral recognize on the intestinal mucosa to enhance the penetrability and ultimately improve the oral adsorption of IMC. Encouragingly, we also prove the versatility of CVSN as oral Nano-DDS.

Enantioselective Oral Absorption of Molecular Chiral Mesoporous Silica Nanoparticles.

Inspired by the unique pharmacological effects of chiral drugs in the asymmetrical body environments, it is assumed that the chirality of nanocarriers is also a key factor to determine their oral adsorption efficiency, apart from their size, shape, etc. Herein, l/d-tartaric acid modified mesoporous silica nanoparticles (l/d-CMSNs) are fabricated via a one-pot cocondensation method, and focused on whether the oral adsorption of nanocarriers will be benefited from their chirality. It is found that l-CMSN performed better in the sequential oral absorption processes, including mucus permeation, mucosa bio-adhesion, cellular uptake, intestinal transport and gastrointestinal tract (GIT) retention, than those of the d-chiral (d-CMSN), racemic (dl-CMSN), and achiral (MSN) counterparts. The multiple chiral recognition mechanisms are experimentally and theoretically demonstrated following simple differential adsorption on biointerfaces, wherein electrostatic interaction is the dominant energy. During the oral delivery task, l-CMSN, which is proven to be stable, nonirritative, biocompatible, and biodegradable, is efficiently absorbed into the blood (1.72-2.05-fold higher than other nanocarriers), and helps the loaded doxorubicin (DOX) to achieve better intestinal transport (2.32-27.03-times higher than other samples), satisfactory bioavailability (449.73%) and stronger antitumor effect (up to 95.43%). These findings validated the dominant role of chirality in determining the biological fate of nanocarriers.

The effect of GelMA/alginate interpenetrating polymeric network hydrogel on the performance of porous zirconia matrix for bone regeneration applications.

Bone tissue is a natural composite, exhibiting complicated structures and unique mechanical/biological properties. With an attempt of mimicking the bone tissue, a novel inorganic-organic composite scaffolds (ZrO2-GM/SA) was designed and prepared via the vacuum infiltration method and the single/double cross-linking strategy by blending GelMA/alginate (GelMA/SA) interpenetrating polymeric network (IPN) into the porous zirconia (ZrO2) scaffold. The structure, morphology, compressive strength, surface/interface properties, and biocompatibility of the ZrO2-GM/SA composite scaffolds were characterized to evaluate the performance of the composite scaffolds. Results showed that compared to ZrO2 bare scaffolds with well-defined open pores, the composite scaffolds prepared by double cross-linking of GelMA hydrogel and sodium alginate (SA) presented a continuous, tunable and honeycomb-like microstructure. Meanwhile, GelMA/SA showed favorable and controllable water-uptake capacity, swelling property and degradability. After the introduction of IPN components, the mechanical strength of composite scaffolds was further improved. The compressive modulus of composite scaffolds was significantly higher than the bare ZrO2 scaffolds. In addition, ZrO2-GM/SA composite scaffolds had highly biocompatibility and displayed a potent proliferation and osteogenesis of MC3T3-E1 pre-osteoblasts compared to bare ZrO2 scaffolds and ZrO2-GelMA composite scaffolds. At the same time, ZrO2-10GM/1SA composite scaffold regenerated significantly greater bone than other groups in vivo. This study demonstrated that the proposed ZrO2-GM/SA composite scaffolds had great research and application potential in bone tissue engineering.

Mesoporous silica nanoparticles with chiral pattern topological structure function as "antiskid tires" on the intestinal mucosa to facilitate oral drugs delivery.

The weak adhesion between nanocarriers and the intestinal mucosa was one of the main reasons caused the failure in oral delivery. Inspired by the "antiskid tires" with complex chiral patterns, mesoporous silica nanoparticles AT-R@CMSN exhibiting geometrical chiral structure were designed to improve the surface/interface roughness in nanoscale, and employed as the hosting system for insoluble drugs nimesulide (NMS) and ibuprofen (IBU). Once performing the delivery tasks, AT-R@CMSN with rigid skeleton protected the loaded drug and reduced the irritation of drug on gastrointestinal tract (GIT), while their porous structure deprived drug crystal and improved drug release. More importantly, AT-R@CMSN functioned as "antiskid tire" to produce higher friction on intestinal mucosa and substantively influenced multiple biological processes, including "contact", "adhesion", "retention", "permeation" and "uptake", compared to the achiral S@MSN, thereby improving the oral adsorption effectiveness of such drug delivery systems. By engineering AT-R@CMSN to overcome the stability, solubility and permeability bottlenecks of drugs, orally administered NMS or IBU loaded AT-R@CMSN could achieve higher relative bioavailability (705.95% and 444.42%, respectively) and stronger anti-inflammation effect. In addition, AT-R@CMSN displayed favorable biocompatibility and biodegradability. Undoubtedly, the present finding helped to understand the oral adsorption process of nanocarriers, and provided novel insights into the rational design of nanocarriers.

Chiral Nanosilica Drug Delivery Systems Stereoselectively Interacted with the Intestinal Mucosa to Improve the Oral Adsorption of Insoluble Drugs.

Chiral nanoparticles (NPs) with nanoscale rough surfaces have enormous application prospects in drug delivery. However, the stereoselective interactions between the chiral NPs and biosurfaces remain challenging and mysterious. Herein, we designed mesoporous silica nanocarriers (l/d/dl-TA-PEI@CMSN) exhibiting the same structural parameters (hydrophilic, electroneutral, spherical NPs, ∼120 nm) but different geometrical chirality as oral nanodrug delivery systems (Nano-DDS) for insoluble drugs nimesulide (NMS) and ibuprofen (IBU) and demonstrated their stereoselective interactions with the intestinal mucosa, that is, l-TA-PEI@CMSN as well as Nano-DDS in the l-configuration displayed apparent superior behaviors in multiple microprocesses associated with oral adsorption, including adhesion, penetration, adsorption, retention and uptake, causing by the stereomatching between the chiral mesostructures of NPs and the inherent chiral topologies of the biosurfaces. As hosting systems, l/d/dl-TA-PEI@CMSN effectively incorporated drugs in amorphous states and helped to overcome the stability, solubility and permeability bottlenecks of drugs. Subsequently, Nano-DDS in the l-configuration (including IBU/l-TA-PEI@CMSN and NMS/d-TA-PEI@CMSN owing to a chiral inversion) showed higher oral delivery efficiency of NMS and IBU evidenced by the larger relative bioavailability (1055.06% and 583.17%, respectively) and stronger anti-inflammatory and analgesic effects. In addition, l/d/dl-TA-PEI@CMSN were stable, nonirritative, biocompatible and biodegradable, benefiting for their clinical applications. These findings provided insights into the rational design of functionalized Nano-DDS and contributed to the further knowledge in the field of chiral pharmaceutical science.

Biomimetic virus-like mesoporous silica nanoparticles improved cellular internalization for co-delivery of antigen and agonist to enhance Tumor immunotherapy.

Nanocarrier antigen-drug delivery system interacts specifically with immune cells and provides intelligent delivery modes to improve antigen delivery efficiency and facilitate immune progression. However, these nanoparticles often have weak adhesion to cells, followed by insufficient cell absorption, leading to a failed immune response. Inspired by the structure and function of viruses, virus-like mesoporous silica nanoparticles (VMSNs) were prepared by simulating the surface structure, centripetal-radialized spike structure and rough surface topology of the virus and co-acted with the toll-like receptor 7/8 agonist imiquimod (IMQ) and antigens oocyte albumin (OVA). Compared to the conventional spherical mesoporous silica nanoparticles (MSNs), VMSNs which was proven to be biocompatible in both cellular and in vivo level, had higher cell invasion ability and unique endocytosis pathway that was released from lysosomes and promoted antigen cross-expression. Furthermore, VMSNs effectively inhibited B16-OVA tumor growth by activating DCs maturation and increasing the proportion of CD8+ T cells. This work demonstrated that virus-like mesoporous silica nanoparticles co-supply OVA and IMQ, could induce potent tumor immune responses and inhibit tumor growth as a consequence of the surface spike structure induces a robust cellular immune response, and undoubtedly provided a good basis for further optimizing the nanovaccine delivery system.

Lead acetate induces cartilage defects and bone loss in zebrafish embryos by disrupting the GH/IGF-1 axis.

Skeletal system toxicity due to lead exposure has attracted extensive attention in recent years, but few studies focus on the skeletal toxicity of lead in the early life stages of zebrafish. The endocrine system, especially the GH/IGF-1 axis, plays an important role in bone development and bone health of zebrafish in the early life. In the present study, we investigated whether lead acetate (PbAc) affected the GH/IGF-1 axis, thereby causing skeletal toxicity in zebrafish embryos. Zebrafish embryos were exposed to lead PbAc between 2 and 120 h post fertilization (hpf). At 120 hpf, we measured developmental indices, such as survival, deformity, heart rate, and body length, and assessed skeletal development by Alcian Blue and Alizarin Red staining and the expression levels of bone-related genes. The levels of GH and IGF-1 and the expression levels of GH/IGF-1 axis-related genes were also detected. Our data showed that the LC50 of PbAc for 120 h was 41 mg/L. Compared with the control group (0 mg/L PbAc), after PbAc exposure, the deformity rate increased, the heart rate decreased, and the body length was shortened at various time periods, in the 20-mg/L group at 120 hpf, the deformity rate increased by 50 fold, the heart rate decreased by 34%, and the body length shortened by 17%. PbAc altered cartilage structures and exacerbated bone loss in zebrafish embryos; in addition, PbAc exposure down-regulated the expression of chondrocyte (sox9a, sox9b), osteoblast (bmp2, runx2) and bone mineralization-related genes (sparc, bglap), and up-regulated the expression of osteoclast marker genes (rankl, mcsf). The GH level increased and the IGF-1 level declined significantly. The GH/IGF-1 axis related genes (ghra, ghrb, igf1ra, igf1rb, igf2r, igfbp2a, igfbp3, igfbp5b) were all decreased. These results suggested that PbAc inhibited the differentiation and maturation of osteoblasts and cartilage matrix, promoted the formation of osteoclasts, and ultimately induced cartilage defects and bone loss by disrupting the GH/IGF-1 axis.

A pH-responsive chiral mesoporous silica nanoparticles for delivery of doxorubicin in tumor-targeted therapy.

The purpose of this study was to develop a nano-drug delivery system with intelligent stimuli-responsive drug delivery in tumor microenvironment (TME). Based on chiral mesoporous silica nanoparticles (CMSN) with a chiral recognition function in our previous research, a pH-responsive CMSN (CS-CMSN) was successfully prepared by chemical modification of chitosan (CS), and the related physicochemical properties, drug release performance, potential anti-tumor effect, and biological safety were studied. The results showed that the CS-CMSN were successfully modified by CS. Moreover, CS-CMSN displayed superior encapsulation ability for doxorubicin (DOX) and exhibited controllable pH-responsive drug release properties. In particular, in a physiological environment (pH 7.4/6.5), CS shielded the nanopores, prevented DOX release, and minimized side effects on normal cells. Once the CS-CMSN was exposed to the TME (pH 5.0), the pH-sensitive moiety of CS was cleaved in an acidic environment, along with the rapid release of DOX. In vitro cell experiments further proved that DOX@CS-CMSN was more strongly taken up by 4T1 cells and could enhance the toxicity to 4T1 tumor cells as well as promote cell apoptosis. More importantly, CS-CMSN were shown to have good biosafety in vitro and in vivo. Overall, the delivery of DOX by CS-CMSN nanocarriers is a promising strategy for tumor-targeted therapy.

Multi-functional extracellular vesicles: Potentials in cancer immunotherapy.

Cancer immunotherapy (CIT) has revolutionized cancer treatment. However, the application of CIT is limited by low response rates and significant individual differences owing to a deficit in 1) immune recognition and 2) immune effector function. Extracellular vesicles (EVs) are cell-derived lipid bilayer-enclosed vesicles that mediate intercellular communication. The specific structure and content of EVs allows for multi-functional modulation of tumor immunity. Given their high biocompatibility, homologous targeting, and permeability across biological barriers, EVs have been evaluated as ideal carriers for promoting the efficacy and specificity of CIT. Herein, we first discuss the role of EVs in regulating tumor immunity and focus on the advantages of using EVs as a therapeutic tool for cancer treatment from a clinical perspective. Further, we outline the current progress in the development of biohybrid EVs for CIT and multi-functional EV-based strategies for overcoming the deficits in tumor immunity. Finally, we discuss the challenges associated with EV-based CIT and future perspectives in the context of ongoing clinical trials involving EV-based therapies, thus offering valuable insights into the future of multi-functional EVs in CIT.

Melatonin Prevents NaAsO2-Induced Developmental Cardiotoxicity in Zebrafish through Regulating Oxidative Stress and Apoptosis.

Melatonin is an indoleamine hormone secreted by the pineal gland. It has antioxidation and anti-apoptosis effects and a clear protective effect against cardiovascular diseases. Our previous studies demonstrated that embryonic exposure to sodium arsenite (NaAsO2) can lead to an abnormal cardiac development. The aim of this study was to determine whether melatonin could protect against NaAsO2-induced generation of reactive oxygen species (ROS), oxidative stress, apoptosis, and abnormal cardiac development in a zebrafish (Danio rerio) model. We found that melatonin decreased NaAsO2-induced zebrafish embryonic heart malformations and abnormal heart rates at a melatonin concentration as low as 10-9 mol/L. The NaAsO2-induced oxidative stress was counteracted by melatonin supplementation. Melatonin blunted the NaAsO2-induced overproduction of ROS, the upregulation of oxidative stress-related genes (sod2, cat, gpx, nrf2, ho-1), and the production of antioxidant enzymes (Total SOD, SOD1, SOD2, CAT). Melatonin attenuated the NaAsO2-induced oxidative damage, DNA damage, and apoptosis, based on malonaldehyde and 8-OHdG levels and apoptosis-related gene expression (caspase-3, bax, bcl-2), respectively. Melatonin also maintained the control levels of heart development-related genes (nkx2.5, sox9b) affected by NaAsO2. In conclusion, melatonin protected against NaAsO2-induced heart malformations by inhibiting the oxidative stress and apoptosis in zebrafish.

Chiral mesoporous silica nano-screws as an efficient biomimetic oral drug delivery platform through multiple topological mechanisms.

In the microscale, bacteria with helical body shapes have been reported to yield advantages in many bio-processes. In the human society, there are also wisdoms in knowing how to recognize and make use of helical shapes with multi-functionality. Herein, we designed atypical chiral mesoporous silica nano-screws (CMSWs) with ideal topological structures (e.g., small section area, relative rough surface, screw-like body with three-dimension chirality) and demonstrated that CMSWs displayed enhanced bio-adhesion, mucus-penetration and cellular uptake (contributed by the macropinocytosis and caveolae-mediated endocytosis pathways) abilities compared to the chiral mesoporous silica nanospheres (CMSSs) and chiral mesoporous silica nanorods (CMSRs), achieving extended retention duration in the gastrointestinal (GI) tract and superior adsorption in the blood circulation (up to 2.61- and 5.65-times in AUC). After doxorubicin (DOX) loading into CMSs, DOX@CMSWs exhibited controlled drug release manners with pH responsiveness in vitro. Orally administered DOX@CMSWs could efficiently overcome the intestinal epithelium barrier (IEB), and resulted in satisfactory oral bioavailability of DOX (up to 348%). CMSWs were also proved to exhibit good biocompatibility and unique biodegradability. These findings displayed superior ability of CMSWs in crossing IEB through multiple topological mechanisms and would provide useful information on the rational design of nano-drug delivery systems.

Nearly 20 Years of Genetic Diversity and Evolution of Porcine Circovirus-like Virus P1 from China.

Porcine circovirus-like virus P1 can infect many kinds of animals and mainly causes postweaning multisystemic wasting syndrome. In China, the genetic diversity, variation, and evolutionary processes of this virus have not been described yet. To improve our knowledge of its genetic diversity, evolution, and gene flow, we performed a bioinformatics analysis using the available nucleotide sequences of the P1 virus; among them, 12 nucleotide sequences were from ten pig farms in Jiangsu Province in this epidemiological survey, and 84 sequences were downloaded from GenBank. The P1 sequences showed a rich composition of AT nucleotides. Analyses of the complete genomic sequences were polymorphic and revealed high haplotype (gene) diversity and nucleotide diversity. A phylogenetic analysis based on the NJ method showed that all P1 virus sequences formed two distinct groups: A and B. High genetic differentiation was observed between strains from groups A and B. The codon usage pattern of P1 was affected by dinucleotide compositions. Dinucleotide UU/CC was overrepresented, and dinucleotide CG was underrepresented. The mean evolutionary rate of the P1 virus was estimated to be 3.64 × 10-4 nucleotide substitutions per site per year (subs/site/year). The neutrality tests showed negative values. The purifying selection and recombination events may play a major driving role in generating the genetic diversity of the P1 population. The information from this research may be helpful to obtain new insights into the evolution of P1.

Carboxyl-functionalized mesoporous silica nanoparticles for the controlled delivery of poorly water-soluble non-steroidal anti-inflammatory drugs.

The purpose of this study was to investigate the delivery of poorly water-soluble non-steroidal anti-inflammatory drugs (NSAIDs) by carboxyl-functionalized mesoporous silica nanoparticles (MSN-COOH) with high specific surface area (SBET). In this study, MSN-COOH was prepared by collaborative self-assembly using cetyltrimethylammonium bromide (CTAB) as template and hydrolysis (3-triethoxyl-propyl) succinic anhydride (TESPSA) as co-structure auxiliary directing agent (CSDA). The drug delivery systems were constructed with NSAIDs including Nimesulide (NMS) and Indomethacin (IMC) as model drugs. Moreover, the characterization techniques, hemolysis and bio-adsorption testes, in vitro drug release and in vivo biological studies of MSN-COOH were also carried out. The characterization results showed that MSN-COOH is spheres with clearly visible irregular honeycomb nanopores and rough surface (SBET: 1257 m2/g, pore volume (VP): 1.17 cm3/g). After loading NMS/IMC into MSN-COOH with high drug loading efficiency (NMS: 98.7 and IMC: 98.2%), most crystalline NMS and IMC converted to amorphous phase confirmed using differential scanning calorimeter (DSC) and X-ray power diffraction (XRD) analysis. Meanwhile, MSN-COOH significantly increased the dissolution of NMS and IMC compared with non-functionalized mesoporous silica nanoparticles (MSN), which was also confirmed by wettability experiments. The results of in vivo biological effects showed that MSN-COOH had higher bioavailability of NMS and IMC than MSN, and exerted strong anti-inflammatory effects by delivering more NMS and IMC in vivo. STATEMENT OF SIGNIFICANCE: This study successfully prepared MSNs-COOH (mesoporous silica nanoparticles modified with negatively charged carboxyl groups on the surface and in the pores) with high specific surface area and pore volume by using the negatively charged carboxyl group (hyd-TESPSA) and the positively charged CTAB self-assembled through electrostatic attraction under alkaline conditions. The drug delivery systems were constructed with Nimesulide (NMS) and Indomethacin (IMC) as model drugs. The results showed MSNs-COOH had high drug loading capacity and also exhibited good in vitro drug release properties. Interestingly, NMS loaded MSNs-COOH also had a potential pH responsive release effect. In vivo biological studies revealed that NMS/IMC loaded MSNs-COOH could evidently improve the bioavailability and played the strong anti-inflammatory effects.

pH/H2O2 Dual-Responsive Chiral Mesoporous Silica Nanorods Coated with a Biocompatible Active Targeting Ligand for Cancer Therapy.

Nano-drug delivery systems (nano-DDSs) with an existing specific interaction to tumor cells and intelligent stimulus-triggered drug delivery performance in a tumor microenvironment (TME) remain hotspots for effective cancer therapy. Herein, multifunctional pH/H2O2 dual-responsive chiral mesoporous silica nanorods (HA-CD/DOX-PCMSRs) were creatively constructed by first grafting phenylboronic acid pinacol ester (PBAP) onto the amino-functioned nanorods, then incorporating doxorubicin (DOX) into the mesoporous structure, and finally coating with the cyclodextrin-modified hyaluronic acid conjugate (HA-CD) through a weak host-guest interaction. Under a physiological environment, the gatekeeper CD could avoid the premature leakage of DOX and minimize the side effects to normal cells. After the uptake by the tumor cells, the H2O2-sensitive moieties of PBAP were exposed and a small amount of DOX was leaked along with the shift of the supramolecular switch HA-CD under the acidic condition. Notably, the self-supplying H2O2 mediated by the released DOX in turn accelerated the PBAP disintegration, further promoted the rapid release of DOX, and increased the DOX accumulation in tumor regions. Innovatively, this nano-DDS could simultaneously achieve the tumor-targeting ability via CD44 receptor-mediated endocytosis and pH/H2O2 dual responsiveness activated by the TME and hence exhibited superior antitumor efficacy. Furthermore, HA acting as the hydrophilic shell could improve the biocompatibility of this nano-DDS.

Facile synthesis of PEI-based crystalline templated mesoporous silica with molecular chirality for improved oral delivery of the poorly water-soluble drug.

The aim of this study was to build up a novel chiral mesoporous silica called PEIs@TA-CMS through a facile biomimetic strategy and to explore its potential to serve as a drug carrier for improving the delivery efficiency of poorly water-soluble drug. PEIs@TA-CMS was synthesized by using a chiral crystalline complex associated of tartaric acid and polyethyleneimine (PEIs) as templates, scaffolds and catalysts. The structural features including morphology, size, pore structure and texture properties were systematacially studied. The results showed that PEIs@TA-CMS was monodispersed spherical nanoparticles in a uniformed diameter of 120-130 nm with well-developed pore structure (SBET: 1009.94 m2/g, pore size <2.21 nm). Then PEIs@TA-CMS was employed as nimodipine (NMP) carrier and compared with the drug carry ability of MCM41. After drug loading, NMP was effectively transformed from the crystalline state to an amorphous state due to the space confinement in mesopores. As expected, PEIs@TA-CMS had superiority in both drug loading and drug release compared to MCM41. It could incorporate NMP with high efficiency, and the dissolution-promoting effect of PEIs@TA-CMS was more obvious because of the unique interconnected curved pore channels. Meanwhile, PEIs@TA-CMS could significantly improve the oral adsorption of NMP to a satisfactory level, which showed approximately 3.26-fold higher in bioavailability, and could effectively prolong the survival time of mice on cerebral anoxia from 10.98 to 17.33 min.

Advances in regulating physicochemical properties of mesoporous silica nanocarriers to overcome biological barriers.

Mesoporous silica nanoparticles (MSNs) with remarkable structural features have been proven to be an excellent platform for the delivery of therapeutic molecules. Biological barriers in various forms (e.g., mucosal barrier, cellular barrier, gastrointestinal barrier, blood-brain barrier, and blood-tumor barrier) present substantial obstacles for MSNs. The physicochemical parameters of MSNs are known to be effective and tunable not only for load and release of therapeutic molecules but also for their biological responsiveness that is beneficial for cells and tissues. This review innovatively provides a description of how and why physicochemical properties (e.g., particle size, morphology, surface charge, hydrophilic-hydrophobic property, and surface modification) of MSNs influence their ability to cross the biological barriers prior to reaching targeted sites. First, the structural and physiological features of biological barriers are outlined. Next, the recent progresses in the critical physicochemical parameters of MSNs are highlighted from physicochemical and biological aspects. Surface modification, as an important strategy for achieving rapid transport, is also reviewed with special attention to the latest findings of bioactive groups and molecular mechanisms. Furthermore, advanced designs of multifunction intelligent MSNs to surmount the blood-tumor barrier and to actively target tumor sites are demonstrated in detail. Lastly, the biodegradability and toxicity of MSNs are evaluated. With perspectives for their potential application and biosafety, the clues in summary might lead to drug delivery with high efficiency and provide useful knowledge for rational design of nanomaterials.

Dual response to pH and chiral microenvironments for the release of a flurbiprofen-loaded chiral self-assembled mesoporous silica drug delivery system.

This study examined the effects of pH and chirality on the release of flurbiprofen (FP)-loaded chiral (L/D) self-assembled mesoporous silica nanoparticles (CSA-L/D-MSNs), which were synthesized using cationic cetyltrimethyl ammonium bromide (CTAB) as a template and chiral modified using L/D-tartaric acids. The morphology and physicochemical properties of the CSA-L/D-MSNs were systemically determined and compared with those of non-functionalized mesoporous silica nanoparticles (MSN). The results showed that the CSA-L/D-MSNs were spherical nanoparticles, and the chirality in the L/D-tartaric acids was successfully imparted to the CSA-L/D-MSNs. FP could be loaded into the CSA-L/D-MSNs and was effectively transformed from the crystalline state to an amorphous state after drug loading due to the finite size effect. The release of FP@CSA-L/D-MSNs was faster than that of FP in a pH 1.2 medium and slower in a pH 6.8 medium, and it was better than that of FP@MSNs in both release mediums. Meanwhile, the FP@CSA-L/D-MSNs exhibited a clearly enhanced pH response because the negatively charged carboxyl groups on their surface induced stronger electrostatic repulsion between FP and CSA-L/D-MSNs. Moreover, the effect of the chiral environment on the release of FP@CSA-L/D-MSNs was further studied by introducing small-molecule chiral additives (L/D-alanine). It was found that the release of FP was inhibited in a chiral environment. Particularly, the CSA-L/D-MSNs began to exert the chiral recognition function, in which the CSA-L-MSN responded to chiral stimuli and enhanced the cumulative release amount from 84.25 %-89.11 % in a pH 6.8-L medium, while the CSA-D-MSN showed a suppressed release in the pH 6.8-L medium. Notably, the CSA-L/D-MSNs exhibited intelligent drug release by both chirality response and pH response, and will provide valuable guidance for the design of drug delivery systems.