Lipase-Responsive Lignin Composite Nanoparticles for the Delivery of Insoluble Bioactives.

Low solubility and chemical instability are the main problems with insoluble bioactives. Lignin, with its exceptional biological properties and amphiphilicity, holds promise as a delivery system material. In this study, glycerol esters were incorporated into alkali lignin (AL) through ether and ester bonds, resulting in the successful synthesis of three hydrophobically modified alkali lignins (AL-OA, AL-OGL, and AL-SAN-OGL). Subsequently, lignin composite nanoparticles (LNPs@BC) encapsulating ß-carotene were prepared using antisolvent and sonication techniques. The encapsulation rates were determined to be 37.69 ± 2.21%, 84.01 ± 5.55%, 83.82 ± 5.23%, and 83.11 ± 5.85% for LNP@BC-1, LNP@BC-2, LNP@BC-3, and LNP@BC-4, respectively, with AL, AL-OA, AL-OGL, and AL-SAN-OGL serving as the wall materials under optimized preparation conditions. The antioxidant properties and UV-absorbing capacity of the four lignins were characterized, demonstrating their efficacy in enhancing the oxygen and photostability of ß-carotene. Following 6 h of UV irradiation, LNP@BC-4 exhibited a retention rate of 83.03 ± 2.85% for ß-carotene, while storage under light-protected conditions at 25 °C for 7 days retained 73.33 ± 7.62% of ß-carotene. Furthermore, the encapsulated ß-carotene demonstrated enhanced thermal and storage stability. In vitro release experiments revealed superior stability of LNPs@BC in simulated gastric fluid (SGF), with ß-carotene retention exceeding 77% in both LNP@BC-3 and LNP@BC-4. LNP@BC-4 exhibited the highest bioaccessibility in simulated intestinal fluid (SIF) at 46.96 ± 0.80%, that LNP@BC-1 only achieved 10.87 ± 0.90%. The enzymatic responsiveness of AL-OGL and AL-SAN-OGL was confirmed. Moreover, LNPs@BC exhibited no cytotoxicity toward L929 cells and demonstrated excellent hemocompatibility. In summary, this study introduces a novel enzyme-responsive modified lignin that has promising applications in the fields of food, biomedicine, and animal feed.

Acid/GSH Dual-Responsive Endosome Escape Dual Pro-drug Micelles Targeted Synergistic Treatment for A549/ADR.

The resistance of cancer cells to anticancer drugs has been recognized as one of the main reasons for chemotherapy failure. Multidrug combination therapy is one of the most effective ways to solve this problem. Therefore, in this article, we designed and synthesized a pH/GSH dual-responsive camptothecin/doxorubicin (CPT/DOX) dual pro-drug synergistic treatment system with the aim of overcoming the resistance of non-small cell lung cancer A549/ADR cells to DOX. The pro-drug cRGD-PEOz-S-S-CPT (cPzT) was obtained by linking CPT to poly(2-ethyl-2-oxazoline) (PEOz) with endosomal escape properties through a GSH-responsive disulfide bond and modifying it with the targeted peptide cRGD. The pro-drug mPEG-NH-N=C-DOX (mPX) was synthesized by attaching DOX to polyethylene glycol (PEG) through acid-sensitive hydrazone bonds. The dual pro-drug micelles cPzT/mPX configured according to the CPT/DOX mass ratio of 3:1 showed a strong synergistic therapeutic effect at IC50 with a combined therapy index CI = 0.49, far less than 1. Moreover, with the further improvement of the inhibition rate, the 3:1 ratio showed a stronger synergistic therapeutic effect than other ratios. The cPzT/mPX micelles not only had better targeted uptake ability but also showed a better therapeutic effect in both 2D and 3D tumor suppression assays relative to free CPT/DOX and significantly enhanced the penetration ability into solid tumors. In addition, the results of confocal laser scanning microscopy (CLSM) showed that cPzT/mPX could effectively overcome the resistance of A549/ADR cells to DOX by delivering DOX into the nucleus to exert its effect. Thus, this dual pro-drug synergistic therapy system combining targeting and endosomal escape ability provides a possible strategy to overcome tumor drug resistance.

Precise delivery of multi-stimulus-responsive nanocarriers based on interchangeable visual guidance.

Cancer treatment is imminent, and controlled drug carriers are an important development direction for future clinical chemotherapy. Visual guidance is a feasible means to achieve precise treatment, reduce toxicity and increase drug efficacy. However, the existing visual control methods are limited by imaging time-consuming, sensitivity and side effects. In addition, the ability of the carrier to respond to environmental stimuli in vivo is another difficulty that limits its application. Here, we propose a highly stimulus-responsive GC liposome with precise tracing and sensitive feedback capabilities. It combines magnetic resonance imaging and fluorescence imaging, and addresses the need for precise visualization by alternating imaging modalities. More importantly, GC liposomes are a carrier that can accumulate stimuli. In this paper, by tracking the fragmentation process of empty GC and drug-loaded D-GC liposomes, we confirm the synergistic effect between multiple stimuli, which can result in a more efficient drug release performance. Finally, in mice models we examined the GC liposome imaging approach and the D-GC + UV group guided by this visualization exhibited the highest tumor inhibition efficiency (6.85-fold). This study highlights the advantages of alternate visualization-guided and co-stimulation treatment strategies, and provides design ideas and potential materials for efficient and less toxic cancer treatments.

Series of High Magnetic Resonance-Guided Photoinduced Nanodelivery Systems for Precisely Improving the Efficiency of Cancer Therapy.

Nanochemotherapy is recognized as one of the most promising cancer treatment options, and the design of the carrier has a crucial impact on the final efficacy. To precisely improve the efficacy and reduce the toxicity, we combined the clinical contrast agent (Gd-DTPA) with a stimulus-sensitive o-nitrobenzyl ester and then prepared a series of nNBGD lipids by varying the carbon chain length of the hydrophobic group. The self-assembled nNBGD liposomes can be tracked by MRI to localize the aggregation of drug carriers in vivo, so as to prompt the application of light stimulation at the optimal time to facilitate the precise release of carriers at the lesion site. And the application potential of this strategy was verified with 88% tumor suppression effect in the 12NBGD-DOX+UV group. In addition, this paper emphasizes that small differences in structure can affect the overall performance of the carriers. By exploration of the differences in stability, drug loading, stimulus responsiveness, MRI imaging effect, and toxicity of the series of nNBGD carriers, the relationship between the length of the hydrophobic group of nNBGD lipids and the overall performance of the carriers is given, which provides experimental support and design reference for other carriers.

Sensitive and precise visually guided drug delivery nanoplatform with dual activation of pH and light.

Controlled-release drug carriers in cancer therapy are the most ideal way to reduce toxicity and improve drug efficacy. Since light stimulation is precise and operable, most multi-stimulation response carriers utilize phototherapy to enhance release efficiency. However, phototoxicity severely limits the application of phototherapy. Herein, we designed and synthesized a Cou-ONB lipid with sensitive fluorescence feedback and multi-stimulus response. COBL liposomes prepared from Cou-ONB lipids will passively aggregate at the tumor and guide phototherapy by fluorescence. More importantly, it can reflect the drug release effect in vivo through its own sensitive fluorescence changes, further enabling precise phototherapy and reducing phototoxicity. In this paper, the multi-stimulus superimposed response and precise fluorescence-guided performance of COBL liposomes were investigated at the molecular, liposome, cellular, and animal levels. Finally, tumor treatment experiments showed that the d-COBL-UV group had the best tumor suppression effect (5.3-fold). This paper highlights a real-time fluorescence-guided multi-stimulus superposition strategy and provides a design idea to precisely implement exogenous stimuli by displaying the degree of drug release, aiming to achieve less toxic and more efficient cancer therapy through timely and precise multi-stimulation. STATEMENT OF SIGNIFICANCE: Multi-stimulus responsive drug carriers have been extensively developed in the last decade. Visual guidance is an important tool to achieve precision medicine and precise control of drug release. However, the available visualization materials are more aimed at directing stimulation at the optimal moment. There is little discussion on when to stop exogenous stimulation and how to minimize the damage of stimulation to the patient. Here, we provide a Cou-ONB lipid that not only responds to multiple stimuli, but also provides sensitive feedback on its own dissociation with a fluorescent signal so that physicians can adjust exogenous stimuli in a timely manner. This paper provides insights to facilitate precision drug delivery systems, providing viable design ideas for precise, efficient, and less toxic cancer therapies.

Magnetic Resonance Imaging-Guided Multi-Stimulus-Responsive Drug Delivery Strategy for Personalized and Precise Cancer Treatment.

The emergence of nano-targeted controlled release liposomal drug carriers has provided a breakthrough in cancer therapy. However, their clinical efficacy is unsatisfactory, which is related to individualized differences in targeted drugs and poor in vivo release efficiency. In this paper, we prepared a class of personalized targeted and precisely controlled-release therapeutic drug carriers (GF liposomes) by co-assembling targeting and traceable o-nitrobenzyl ester lipids to propose a magnetic resonance imaging (MRI)-guided personalized in vivo targeted drug screening strategy and a multi-stimulus superimposed controlled-release strategy. Furthermore, by following the drug release process of drug-loaded liposomes (GF-D), it was found that these liposomes could rely on energy superposition to achieve more sensitive and efficient controlled drug release. In addition, the indispensable adjustment of liposome formulation for personalized MRI-based targeted therapy was verified by differential cellular uptake and in vivo magnetic resonance imaging. In the end, the 10.22-fold tumor suppression effect in the stimulus superposition group (GF-D-UV) indicates that the multi-stimulus cumulative response strategy and MRI-guided in vivo screening strategy can more effectively treat cancer. This contribution provides a concise and clever design idea for the future development of personalized precise and efficient clinical cancer therapies.

Selective Synthesis of Carbon Nanorings via Asymmetric Intramicellar Phase-Transition-Induced Tip-to-Tip Assembly.

The selective synthesis of energetically less favorable ring-shaped nanostructures by liquid phase synthetic chemistry is a huge challenge. Herein, we report a precise synthesis of carbon nanorings with a well-defined morphology and tunable thickness based on asymmetric intramicellar phase-transition-induced tip-to-tip assembly via mixing hydrophobic long-chain octadecanol and block copolymer F127. This orientational self-assembly depends on the hydrophobicity difference of the intermediate's surface, which triggers directional interactions that surpass the entropy cost of undesired connections and help assemble intermediates into defined ringlike structures. Based on a ringlike template, carbon nanorings with adjustable sizes can be attained by changing synthetic variables. More importantly, diverse units including crescentlike, podlike, and garlandlike nanostructures can also be created through controlling the kinetics of the self-assembly process. This discovery lays a solid foundation for the challenging construction of such a precise configuration on the nanoscale, which would not only promote fundamental studies but also pave the way for the development of advanced nanodevices with unique properties.

An MRI-guided targeting dual-responsive drug delivery system for liver cancer therapy.

The targeting dual-responsive drug delivery system was employed for cancer treatment as a positive strategy. Herein, Lactobionic acid (LA)-modified and non-modified UV/reduction dual-responsive molecules (10,10-NB-S-S-P-LA and 10,10-NB-S-S-P-OMe) were synthesized. Functional magnetic resonance imaging (MRI) contrast agent (12,12-NB-DTPA-Gd) was mixed with 10,10-NB-S-S-P-LA or 10,10-NB-S-S-P-OMe in the optimal ratio (3:1) to develop targeted empty liposomes (GNSPL) or non-targeted empty liposomes (GNSPM) with superior UV/reduction dual-responsiveness, biocompatibility and magnetic resonance imaging (MRI) performance. The drug-loaded liposomes (GNSPLD and GNSPMD) can keep stable in two weeks, and the drug cumulative release rate reached to the maximum under dual stimulation of ultraviolet (UV) and reducing agent (TCEP). The treatment with GNSPLD + UV significantly inhibited the growth and migration of cancer cells in vitro. The GNSPLD liposomes were more effectively accumulated in tumor site than GNSPMD liposomes, due to the targeting property of GNSPLD liposomes. The treatment with GNSPLD + UV showed a better therapeutic efficacy than Doxorubicin (DOX) in vivo, and almost no side effects during the treatment period. Thus, the MRI-guided targeting dual-responsive drug delivery system provided a reliable therapeutic strategy for treating liver cancer.

Endogenous reactive oxygen species burst induced and spatiotemporally controlled multiple drug release by traceable nanoparticles for enhancing antitumor efficacy.

Reactive oxygen species (ROS) are not only used as a therapeutic reagent in chemodynamic therapy (CDT), to stimulate the release of antineoplastic drugs, they can also be used to achieve a combined effect of CDT and chemotherapy to enhance anticancer effects. Herein, we synthesized a pH-responsive prodrug (PEG2k-NH-N-DOX), ROS-responsive prodrug (PEG2k-S-S-CPT-ROS), organic CDT agents (TPP-PEG2k-LND, TPP-PEG2k-TOS), and T1-enhanced magnetic resonance imaging contrast agents (Gd-DTPA-N16-16), and used them to encapsulate combrestatinA4 (CA4) to prepare traceable pH/ROS dual-responsive multifunctional nanoparticles (TLDCAG NPs) with endogenous ROS burst and spatiotemporally controlled multiple drug release ability. Firstly, TLDCAG NPs were accumulated in the tumor cell microenvironment via an enhanced permeability and retention (EPR) effect. Secondly, CA4 was released and specifically destroyed angiogenesis to facilitate the interaction between the tumor and the remaining TLDCG NPs. After accumulating in tumor cells, the TLDCG NPs could be destroyed under acidic conditions to quickly release doxorubicin (DOX), TPP-PEG2k-LND, and TPP-PEG2k-TOS. Thirdly, TPP-PEG2k-LND and TPP-PEG2k-TOS quickly targeted mitochondria, induced endogenous ROS bursts, reduced the mitochondrial membrane potential, and induced tumor cell apoptosis. Endogenous ROS can not only be used as a therapeutic reagent for CDT, but also can cut off the thioketal bond in PEG2k-S-S-CPT-ROS and release camptothecin (CPT). Finally, TLDCAG NPs were traced by magnetic resonance imaging (MRI). Furthermore, in vitro and vivo results indicate that the TLDCAG NPs have vigorous antitumor activity and negligible systemic toxicity. Therefore, the TLDCAG NPs provide an efficient strategy for enhancing antitumor efficacy.

A traceable, GSH/pH dual-responsive nanoparticles with spatiotemporally controlled multiple drugs release ability to enhance antitumor efficacy.

Constructing highly efficient and multifunctional nanoparticles to overcome the multiple challenges of targeted drug delivery is a new strategy urgently needed in tumor therapy. Here, we synthesized pH-responsive prodrug (PEG2K-NH-N-DOX), GSH-responsive prodrug (PEG2K-S-S-CPT), folate-receptor targeting polymers (FA-PEG2K-L8, FA-PEG2K-TOS) and T1-enhanced magnetic resonance imaging contrast agents (Gd-DTPA-N16-16), used to encapsulate combrestatinA4 (CA4) to prepare multifunctional nanoparticles (FTDCAG NPs). Unlike other nanoparticles, FTDCAG NPs contains three drugs with the ability to control the release in time and space, which can maximize the effectiveness of precise cancer chemotherapy. We first confirmed that specific binding between FTDCAG NPs and overexpressed folate-receptor cells by flow cytometry and confocal laser scanning microscopy. We then investigated the spatiotemporally controlled release ability of FTDCAG NPs loaded with doxorubicin (DOX), CA4 and camptothecin (CPT). Relative to pH = 7.4, the release efficiency of CA4 in the pH = 6.5 increased by 63.4 %. The first released CA4 is able to destroy the angiogenesis and help tumor cells to be exposed to the remaining FTDCG NPs. After being internalized into the tumor cells, FTDCG NPs is disassembled and the CPT and DOX were released due to the increase of intracellular GSH concentration and the decrease of pH value. Besides, the relaxation time of FTDCAG NPs is 3.86 times that of clinical Gd-DTPA, and the in vitro and vivo T1-weighted imaging is brighter, which can be used to trace the nanoparticles by MRI. Therefore, FTDCAG NPs provide an efficient strategy for the design of multifunctional drug delivery systems for enhancing antitumor efficacy.

Biomimetic hydroxyapate/polydopamine composites with good biocompatibility and efficiency for uncontrolled bleeding.

Uncontrolled bleeding is thought to be the most deadly cause of pre-hospital, traffic, and military accidents death. However, the popular commercial hemostats can only realize the hemostasis of mild bleeding. Therefore, we developed polydopamine (PDA) composite materials (PMs), which applied hydroxyapatite as the parent body. The PMs were produced via lyophilization and functionalized with amino, phenol hydroxyls groups, which endowed hydrophobicity to materials. This ensured a high aggregation ability of blood cells to the PMs and they were tested to be as high as 300% compared with the negative control group. The clotting time was shortened to 79.7% compared with the usually used commercial hemostat (Celox) in the test of in vitro hemostasis. Through the results of PT and APTT tests, blood coagulation index test, and the analysis of intracellular Ca2+ activation, we further understood the mechanism of the hemostasis of the materials, which explained the low blood loss and quick coagulation time of the PM hemostats in detail. Besides, the low hemolysis and cytotoxicity of the PMs suggested the good biocompatibility of the hemostats, which was further proved by the regular morphology maintained by erythrocytes in the hemolysis tests. The study of nanoscale composites led the research for the methods of hemostasis.

Assembly of Building Blocks by Double-End-Anchored Polymers in the Dilute Regime Mediated by Hydrophobic Interactions at Controlled Distances.

Hierarchical assembly of building blocks via competing, orthogonal interactions is a hallmark of many of nature's composite materials that do not require highly specific ligand-receptor interactions. To mimic this assembly mechanism requires the development of building blocks capable of tunable interactions. In the present work, we explored the interplay between repulsive (steric and electrostatic) and attractive hydrophobic forces. The designed building blocks allow hydrophobic forces to effectively act at controlled, large distances, to create and tune the assembly of membrane-based building blocks under dilute conditions, and to affect their interactions with cellular membranes via physical cross-bridges. Specifically, we employed double-end-anchored poly(ethylene glycol)s (DEA-PEGs)-hydrophilic PEG tethers with hydrophobic tails on both ends. Using differential-interference-contrast optical microscopy, synchrotron small-angle X-ray scattering (SAXS), and cryogenic electron microscopy, we investigated the ability of DEA-PEGs to mediate assembly in the dilute regime on multiple length scales and on practical time scales. The PEG length, anchor hydrophobicity, and molar fraction of DEA-PEG molecules within a membrane strongly affect the assembly properties. Additional tuning of the intermembrane interactions can be achieved by adding repulsive interactions via PEG-lipids (steric) or cationic lipids to the DEA-PEG-mediated attractions. While the optical and electron microscopy imaging methods provided qualitative evidence of the ability of DEA-PEGs to assemble liposomes, the SAXS measurements and quantitative line-shape analysis in dilute preparations demonstrated that the ensemble average of loosely organized liposomal assemblies maintains DEA-PEG concentration-dependent tethering on defined nanometer length scales. For cationic liposome-DNA nanoparticles (CL-DNA NPs), aggregation induced by DEA-PEGs decreased internalization of NPs by cells, but tuning the DEA-PEG-induced attractions by adding repulsive steric interactions via PEG-lipids limited aggregation and increased NP uptake. Furthermore, confocal microscopy imaging together with colocalization studies with Rab11 and LysoTracker as markers of intracellular pathways showed that modifying CL-DNA NPs with DEA-PEGs alters their interactions with the plasma and endosomal membranes.

Efficient antibacterial dextran-montmorillonite composite sponge for rapid hemostasis with wound healing.

Montmorillonite (MMT) powder, as the most effective hemostats in natural silicates, is restricted for commercial application due to its embolic effect. Until now, it's still a challenge to control the leakage of MMT and avoid its side-effects. Herein, poly aldehyde dextran (PDA)/MMT composite sponge (PM) with commendable tissue adhesion, antibacterial, and wound healing performances is developed for massive hemorrhage control. Based on the high degree of perfect synergism of PDA and MMT, the PM sponge can rapidly seal the wound, and promote cells aggregation and adhesion, whole coagulation system activation, resulting in shortened clotting time from 480 s to <10 s in vitro. Therefore, PM sponge with low exothermic effects achieves hemostasis in limited time, decreasing nearly 95% blood loss in the femoral artery and vein incision in rat models. Furthermore, with the intensive tissue adhesion (~47 kPa), PM sponge not only exhibits antibacterial activity to Escherichia coli, but also succeeds in accelerating wound healing. Importantly, the low cytotoxic sponge verifies to be a little hemolytic and skin irritant hemostat. Thus, the biocompatible PM sponge may provide a new strategy for reintroduction of MMT in hemostatic fields, and a safe-effective avenue for clays to control bleeding.

A Multifunctional Lipid Incorporating Active Targeting and Dual-Control Release Capabilities for Precision Drug Delivery.

Active targeting and precise control of drug release based on nanoparticle therapies are urgently required to precisely treat cancer. We have custom-synthesized a functional lipid (termed Fa-ONB) by introducing a folic acid-targeting group into an o-nitro-benzyl ester lipid. As designed, the liposomes formed by Fa-ONB combine active targeting and dual trigger release capabilities, which help to improve drug efficacy and reduce the toxicity of traditional liposomes. We first verified that both pH-induced hydrolysis and light treatment were able to cleave the Fa-ONB lipid. We then prepared a series of liposomes (termed FOBD liposomes) by compounding the Fa-ONB lipid with DOPC at different ratios. After encapsulation of doxorubicin (DOX), we found that the particle size of DOX-loaded FOBD liposomes (DOX/FOBD) first increased (290 to 700 nm) and then decreased again (to 400 nm) under continuous UV irradiation (120 min). The photocatalytic release efficiency under different pH conditions was investigated by dialysis experiments, and it was found that the release efficiency in an acidic environment was significantly increased relative to neutral pH. This pH-triggered release response helps distinguish pathological tissues such as lysosomal compartments and tumors. The light-induced formation of a DOX precipitate increases in efficiency with increasing UV exposure time as well as with increasing environmental acidity or alkalinity. In addition, confocal imaging and flow cytometry showed that the ability of FOBD lipids to actively target HeLa cells increased with increasing Fa-ONB lipid content. Real-time in vivo fluorescence small animal experiments proved targeting to tumors and pH- and photo-induced release properties. Furthermore, therapeutic experiments using a mouse model found a significant tumor inhibitory effect for DOX/FOBD55 liposomes with UV irradiation, clearly demonstrating the benefit of light treatment: the tumor size of the control (PBS) group was 7.59 times that of the light treatment group. Therefore, this research demonstrates the benefits of combining triggerable release functions and effective active tumor targeting in one small lipid molecule for precise cancer treatment.

A multifunctional lipid that forms contrast-agent liposomes with dual-control release capabilities for precise MRI-guided drug delivery.

Monitoring of nanoparticle-based therapy in vivo and controlled drug release are urgently needed for the precise treatment of disease. We have synthesized a multifunctional Gd-DTPA-ONB (GDO) lipid by introducing the Gd-DTPA contrast agent moiety into an o-nitro-benzyl ester lipid. By design, liposomes formed from the GDO lipid combine MRI tracking ability and dual-trigger release capabilities with maximum sensitivity (because all lipids bear the cleavable moiety) without reducing the drug encapsulation rate. We first confirmed that both photo-treatment and pH-triggered hydrolysis are able to cleave the GDO lipid and lyse GDO liposomes. We then investigated the efficiency of drug release via the combined release processes for GDO liposomes loaded with doxorubicin (DOX). Relative to neutral pH, the release efficiency in acidic environment increased by 10.4% (at pH = 6.5) and 13.3% (at pH = 4.2). This pH-dependent release response is conducive to distinguishing pathological tissue such as tumors and endolysosomal compartments. The photo-induced release efficiency increases with illumination time as well as with distance of the pH from neutral. Photolysis increased the release efficiency by 13.8% at pH = 4.2, which is remarkable considering the already increased amount of drug release in the acidic environment. In addition, the relaxation time of GDO liposomes was 4.1 times that of clinical Gd-DTPA, with brighter T1-weighted imaging in vitro and in vivo. Real-time MRI imaging and in vivo fluorescence experiments demonstrated tumor targeting and MRI guided release. Furthermore, significant tumor growth inhibition in a treatment experiment using DOX-loaded GDO liposomes clearly demonstrated the benefit of photo-treatment for efficacy: the tumor size in the photo-treatment group was 3.7 times smaller than in the control group. The present study thus highlights the benefit of the design idea of combining efficient imaging/guiding, targeting, and triggerable release functions in one lipid molecule for drug delivery applications.

Effective wound dressing based on Poly (vinyl alcohol)/Dextran-aldehyde composite hydrogel.

Wound dressing is of significant importance to promote cutaneous wound healing process. To develop an effective wound dressing, a PVA/DA hydrogel was prepared using a Poly (vinyl alcohol)/Dextran-aldehyde solution blend, followed by crosslinking via freeze-thaw method and freeze-drying. We characterized the hydrogel by infrared spectroscopy, mechanical property tests, swelling behavior test and biocompatibility test. Results showed that the PVA/DA hydrogels had a 3-dimensional, highly porous structure with uniformly distributed pores of 5-10 µm, strong tensile strength of 5.6 MPa, efficient ability to absorb fluid of 6 time its weight and suitable water vapor transmission rate of 2100 g m-2day-1 to keep a moist environment and good biocompatibility shown by very low hemolysis and no cytotoxicity. In wound healing tests using a full-thickness skin wound model, macroscopic observations showed that the wound covered by the PVA/DA hydrogel almost reached complete healing faster by 10 days, while histological analysis indicated a faster regeneration of skin. Thus, the PVA/DA hydrogel was suitable for application as a wound dressing and may have potential for use in various biomedical applications.

A highly efficient, in situ wet-adhesive dextran derivative sponge for rapid hemostasis.

Uncontrolled hemorrhage is closely related to the high risk of death. However, local hemostats still have various defects and side effects. Herein, an aldehyde dextran (PDA) sponge with proper absorption and adhesion properties is developed for hemorrhage control. PDA sponge with pore size of ∼30-50 µm fabricated by lyophilization not only absorbs blood quickly (47.7 g/g), but also possesses strong tissue adhesion (∼100 kPa). PDA sponge with low cytotoxicity and hemolysis achieves effective hemostasis and remarkable blood loss reduction in the ear vein, femoral artery and liver injuries of rabbit models. Furthermore, the exploration of hemostatic mechanisms related to tissue, blood, plasma, cells and coagulation system indicates that PDA sponge can significantly accelerate coagulation by rapid wound block, fast cells aggregation and initiation, and high coagulation factors concentration, instead of by the coagulation cascade activation. Importantly, this hemostat exhibits excellent biodegradability and nearly no skin irritation. Overall, the biodegradable and tissue adhesive PDA sponge will be a promising quick-hemostatic dressing for uncontrollable hemorrhage.

Synthesis and evaluation of mono- and multi-hydroxyl low toxicity pH-sensitive cationic lipids for drug delivery.

Cationic lipids can easily assemble into spherical liposomes in aqueous phase which showed unique superiority in drug and gene delivery. However, the toxicity of cationic lipids is still an obstacle to application. To develop low toxicity cationic lipids, we designed two cationic lipids contained different number of hydroxyl groups. Biocompatible mono-hydroxyl and multi-hydroxyl galactose head group was respectively modified to a biodegradable quaternary amine lipid, and two novel hydroxyl cationic lipids were synthesized and characterized by MS, 1H NMR and 13C NMR. Two lipids showed good surface activity and both of them can assemble to about 80 nm stable small unilamellar vesicles (SUVs) with cholesterol in aqueous phase. Both of lipids showed relatively lower toxicity than the well-known cationic lipid 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP). In vitro 24 h IC50 of two assemblies were more than 50 µg/mL, which were about 10 µg/mL higher than the IC50 of DOTAP. Multi-hydroxyl galactose lipids group showed much lower toxicity than mono-hydroxyl lipids group. Moreover, Both of the assemblies with lower hemolysis were nearly non-hemolytic risk under the concentration of 30 µg/mL. Transmission electron microscopy (TEM) and dynamic light scattering (DLS) showed that the average sizes of both doxorubicin (DOX) loaded liposomes were about 110 nm. The DOX entrapment efficiencies of galactose liposome and mono-hydroxyl liposome were 58% and 91%, respectively. Both of the DOX loaded liposomes were stable after one month placed at room temperature. Two DOX loaded liposomes showed better anti-cancer effect than free DOX above 5 µg/mL, and they can be internalized into cells and produce more release of DOX inside MCF-7 cells and HepG2 cells at pH 5.0. These results suggested that synthesized lipids are suitable as potential low toxicity cationic drug delivery systems.

Reversible Control of Spacing in Charged Lamellar Membrane Hydrogels by Hydrophobically Mediated Tethering with Symmetric and Asymmetric Double-End-Anchored Poly(ethylene glycol)s.

Complex materials often achieve their remarkable functional properties by hierarchical assembly of building blocks via competing and/or synergistic interactions. Here, we describe the properties of new double-end-anchored poly(ethylene glycol)s (DEA-PEGs)-macromolecules designed to impart hydrophobically mediated tethering attractions between charged lipid membranes. We synthesized DEA-PEGs (MW 2000 (2K) and 4.6K) with two double-tail (symmetric) or a double-tail and a single-tail (asymmetric) hydrophobic end anchors and characterized their equilibrium and kinetic properties using small-angle X-ray scattering. Control multilayer membranes without and with PEG lipid (i.e., single-end-anchored PEG) swelled continuously, with the interlayer spacing increasing between 30 and 90 wt % water content due to electrostatic as well as, in the case of PEG lipid, steric repulsion. In contrast, interlayer spacings in lamellar membrane hydrogels containing DEA-PEGs expanded over a limited water dilution range and reached a "locked" state, which displayed a near constant membrane wall-to-wall spacing (δw) with further increases in water content. Remarkably, the locked state displays a simple relation to the PEG radius of gyration δw ≈ 1.6 RG for both 2K and 4.6K PEG. Nevertheless, δw being considerably less than the physical size of PEG (2(5/3)1/2 RG) is highly unexpected and implies that, compared to free PEG, anchoring of the PEG tether at both ends leads to a considerable distortion of the PEG conformation confined between layers. Significantly, the lamellar hydrogel may be designed to reversibly transition from a locked to an unlocked (membrane unbinding) state by variations in the DEA-PEG concentration, controlling the strength of the interlayer attractions due to bridging conformations. The findings with DEA-PEGs have broad implications for hydrophobic-mediated assembly of lipid- or surfactant-coated building blocks with distinct shape and size, at predictable spacing, in aqueous environments.

Mussel-inspired degradable antibacterial polydopamine/silica nanoparticle for rapid hemostasis.

High-performance hemostasis becomes increasingly essential in civilian and military trauma. However, available topical hemostats still exist various drawbacks and side-effects. Herein, a silica nanoparticle coated with polydopamine (PDA/SiNP) with good degradability, antibacterial performance was developed for hemorrhage control. PDA/SiNP formed a porous network via lyophilization and rendered material with phenol hydroxyls, aminos, proper hydrophobicity, promising for further cells aggregation and inducing clotting. The degradation behaviors in vitro indicated that the weight loss of PDA/SiNP could attain approximately 40% just after 24 h. All results demonstrated that clotting time of blood was shortened by nearly 150 s for PDA/SiNP compared with that of commercial Celox in vitro hemostasis. PDA/SiNP could significantly accelerate coagulation by activating the extrinsic pathway of the coagulation cascade, adhering platelets and aggregating erythrocytes. Therefore, not only the PDA/SiNP achieved adequate hemostasis with low exothermic effects, but also blood loss was remarkably reduced in the femoral artery and vein injury, liver injury models. Importantly, PDA/SiNP exhibited long-lasting inhibition of Escherichia coli even after 208 h. Also, the hemolysis of PDA/SiNP with low cytotoxicity was much lower, while erythrocytes maintained regular morphology. Thus, amorphous nanoscale PDA/SiNP provided a new avenue for design of silica hemostats and nonmetallic ion antimicrobial.