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Wearable sensors have been widely studied because of their small size, light weight, and potential for the noninvasive tracking and monitoring of human physiological information. Wearable flexible sensors generally consist of two parts: a flexible substrate in contact with the skin and a signal processing module. At present, wearable electronics cover many fields, such as machinery, physics, chemistry, materials science, and biomedicine. The design concept and selection of materials are very important to the function of a sensor. In this review, we summarize the latest developments in flexible materials for wearable sensors, including developments in flexible materials, electrode materials, and new flexible biodegradable materials, and describe the important role of innovation in material and sensor design in the development of wearable flexible sensors. Strategies and challenges related to the improvement of the performances of wearable flexible sensors, as well as the development prospects of wearable devices based on flexible materials, are also discussed.

Inspired by the natural phenomenon of phenolic-protein interactions, we translate this "naturally evolved interaction" to a "phenolic acid derivative based albumin bound" technology, through the synthesis of phenolic acid derivatives comprising a therapeutic cargo linked to a phenolic motif. Phenolic acid derivatives can bind to albumin and form nanocomplexes after microfluidic mixing. This strategy has been successfully applied to different types of anticancer drugs, including taxanes, anthraquinones, etoposides, and terpenoids. Paclitaxel was selected as a model drug for an in-depth study. Three novel paclitaxel-phenolic acid conjugates have been synthesized. Molecular dynamics simulations provide insights into the self-assembled mechanisms of phenolic-protein nanocomplexes. The nanocomplexes show improved pharmacokinetics, elevated tolerability, decreased neurotoxicity, and enhanced anticancer efficacies in multiple murine xenograft models of breast cancer, in comparison with two clinically approved formulations, Taxol (polyoxyethylated castor oil-formulated paclitaxel) and Abraxane (nab-paclitaxel). Such a robust system provides a broadly applicable platform for the development of albumin-based nanomedicines and has great potential for clinical translation.

To increase the efficiency and accuracy of clinical tumor detection, we explored multiple imaging by preparing carbon quantum dot (CQD)-loaded nanobubbles for ultrasonic fluorescence dual detection. In this experiment, we prepared 1,2-dioleoyl3-trimethylammonium-propane chloride (DOTAP) cationic liposomes using the film dispersion method and chose perfluoropentane as the core gas material of the nanobubbles. The nanobubbles were coupled with the negatively charged CQDs through the charge effect to prepare the testing agent for two-way diagnosis with ultrasound contrast and fluorescence detection. The formulation and preparation of the loaded CQD liposome nanobubbles were screened. In vivo experiments showed that nanobubbles can be enriched to the tumor site within 5 min, which enables clearer ultrasound imaging and is conducive to tumor detection. We expect CQD-loaded liposome (Lip-CQD) nanobubbles to become a new ultrasonic contrast agent for clinical applications that can provide a basis for early tumor diagnosis and thus earlier treatment.

Bone defects are the second most common tissue grafts after blood. However, bone grafts face several problems, such as bone scaffolds, which have low bioactivity and are prone to corrosion. Much of the current research on bone scaffolds is focused on the mechanical aspects such as structure and strength. Surface modification of the bone scaffold is carried out in terms of the mechanical structure or structural design of the bone scaffold with reference to a bionic structure. However, with the development of mechanical designs, materials science, and medicine, many studies have reported that promoting bone growth by modifying the structure of the scaffold or coating is not possible. Therefore, the application of a bioactive coating to the surface of the bone scaffold is particularly important to generate a synergistic effect between the structure and active coating. In this article, we present several perspectives to improve the bioactivity of bone scaffolds, including corrosion resistance, loading of bioactive coatings or drugs on bone scaffolds, improved adhesion to the surface of the bone scaffolds, immune response modulation, and drawing on bionic structures during manufacturing.

Therapeutic efficacy against cancer relies heavily on the ability of the therapeutic agents to reach their final targets. The optimal targets of most cancer therapeutic agents are usually biological macromolecules at the subcellular level, which play a key role in carcinogenesis. Therefore, to improve the therapeutic efficiency of drugs, researchers need to focus on delivering not only the therapeutic agents to the target tissues and cells but also the drugs to the relevant subcellular structures. In this review, we discuss the most recent construction strategies and release patterns of various cancer cell subcellular-targeting nanoformulations, aiming at providing guidance in the overall design of precise nanomedicine. Additionally, future challenges and potential perspectives are illustrated in the hope of enhancing anticancer efficacy and accelerating the translational progress of precise nanomedicine.

Two novel effective antioxidative tripeptides GWY and QWY were designed based on 3D-QSAR models. Their activities were confirmed by an improved TEAC assay. The experimental results showed that GWY and QWY possessed good antioxidant activity, equaling 3.32 mM TE and 2.97 mM TE respectively. This indicated that 3D-QSAR models possessed significant predictive capacity for drug design. In addition, molecular docking and molecular dynamics simulation were applied to reveal the potential molecular mechanism of antioxidant peptides. The result showed that GWY and QWY could enhance the stability of Keap1 by interacting with the key residues Arg415, Arg483, Arg380 and Ser555 in the active sites. Interestingly, the key residues were exactly the binding site of Nrf2 in the active pocket of Keap1. Thus, GWY and QWY could compete with Nrf2 for binding to Keap1. This demonstrated that the new tripeptides might have the ability to activate the signaling pathway Keap1-Nrf2-ARE and improve the antioxidant defense system of the body as well.

Purpose Thymosin β-4(Tβ-4) is a macromolecular protein drug with potential for drug development in wound repair but is limited by the shortcomings of macromolecular protein, such as large volumes, poor membrane permeability, and unstable physicochemical characteristics. Ethosomes could enhance cell membrane fluidity and reduce epidermal membrane density to make macromolecular drugs through the stratum corneum into the deeper layers of the skin easily. Herein, we developed and characterized a novel transdermal delivery vehicle to load macromolecular protein peptides and use Tβ-4 as a model drug wrapped into ethosomes. Methods We used the orthogonal method to optimize the formulation of the ethosome preparation prepared by the ethonal infusion method. Ethosomal gels were characterized by using different analytical methods. Transdermal release rate in vitro have been demonstrated in Franz diffusion cells and the efficacy of drug-loaded nanocarriers in vivo was investigated in a mouse model. Results Optimized Tβ-4 ethosomal gels have good physicochemical properties. The drug amounts of the cumulative release in the ethosomal gel within 5 hours were 1.67 times that of the T-β4 gel in vitro release study, and the wound healing time of ethosomal gel group was only half of the T-β4 gel group in vivo pharmacokinetic study. Compared with the free drug group, the ethosome preparation not only promotes the percutaneous absorption process of the macromolecular protein drugs but also shortened wound recovery time. Conclusion Hence, we provide a possible good design for ethosomal gel system that can load macromolecular protein peptide drugs to achieve transdermal drug administration, promoting the percutaneous absorption of the drug and improving the effect.

Some chemotherapy can damage tumor cells, releasing damage-related molecular patterns including ATP to improve immunological recognition against the tumor by immunogenic cell death (ICD). However, the immune-stimulating ATP may be rapidly degraded into immunosuppressive adenosine by highly expressed CD39 and CD73 in the tumor microenvironment, which leads to immune escape. Based on the above paradox, a liposome nanoplatform combined with ICD inducer (oxaliplatin) and CD39 inhibitor (POM-1) is designed for immunochemotherapy. The liposomes efficiently load the phospholipid-like oxaliplatin prodrug, and the cationic charged surface could adsorb POM-1. Rationally designed DSPE-PEG

Metal complexes are of increasing interest as pharmaceutical agents in cancer diagnostics and therapeutics, while some of them suffer from issues such as limited water solubility and severe systemic toxicity. These drawbacks severely hampered their efficacy and clinical applications. Liposomes hold promise as delivery vehicles for constructing metal complex-based liposomes to maximize the therapeutic efficacy and minimize the side effects of metal complexes. This review provides an overview on the latest advances of metal complex-based liposomal delivery systems. First, the development of metal complex-mediated liposomal encapsulation is briefly introduced. Next, applications of metal complex-based liposomes in a variety of fields are overviewed, where drug delivery, cancer imaging (single photon emission computed tomography (SPECT), positron emission tomography (PET), and magnetic resonance imaging (MRI)), and cancer therapy (chemotherapy, phototherapy, and radiotherapy) were involved. Moreover, the potential toxicity, action of toxic mechanisms, immunological effects of metal complexes as well as the advantages of metal complex-liposomes in this content are also discussed. In the end, the future expectations and challenges of metal complex-based liposomes in clinical cancer therapy are tentatively proposed.

In recent years, immunotherapy has produced many unexpected breakthroughs in oncological therapy; however, it still has many deficiencies. For example, the number of patients who are unresponsive to anti-programmed death-ligand 1 (PD-L1), anti-cytotoxic T-like antigen-4 (CTLA4), and anti-programmed death-1 (PD1) therapies cannot be ignored, and the search for an undiscovered immunosuppressive pathway is imminent. Five decades ago, researchers found that activation of the adenosinergic pathway was negatively correlated with prognosis in many cancers. This review describes the entire process of the adenosinergic pathway in the tumor microenvironment and the mechanism of immunosuppression, which promotes tumor metastasis and drug resistance. Additionally, the review explores factors that regulate this pathway, including signaling factors secreted by the tumor microenvironment and certain anti-tumor drugs. Additionally, the combination of adenosinergic pathway inhibitors with chemotherapy, checkpoint blockade therapy, and immune cell-based therapy is summarized. Finally, certain issues regarding treatment via inhibition of this pathway and the use of targeted nanoparticles to reduce adverse reactions in patients are put forward in this review. Graphical Abstract The inhibitors of adenosinergic pathway loaded nanoparticles enter tumor tissue through EPR effect, and inhibit adenosinergic pathway to enhance or restore the effect of immune checkpoint blockade therapy, chemotherapies and immune cell-based therapy. Note: EPR means enhanced penetration and retention, × means blockade.

Skeletal biomechanics focuses on both transient and long-term effects of bone stress, using the basic theory and method of material mechanics, elasto-plasticity theory, and fracture mechanics,is considered to be one of the most important branches in biomechanics. In order to achieve complete and comprehensive evaluation of skeletal biomechanics, researchers developed a variety of levels of skeletal biomechanical evaluation methods, including mechanical testing, theoretical research, microstructure research and finite element analyses. At present, most of the mechanical evaluation methods were performed by a combination of mechanical tests and finite element (FE) simulation studies for the evaluation of mechanical properties. This study summerized the research in multi-level mechanical test methods, different research methods of microstructure, and the reconstruction of various FE skeletal models to study bone mechanics. The mentioned methods and techniques can be served as the basis for systematic studies of the biomechanical properties of bones.

Two CFD models A and B were developed based on APV high-pressure homogenizer and it was determined that the mathematical model and analysis method of B were more consistent with the actual homogenization process. The internal flow field of the high-pressure micro-jet homogenizer was simulated using Fluent software. The homogenization pressure, ratio of oil to water, and temperature were investigated. The optimal parameter combination obtained from numerical simulation of orthogonal experiment was 20 °C, 70 MPa, and 1:12. APV high-pressure homogenizer orthogonal experiment was conducted and the optimal experimental parameter combination obtained was 50 °C, 70 MPa, and 1:15. The two groups of optimal parameters were used in the homogeneous experiments. TEM images were used for comparative analysis of the particle size，and the particle size obtained by numerical simulation was slightly larger. A comparison of experimental and numerical simulation results indicate that the single factor experiment and the orthogonal experiment were not entirely chime. The reason for the discrepancy is because the emulsifier was added in the homogeneous experiment such that there were more flow field variation factors in the homogenization process and the numerical process did not define all relevant conditions. However, the highly similar development trend verifies the effectiveness of the B model, which can provide an important reference in the development and use of homogenizers.

Sonodynamic therapy (SDT) has been proposed as a new modality for cancer management through low-intensity ultrasound induced activation of sonosensitizers. Here, we designed a novel redox/enzyme/ultrasound responsive chondroitin sulfate-chlorin e6-lipoic acid nanoplatform loading docetaxel, combining SDT and chemotherapy, for antiproliferation and antimetastasis of melanoma. The reversibly crosslinked and self-assembled nanoparticles possessed monodispersive size distribution, stability in physical conditions, while showing increased uptake with rapid drug release in simulated tumor microenvironment (reductive potentials and degradative hyaluronidase-1). With synthesized ultrasound sensitive polymer backbones, SDT induced the generation of cellular reactive oxygen species and mitochondrial damage, exerting the apoptotic effect through the release of cytochrome C, the expression of cleaved caspase-9 followed by the functional cleaved caspase-3. Chemo-sonodynamic therapy not only inhibited tumor growth and metastasis with reduced metastatic protein expression, but also caused immune response via the release of tumor-associated antigens. It was initially demonstrated that SDT could induce the tumor cell death, therefore having potentials to recruit cytotoxic lymphocytes into tumor sites. Notably, the nanoplatforms exhibited good in vivo stability and blood compatibility, indicating the safety and efficiency in drug delivery. Our work thus presents a convenient approach to fabricate intelligent multifunctional nanoparticles and paves a path for effective cancer therapies.

Autologous or allogeneic bone grafts are common methods to treat bone defects. Bone tissue engineering combining carrier material with the active factor can induce a generation of new bone at the bone defect site. However, its clinical application is restricted by the limited donors, the high morbidity at the donor site, the low activity in vivo, and dose-independent adverse effect. To overcome the limitations of traditional therapies, it is urgent to find and develop a repair material that can replace natural bones. Hence, we designed and prepared suitable MPEG-PCL microspheres loaded bone morphogenetic protein-2 (BMP-2/MPEG-PCL-MS) to effectively solve the problem mentioned above, prolong its reaction time at the targeted site, and avoid the pain of patients caused by frequent administration. The physicochemical properties and in vitro release behaviors were good. The microspheres showed high biocompatibility and strongly induced osteogenesis in vivo. BMP-2/MPEG-PCL-MS has been proven to exert sustained-release in vivo and maintain the inherent BMP-2 activity. They can be directly injected into the bone defect site, or implanted to a large bone defect site together with stent material to exert therapeutic effects. Hence, this smart drug delivery system has promising potential for clinical applications and provides a well-controlled design for combination of tissue engineering and pharmaceutics for further exploration.

Liposomes have made remarkable achievements as drug delivery vehicles in the clinic. Liposomal products mostly benefited from remote drug loading techniques that succeeded in amphipathic and/or ionizable drugs, but seemed impracticable for nonionizable and poorly water-soluble therapeutic agents, thereby impeding extensive promising drugs to hitchhike liposomal vehicles for disease therapy. In this study, a series of weak acid drug derivatives were designed by a simplistic one step synthesis, which could be remotely loaded into liposomes by pH gradient method. Cabazitaxel (CTX) weak acid derivatives were selected to evaluate regarding its safety profiles, pharmacodynamics, and pharmacokinetics. CTX weak acid derivative liposomes were superior to Jevtana® in terms of safety profiles, including systemic toxicity, hematological toxicity, and potential central nerve toxicity. Specifically, it was demonstrated that liposomes had capacity to weaken potential toxicity of CTX on cortex and hippocampus neurons. Significant advantages of CTX weak acid derivative-loaded liposomes were achieved in prostate cancer and metastatic cancer therapy resulting from higher safety and elevated tolerated doses., Graphical abstract A facile and universal method was constructed to achieve liposomal remote loading of non-ionizable drugs. The developed cabazitaxel weak acid derivatives liposomes were superior to the marketed formulations, Jevtana®, concerning the safety profiles and antitumor efficiency.Image 1

Bone defects are a major threat to human health, and heterotopic bone provides advantages that other materials do not provide in the treatment of bone defects. MPEG-PCL microspheres loaded with bone morphogenetic protein-2 (BMP-2/MPEG-PCL-MS) are an emerging means of culturing heterotopic bone. However, the effect of such microspheres on the quality of heterotopic bone osteogenesis has rarely been studied. The performance of heterotopic bone as a bone repair material has also rarely been reported. To explore the effect of microspheres on heterotopic bone osteogenesis and to explore the performance of heterotopic bone in bone repair, we designed compression tests, nanoindentation tests, and a finite element (FE) simulation. The effects of microspheres on the quality of heterotopic bone osteogenesis and performance of heterotopic bone as a bone repair material were evaluated from the mechanical properties, material properties, and FE simulation. The results demonstrate that eight-week heterotopic bone using microspheres has suitable mechanical and material properties, performs well in bone repair FE simulation, and can meet the material requirements of bone repair. Hence, this heterotopic bone as bone repair material has promising potential for clinical applications, and provides a good strategy for combination between tissue engineering and pharmaceutical science.

Liposomes are among the most successful nanocarriers; several products have been marketed, all of which were prepared by active loading methods. However, poorly water-soluble drugs without ionizable groups are usually incorporated into the lipid bi-layer of liposomes by passive loading methods, with serious drug leakage during blood circulation. Furthermore, there have been few improvements in their anti-cancer activity and safety. Herein, we designed and synthesized three weak-acid modified paclitaxel (PTX) derivatives with a one-step reaction for the remote loading of liposomal formulations. By comparison, PTX-succinic acid liposomes (PTX-SA LPs) exhibited the highest encapsulation efficiency (97.2 ± 1.8%) and drug loading (8.84 ± 0.16%); meanwhile, there was almost no change in their particle size or zeta potential within one month. Furthermore, compared with Taxol®, the PTX-SA LPs showed a 4.35-fold prolonged half-time, enhanced tumor accumulation, and an increased maximum tolerated dose (MTD) of more than 30 mg kg−1. As a result, the PTX-SA LPs displayed significantly improved in vivo anti-cancer efficacy in comparison with Taxol®. Therefore, weak-acid modification is proved to be a simple and effective method to achieve remote loading and high encapsulation efficiency of poorly soluble drugs, showing great potential for clinical application.

Background and objective Although nanoparticle preparations have great potential in the treatment of tumors, nanoparticle preparations have not achieved the desired therapeutic effect. The reason is that the abnormal tumor microenvironment prevents nanoparticles from effective concentrating and reaching tumor area. Therefore, it's very necessary to better understand the effect of the abnormal tumor microenvironment on the transvascular transport of nanoparticles to overcome this critical problem. Methods In this paper, a tumor abnormal vascular-interstitial model was established, and the transvascular transport process of nanoparticles was simulated in the model by computational fluid dynamics (CFD) modeling. Results The simulation results showed that the transport efficiency of nanoparticles decreased with increasing interstitial fluid pressure (IFP), and nanoparticles could not cross the blood vessel wall when the IFP approached the blood vessel wall pressure. Interestingly, the transport efficiency of nanoparticles first increased with blood flow velocity, and then decreased with blood flow velocity. Conclusions The results showed that with the continuous malignant development of tumors, the ability of nanoparticles to passively diffuse has almost disappeared. The enhanced permeability and retention (EPR) effect of the nanoparticles disappeared with the disappearance of the pressure gradient inside the tumor. These results provided guidance for future research on the vascular transport pathways and mechanisms of nanoparticles.

The combination of paclitaxel (PTX) and doxorubicin (DOX) has been widely used in the clinic. However, it remains unsatisfied due to the generation of severe toxicity. Previously, we have successfully synthesized a prodrug PTX-S-DOX (PSD). The prodrug displayed comparable in vitro cytotoxicity compared with the mixture of free PTX and DOX. Thus, we speculated that it could be promising to improve the anti-cancer effect and reduce adverse effects by improving the pharmacokinetics behavior of PSD and enhancing tumor accumulation. Due to the fact that copper ions (Cu2+) could coordinate with the anthracene nucleus of DOX, we speculate that the prodrug PSD could be actively loaded into liposomes by Cu2+ gradient. Hence, we designed a remote loading liposomal formulation of PSD (PSD LPs) for combination chemotherapy. The prepared PSD LPs displayed extended blood circulation, improved tumor accumulation, and more significant anti-tumor efficacy compared with PSD NPs. Furthermore, PSD LPs exhibited reduced cardiotoxicity and kidney damage compared with the physical mixture of Taxol and Doxil, indicating better safety. Therefore, this novel nano-platform provides a strategy to deliver doxorubicin with other poorly soluble antineoplastic drugs for combination therapy with high efficacy and low toxicity., Graphical abstract The authors designed a remote loading paclitaxel–doxorubicin prodrug liposomal formulation for combination of PTX and DOX. The prodrug could respond to high ROS/GSH of the tumor microenvironment. The stimuli-responsive liposomes were proved to be a high-efficacy and low-toxicity formulation. This technology provides a novel pathway for cancer combination therapy.Image 1

Cancer has become one of the major threats to human survival. Because of antibodies specificity and low toxicity, it is the primary choice to diagnose and treat cancer. It is easy to be cleared from the blood circulation or distributing throughout the body and causes unnecessary side effects. It is necessary to delivery antibodies to the tumour region in a stable, safe and effective manner. In this review, we discuss the latest studies that aimed to delivery antibodies to tumour sites via several vector forms, such as liposomes, carbon nanomaterials, and gold nanomaterials. How to deliver antibodies to the target site is a difficulty for antibody therapy. This review summarises the antibody's therapeutic forms and carrier materials in recent years, and to explore how antibodies can be safely and stably delivered to the target site.

Immunotherapy has exhibited enormous practice in the treatment of melanoma because of the intrinsic properties of tumor. Tumor can downmodulate immune function via multiple mechanisms such as immune checkpoint pathways. The PD-L1 monoclonal antibodies that block the PD1/PD-L1 pathway, which induced tumor cells to evade an immune attack, can delay tumor growth efficiently with inevitable disadvantages such as low selectivity and systemic toxicity. Nanomedicine is clearly an approach that holds tremendous potential for addressing the shortcomings and assisting delivery of drugs with proper biodistribution. Herein, we developed a smart nanoplatform with precisely active targeting liposome co-loaded chemotherapy and immunotherapy drugs for synergistic antitumor effects while decreasing systemic toxicity. Immunoliposomes have stable pharmaceutical properties and show a significant antitumor effect in vivo and in vitro. Cellular uptake in vitro and biodistribution in vivo demonstrated that immunoliposomes could be delivered and accumulated more in tumor tissues. These immunoliposomes exhibited effective tumor inhibition and prolonged survival time due to activation of tumor-specific CD8+ T cell and highly selective tumor killing. In addition, safety evaluation of liposomes also demonstrated their increased tumor accumulation and decreased systemic toxicity. Hence, this smart pH-sensitive nanoplatform has promising potential for clinical applications and possibly provides a well-controlled design for combination of chemotherapy with various immunotherapies for further exploration.

To realize the controlled mass production of microspheres prepared by a high-pressure homogenizer and solve the problem of protein structure damage caused by very high pressure and overheating. This study established a numerical model based on the high-pressure homogenizer and performed simulation calculations using computational fluid dynamics (CFD). Through multipressure gradient microsphere preparation experiments, the particle size obtained by experiment and numerical calculation were compared and analyzed. According to the principle of conservation of energy, the speed was established as the optimization reference target, the structure of homogenizer was optimized and designed, and the corner spacing, corner radian, and corner taper of the homogeneous cavity were determined as the optimization objects. The ternary and cubic relationship equations of the optimized structure were fitted, and the continuous optimization of multi factor relations were realized. The results show that the optimal structural parameters are 0.496 mm corner spacing, 0.493 mm corner radian and 1.86 degrees corner taper, the fluid motion velocity of the high-pressure homogenizer increases from 234 m/s to 297 m/s under 30 MPa, and the velocity increases by 26.9%, and the particle size of the microsphere reaches the treatment effect of 50 MPa. The increase in kinetic energy indicates that the friction is overcome, the heat generation is reduced. The research has solved the problems of high pressure and overheating encountered in the process of homogeneous production, realized the social needs of efficient and green production, and provided support for the further development of homogenizer technology.

In this study, novel prodrug-modified cationic liposome nanocomplexes (Combo NCs) were reported for gemcitabine (GEM) and docetaxel (DTX) co-delivery. This nanoplatform exhibited multiple favorable characteristics, such as a 'green' fabrication with a one-step chemical reaction, appropriate size (∼200nm) and distribution (PDI0.2), low zeta potential (-31.1mv), high drug-loading efficiency (9.3% GEM plus 3.1% DTX, wt%) and pH and enzymatic dual-stimulus-responsive release properties. Immunofluorescence and cellular uptake studies showed that Combo NCs efficiently targeted overexpressed CD44 in MDA-MB-231 carcinoma. In vitro studies revealed that Combo NCs played a critical role in the synergistic induction of cytotoxicity, apoptosis and inhibition of wound healing. Combo NCs were confirmed to exhibit great potency for increasing S phase arrest and remodeling the CDA and dCK balance by decreasing the mRNA expression of CDA down to 0.09-fold and increasing the mRNA expression of dCK by 1.36-fold, remarkably increasing the dCK/CDA ratio to 15.3-fold compared with the blank control. The biodistribution results obtained in vivo revealed an effective accumulation in tumor foci. All of these advantages of Combo NCs contributed to their remarkable anti-tumor efficacy without systemic toxicity as well as their apoptosis-enhancing and anti-proliferative capacities, as determined by TUNEL and Ki67 immunohistochemistry in vivo. Consequently, such a rationally contemplated co-delivery system demonstrated the promising potential of clinical applications for triple-negative breast cancer therapy.The Combo NCs were innovatively applied for co-delivery of hydrophilic GEM and hydrophobic DTX. The ester bond linking and shielding effect of HA-GEM made the carriers achieve synchronous release properties, which was determined in in vitro release study. Due to the HA modification, the vectors own great potency for positive targeting to CD44 overexpressed triple-negative breast cancer cells MDA-MB-231. Cytotoxicity and apoptosis studies confirmed the targeting effect and synergism between two drugs. Interestingly, we found in cell cycle study, drug combinations (free combination or Combo NCs) didn't show a rise in G2M phase, which was significantly higher when treated DTX alone. We further discovered the role of DTX in combinations may involve in modulating GEM associated enzymes thus enhancing the efficacy of GEM. Consequently, this nanoplatform provided a novel solution for achieving targeted co-delivery and potentiating effect in cancer therapy.

Background and objective Porous bone repair scaffolds are an important method of repairing bone defects. Fluid flow in the scaffold plays a vital role in tissue differentiation and permeability and fluid shear stress (FSS) are two important factors. The differentiation of bone tissue depends on the osteogenic differentiation of cells, FSS affects cell proliferation and differentiation, and permeability affects the transportation of nutrients and metabolic waste. Therefore, it is necessary to better understand and analyze the FSS on the cell surface and the permeability of the scaffold to obtain better osteogenic performance. Methods In this study, computational fluid dynamics (CFD) was used to analyze fluid flow in the scaffold. Three structures and nine scaffold unit cell models were designed and the cell models were loaded onto the scaffold surface. Considering cell deformability, the two-way fluid-structure interaction (FSI) method was used to evaluate the FSS on the cell surface. Results The simulation results showed that as the pore size of the scaffold increases, its permeability increases and the FSS decreases. The FSS received on the cell surface was much larger than scaffold surface. Moreover the FSS on the cell surface was distributed in steps. Conclusions The results showed the permeability of all models matches that of human bone tissue. Based on the cell surface FSS as the criterion, it was found that the spherical-560 scaffold exhibited the best osteogenic performance. This provided a strategy to design a better bone repair scaffold from biological aspects.

Currently, the phosphatidylethanolamine-based, pH-sensitive, liposome drug-delivery system has been widely developed for efficient, targeted cancer therapy. However, the mechanism of pH sensitivity was unclear; it is a main obstacle in controlling the preparation of pH-sensitive liposomes (PSLs).Therefore, our research is aimed at clarifying the pH-response mechanism of the various molecules that compose liposomes. We chose the small pH-sensitive molecules oleic acid (OA), linoleic acid (LA) and cholesteryl hemisuccinate (CHEMS) and the fundamental lipids cholesterol and phosphatidylethanolamine (PE) as test molecules. The PSLs were prepared using the thin-film hydration method and characterized in detail at various pH values (pH 5.0, 6.0 and 7.4), including particle size, ζ-potential, drug encapsulation efficiency and drug loading. The surface structure was observed by transmission electron microscopy (TEM), and the electrical conductivity of the liposome dispersion was also tested. The calorimetric analysis was conducted by Nano-differential scanning calorimetry (Nano-DSC). The in vitro drug release profile showed that PSLs exhibit good pH sensitivity. At neutral pH, the particle size was approximately 150nm, and it dramatically increased at pH 5.0. The ζ-potential increased as the pH decreased. The Nano-DSC results showed that cholesterol and CHEMS can both increase the stability and phase transfer temperature of PSLs. Conductivity increased to a maximum at pH 5.0 and was rather low at pH 7.4. In conclusion, results show that the three kinds of liposomes have pH responsive release characteristics in acidic pH. The OA-PSLs have a pH sensitive point of 5. Since CHEMS has a cholesterol-like structure, it can stabilizes the phospholipid bilayer under neutral conditions as shown in the Nano-DSC data, and because it has a special steroidal rigid structure, it exhibits better pH response characteristics under acidic conditions.

Recently, nanomedicine without drug carriers has attracted many pharmacists' attention. A novel paclitaxel-s-s-paclitaxel (PTX-s-s-PTX) conjugate with high drug loading (∼78%, w/w) was synthesized by conjugating paclitaxel to paclitaxel by using disulfide linkage. The conjugate could self-assemble into uniform nanoparticles (NPs) with 1,1-dioctadecyl-3,3,3,3-tetramethylindotricarbocyanine iodide (DiR) encapsulated within the core of PTX-s-s-PTX NPs for photothermal therapy (PTT). The DiR-loaded self-assembled nanoparticles (DSNs) had a mean diameter of about 150 nm and high stability in biological condition. A disulfide bond is utilized as a redox-responsive linkage to facilitate a rapid release of paclitaxel in tumor cells. DSNs indicated significant cytotoxicity as a result of the synergetic chemo-thermal therapy. DSNs were featured with excellent advantages, including high drug loading, redox-responsive releasing behavior of paclitaxel, capability of loading with photothermal agents, and combinational therapy with PTT. In such a potent nanosystem, prodrug and photothermal strategy are integrated into one system to facilitate the therapy efficiency.

The goal of this research was to formulate dual-targeting liposomes (RGD/DTX-PSL) that can selectively release loaded contents in a low pH level environment and to actively target to the tumor using liposomes that had surface arginine-glycine-aspartic (RGD) tripeptides. We investigated whether RGD/DTX-PSL could serve as an effective tumor-targeted nanoparticle that is capable of suppressing tumor growth. The results suggest that DTX is released from liposomes faster at pH 5.0 than pH 7.4, demonstrating their pH sensitivity. RGD/DTX-PSL has a longer blood circulation than Duopafei(®) in rats. The RGD/DTX-PSL formulation displayed stronger antiproliferative effects than DTX alone and the strongest inhibition of tumor growth of the formulations tested, thus expanding therapeutic window of DTX. In conclusion, we established a novel, promising and easy-to-handle liposome formulation that has a considerable antitumor activity in vitro and in vivo. This study provides important prerequisite for the clinical application of dual-targeting liposomes in delivering therapies.

Mounting researches continue to support a favorable role for the drug metal complex against cancer progress and metastasis. However, pharmaceutical barriers were encountered when drug metal complexes needed further pre-clinical and clinical evaluations due to their poor aqueous solubility. In this research, liposomes loaded metal ion as nano-scaled reaction vehicles were used to carry out a synthesis reaction between metal ion and curcumin (Cur) to prepare Cur-metal drug liposomal formulations. The unique flower-like conformation of Cur-M liposomes was observed for the first time and dominated in the Cur-M liposomal formulations system by the cryo-transmission electron microscopy. Different metal ions behaved significant differences in formulations' appearance, release profile, cytotoxic effect against various cell lines, pharmacokinetic profiles, biodistribution and antitumor efficiency. Cur-M liposomes presented enhanced cellular uptake and ROS generation effects, thus augmenting the cytotoxicity of Cur. Superior performances of Cur-copper complexes liposomes were observed in improving Cur stability, promoting apoptosis, inhibiting the proliferation and angiogenesis, therefore enhancing therapeutic effect for primary and metastatic breast cancer. Overall, the current work highlights the potentially significant development value of Cur-M liposomes as an injectable agent for cancer treatment, even superior to the commercial agent Doxil.

Along with the malignant proliferation of tumor requiring nutrients, the expression of L-type amino acid transporter 1(LAT1) and amino acid transporter B0,+ (ATB0,+) in cancer cells is up-regulated that can be used as new targets for active targeting of tumor. However, since normal cells also express amino acid transporters in small amounts, traditional ligand-exposure drug delivery systems are potentially toxic to the body. Therefore, we designed a smart-response drug delivery system that buries the tyrosine ligand in PEG hydration layer at normal tissues and exposes the ligand by cleaving the pH-sensitive bond of PEG at the tumor site. Irinotecan (CPT-11) is actively loaded into the inner aqueous phase of liposomes via a copper ion gradient mechanism which has high encapsulation efficiency and stable drug release profile. Smart-response liposomes showed the strongest cytotoxicity and the maximum cellular uptake in vitro, the largest amount of tumor site accumulation and the best antitumor effect in vivo, compared with non-targeted liposomes and non-sensitive liposomes. It is worth noting that smart-response liposomes not only achieved enhanced antitumor effect but also attenuated side effects compared to ligand-exposure liposomes. This provides a smart responsive drug delivery system for precise treatment and shows a good application prospect.

3D-QSAR, molecular docking and molecular dynamics (MD) simulations were performed to investigate the mechanism of ACE-inhibitory (ACEi) peptides with tryptophan C-terminal in aqueous solutions. In this work, COMFA (Q2 = 0.85, R2 = 0.993) and COMSIA (Q2 = 0.706, R2 = 0.997) models of di- and tri-peptides were established. Novel tripeptides were predicted by the 3D-QSAR models. Different conformations and interactions between VKW with high activity and GTW with low activity were compared by MD simulation. The results revealed VKW had stronger electrostatic interaction and binding affinity with key residues of ACE. ACE-VKW complex performed more stable than ACE-GTW. Thus, VKW showed a higher activity. Moreover, ACEi tripeptides with Trp C-terminal potentiate the combination with Zn of ACE active pockets.

Background and Objective The process of nanoparticles (NPs) entering blood circulation to actively target tumor cells involves four stages—the transport of NPs in blood vessels, transvascular transport of NPs, transport of NPs in the tumor interstitial matrix and entry of NPs into tumor cells. These four stages are a complex process involving mechanical, physical, biochemical, and biophysical factors, the tumor microenvironment (TME) and properties of NPs play important roles in this process. Because this process involves a large number of factors and is very complex, it is difficult to study with conventional methods. Methods Using mathematical models for simulation is suitable for addressing this complex situation and can describe the complexity well. Results This work focuses on the theoretical simulation of NPs that target tumor cells to illustrate the effects of the abnormal microenvironment of tumors and properties of NPs on the transport process. Mathematical models constructed by different methods are enumerated. Through studying these mathematical models, different methods to overcome nanoparticle (NP) transport obstacles are illustrated. Conclusions It is necessary to construct a theoretical model of active targeting nanodrug delivery under the coupling of micro-flow field and specific binding force field, and to simulate and analyze the delivery process at mesoscopic scale using computational fluid dynamics (CFD) method, so as to reveal the law and characteristics of drug delivery and cell uptake in the micro-environment of tumors in vivo. The methods and techniques discussed can serve as the basis for systematic studies of active targeting of functional nanoparticles to tumor cells.

Future cancer therapy will depend on combination therapy with multiple drugs to achieve maximum effects and minimum toxicity. Due to the complexity and significance of the tumor microenvironment (TME), it is vital to elucidate this complicated environment when designing a co-delivery system. There are numerous potent target sites in the TME to facilitate simultaneous and selective delivery. Currently, nanocarriers are used frequently in co-delivery systems for multiple antitumor treatments. Nanocarriers can efficiently deliver drugs and achieve synergistic effects, but the potent barriers in the TME and their inherent limitations have restricted their use. It is crucial to design an effected co-delivery system associated with the TME to achieve better anti-tumor activity, which we define as a "stereoscopic response." Although there are many obstacles in this field, the combination of simultaneous response in the TME with drug activity may present a promising strategy to achieve innovative, safe, and effective treatment.