Lactoferrin/CD133 antibody conjugated nanostructured lipid carriers for dual targeting of blood-brain-barrier and glioblastoma stem cells.

The main reasons for the difficulty in curing and high recurrence rate of glioblastoma multiforme (GBM) include: 1. The difficulty of chemotherapy drugs in penetrating the blood-brain barrier (BBB) to target tumor cells; 2. The presence of glioma stem cells (GSCs) leading to chemotherapy resistance. Therefore, breaking through the limitations of the BBB and overcoming the drug resistance caused by GSCs are the main strategies to address this problem. This study presents our results on the development of lactoferrin (Lf)/CD133 antibody conjugated nanostructured lipid carriers (Lf/CD133-NLCS) for simultaneously targeting BBB and GSCs. Temozolomide (TMZ) loaded Lf/CD133-NLCS (Lf/CD133-NLCS-TMZ) exhibited high-efficiencyin vitroanti-tumor effects toward malignant glioma cells (U87-MG) and GSCs, while demonstrating no significant toxicity to normal cells at concentrations lower than 200 µg ml-1. The results of thein vitrotargeting GBM study revealed a notably higher cellular uptake of Lf/CD133-NLCS-TMZ in U87-MG cells and GSCs in comparison to Lf/CD133 unconjugated counterpart (NLCS-TMZ). In addition, increased BBB permeability were confirmed for Lf/CD133-NLCS-TMZ compared to NLCS-TMZ bothin vitroandin vivo. Taking together, Lf/CD133-NLCS-TMZ show great potential for dual targeting of BBB and GSCs, as well as GBM therapy based on this strategy.

Targeted codelivery of doxorubicin and oleanolic acid by reduction responsive hyaluronic acid-based prodrug nano-micelles for enhanced antitumor activity and reduced toxicity.

Chemotherapy remains one of the most commonly used strategies in cancer treatment but suffers from damages to healthy tissues and organs. How to precisely co-deliver two or more drugs with different mechanisms of action to the tumors for synergistic function is a challenge for chemotherapy. Herein, Oleanolic acid (OA)-conjugated Hyaluronic acid self-assembled nano-micelles loaded with Doxorubicin (DOX) (HSO NPs/DOX) were constructed for CD44 positive cancer targeted codelivery of DOX and OA. HSO NPs/DOX exhibited reduction triggered drug release under high concentration of glutathione, more efficient uptake by 4T1 breast cancer cells than free DOX leading to higher cytotoxicity, pro-apoptotic, and migration inhibitory activities against 4T1 cells. The ex vivo biodistribution experiment demonstrated more HSO NPs/DOX were accumulated in the tumor tissues than free DOX and less in the non-tumor tissues after injections in 4T1 tumor bearing mice. More importantly, synergistic anti-tumor effects of DOX and OA were obtained using HSO NPs/DOX in 4T1 breast tumor-bearing mice and toxicity of DOX to liver and heart were circumvented through regulating the Nuclear Factor kappa-light-chain-enhancer of activated B cells (NF-κB) and Silent Information Regulator 1 (Sirt1) expressions. Taken together, HSO NPs/DOX may become a promising codelivery system for chemotherapeutics in cancer therapy.

Lipid-based nanoparticles to address the limitations of GBM therapy by overcoming the blood-brain barrier, targeting glioblastoma stem cells, and counteracting the immunosuppressive tumor microenvironment.

Glioblastoma multiforme (GBM) is the most common primary malignant brain tumor, characterized by high heterogeneity, strong invasiveness, poor prognosis, and a low survival rate. A broad range of nanoparticles have been recently developed as drug delivery systems for GBM therapy owing to their inherent size effect and ability to cross the blood-brain barrier (BBB). Lipid-based nanoparticles (LBNPs), such as liposomes, solid lipid NPs (SLNs), and nano-structured lipid carriers (NLCs), have emerged as the most promising drug delivery system for the treatment of GBM because of their unique size, surface modification possibilities, and proven bio-safety. In this review, the main challenges of the current clinical treatment of GBM and the strategies on how novel LBNPs overcome them were explored. The application and progress of LBNP-based drug delivery systems in GBM chemotherapy, immunotherapy, and gene therapy in recent years were systematically reviewed, and the prospect of LBNPs for GBM treatment was discussed.

The impact of electricity-carbon market coupling on system marginal clearing price and power supply cost.

In this study, we assessed the impacts of the benchmark designs of emissions allowance allocation in China's national carbon emissions trading system with plant-level data and further estimated the marginal clearing price and power supply cost in Guangdong power market under electricity-carbon market coupling with unit commitment and economic dispatch model. We find that the existing allowances benchmark would result in a considerable surplus of allowances at about 222 Mt. But the benchmarking and exemplary levels on the heat rate of power supply would motivate thermal power units to reduce CO2 emissions. Under a tight balance of supply and demand in Guangdong, peaking thermal power plants will become the marginal clearing units and higher clearing prices will add to the revenue of lower cost inframarginal renewable energy power units. However, the combined impact of electricity-carbon market coupling would cause the marginal clearing price fluctuates obviously from 0 to 1159 CNY/MWh. Compared to the baseline scenario with free CO2 allowances allocation, the efficiency of thermal power utilization would decrease by 23%-59% and the net revenue per MWh power supply of coal-fired power units would decrease by 275%-325% under the stress scenario. Our study suggests that setting a more stringent allowances allocation benchmark for carbon price discovery is necessary. As electricity-carbon market coupling changes the role of coal-fired power plants to provide flexibility service and decrease their revenues, it calls for further market designs on proper reimbursement of flexible resources, under which the electricity market can effectively achieve the synergy among accommodating new energy, ensuring resource adequacy, and delivering cost efficiency. In addition, the synergy can be enhanced by formulating a tax program, which can promote renewable energy investment.

Marsdenia tenacissima genome reveals calcium adaptation and tenacissoside biosynthesis.

Marsdenia tenacissima is a medicinal plant widely distributed in the calcium-rich karst regions of southwest China. However, the lack of a reference genome has hampered the implementation of molecular techniques in its breeding, pharmacology and domestication. We generated the chromosome-level genome assembly in Apocynaceae using combined SMRT sequencing and Hi-C. The genome length was 381.76 Mb, with 98.9% of it found on 11 chromosomes. The genome contained 222.63 Mb of repetitive sequences and 21 899 predicted gene models, with a contig N50 of 6.57 Mb. Phylogenetic analysis revealed that M. tenacissima diverged from Calotropis gigantea at least 13.43 million years ago. Comparative genomics showed that M. tenacissima underwent ancient shared whole-genome duplication. This event, together with tandem duplication, contributed to 70.71% of gene-family expansion. Both pseudogene analysis and selective pressure calculations suggested calcium-related adaptive evolution in the M. tenacissima genome. Calcium-induced differentially expressed genes (DEGs) were mainly enriched in cell-wall-related processes. Domains (e.g. Fasciclin and Amb_all) and cis-elements (e.g. MYB and MYC) frequently occurred in the coding and promoter regions of cell-wall DEGs, respectively, and the expression levels of these genes correlated significantly with those of calcium-signal-related transcription factors. Moreover, calcium addition increased tenacissoside I, G and H contents. The availability of this high-quality genome provides valuable genomic information for genetic breeding and molecular design, and lends insights into the calcium adaptation of M. tenacissima in karst areas.

Cold Tolerance of ScCBL6 Is Associated with Tonoplast Transporters and Photosynthesis in Arabidopsis.

Plants that are adapted to harsh environments offer enormous opportunity to understand stress responses in ecological systems. Stipa capillacea is widely distributed in the frigid and arid region of the Tibetan Plateau, but its signal transduction system under cold stress has not been characterized. In this study, we isolated a cDNA encoding the signal transduction protein, ScCBL6, from S. capillacea, and evaluated its role in cold tolerance by ectopically expressing it in Arabidopsis. Full-length ScCBL6 encode 227 amino acids, and are clustered with CBL6 in Stipa purpurea and Oryza sativa in a phylogenetic analysis. Compared with tolerance in wild-type (WT) plants, ScCBL6-overexpressing plants (ScCBL6-OXP) were more tolerant to cold stress but not to drought stress, as confirmed by their high photosynthetic capacity (Fv/Fm) and survival rate under cold stress. We further compared their cold-responsive transcriptome profiles by RNA sequencing. In total, 3931 genes were differentially expressed by the introduction of ScCBL6. These gene products were involved in multiple processes such as the immune system, lipid catabolism, and secondary metabolism. A KEGG pathway analysis revealed that they were mainly enriched in plant hormone signal transduction and biomacromolecule metabolism. Proteins encoded by differentially expressed genes were predicted to be localized in chloroplasts, mitochondria, and vacuoles, suggesting that ScCBL6 exerts a wide range of functions. Based on its tonoplast subcellular location combined with integrated transcriptome and physiological analyses of ScCBL6-OXP, we inferred that ScCBL6 improves plant cold stress tolerance in Arabidopsis via the regulation of photosynthesis, redox status, and tonoplast metabolite transporters.

A Novel Graphene Quantum Dot-Based mRNA Delivery Platform.

During the last decades, there has been growing interest in using therapeutic messager RNA (mRNA) together with drug delivery systems. Naked, unformulated mRNA is, however, unable to cross the cell membrane and is susceptible to degradation. Here we use graphene quantum dots (GQDs) functionalized with polyethyleneimine (PEI) as a novel mRNA delivery system. Our results show that these modified GQDs can be used to deliver intact and functional mRNA to Huh-7 hepatocarcinoma cells at low doses and, that the GQDs are not toxic, although cellular toxicity is a problem for these first-generation modified particles. Functionalized GQDs represent a potentially interesting delivery system that is easy to manufacture, stable and effective.

Evaluation of remodeling and regeneration of electrospun PCL/fibrin vascular grafts in vivo.

The success of artificial vascular graft in the host to obtain functional tissue regeneration and remodeling is a great challenge in the field of small diameter tissue engineering blood vessels. In our previous work, poly(ε-caprolactone) (PCL)/fibrin vascular grafts were fabricated by electrospinning. It was proved that the PCL/fibrin vascular graft was a suitable small diameter tissue engineering vascular scaffold with good biomechanical properties and cell compatibility. Here we mainly examined the performance of PCL/fibrin vascular graft in vivo. The graft showed randomly arranged nanofiber structure, excellent mechanical strength, higher compliance and degradation properties. At 9 months after implantation in the rat abdominal aorta, the graft induced the regeneration of neoarteries, and promoted ECM deposition and rapid endothelialization. More importantly, the PCL/fibrin vascular graft showed more microvessels density and fewer calcification areas at 3 months, which was beneficial to improve cell infiltration and proliferation. Moreover, the ratio of M2/M1macrophage in PCL/fibrin graft had a higher expression level and the secretion amount of pro-inflammatory cytokines started to increase, and then decreased to similar to the native artery. Thus, the electrospun PCL/fibrin tubular vascular graft had great potential to become a new type of artificial blood vessel scaffold that can be implanted in vivo for long term.

Synthesis of graphene quantum dots and their applications in drug delivery.

This review focuses on the recent advances in the synthesis of graphene quantum dots (GQDs) and their applications in drug delivery. To give a brief understanding about the preparation of GQDs, recent advances in methods of GQDs synthesis are first presented. Afterwards, various drug delivery-release modes of GQDs-based drug delivery systems such as EPR-pH delivery-release mode, ligand-pH delivery-release mode, EPR-Photothermal delivery-Release mode, and Core/Shell-photothermal/magnetic thermal delivery-release mode are reviewed. Finally, the current challenges and the prospective application of GQDs in drug delivery are discussed.

Directional Osteo-Differentiation Effect of hADSCs on Nanotopographical Self-Assembled Polystyrene Nanopit Surfaces.

INTRODUCTION: Cells exhibit high sensitivity and a diverse response to the nanotopography of the extracellular matrix, thereby endowing materials with instructive performances formerly reserved for growth factors. This finding leads to opportunities for improvement. However, the interplay between the topographical surface and cell behaviors remains incompletely understood. METHODS: In the present study, we showed nanosurfaces with various dimensions of nanopits (200-750 nm) fabricated by self-assembling polystyrene (PS) nanospheres. Human adipose-derived stem cell behaviors, such as cell morphology, adhesion, cytoskeleton contractility, proliferation, and differentiation, were investigated on the prepared PS nanopit surface. RESULTS: The osteogenic differentiation can be enhanced by nanopits with a diameter of 300-400 nm. DISCUSSION: The present study provided exciting new avenues to investigate cellular responses to well-defined nanoscale topographic features, which could further guide bone tissue engineering and stem cell clinical research. The capability to control developing biomaterials mimicking nanotopographic surfaces promoted functional tissue engineering, such as artificial joint replacement, bone repair, and dental applications.

Multifunctional red carbon dots: a theranostic platform for magnetic resonance imaging and fluorescence imaging-guided chemodynamic therapy.

In recent years, carbon dots (CDs) with red-emitting wavelengths have received increasing attention in cancer therapy and imaging. Here, we reported a multi-functional CD based platform combining bimodal magnetic resonance/fluorescence (MR/FL) imaging and chemodynamic therapy (CDT) for in vivo imaging of tumor tissues and efficient anticancer treatment. The red-emitting CDs were synthesized via a one-step solvothermal method with p-phenylenediamine as the carbon source. Ethylenediaminetetraacetic acid (EDTA) was covalently coupled to the surface of CDs and then complexed with Fe2+ and Gd3+ to obtain functionalized red CDs (CDs@EDTA@Gd@Fe). CDs@EDTA@Gd@Fe exhibited bright and stable fluorescence and strong T1-weighted MR imaging (MRI) contrast. Moreover, the CDs@EDTA@Gd@Fe showed an excellent anticancer effect both in vitro and in vivo via a Fenton reaction-based CDT by releasing Fe2+ in the tumor. Our study offers a promising strategy for developing multi-functional CDs for cancer theranostics.

Transcriptomic response to cold of thermophilous medicinal plant Marsdenia tenacissima.

Extracts from Marsdenia tenacissima, involving tenacissoside H, I and G, have been used as remedies of cancer, inflammation and asthma. Low temperature serves as one of the main factors constrain the planting expansion and quality of M. tenacissima, but its functional mechanism has been known scarcely for the lack of genomic information and transcriptional profile. Here we investigated the transcriptomic responses of M. tenacissima under cold stress to gain insight into the molecular mechanism of low temperature sensitivity. Total RNAs were collected from samples obtained at 4-time points (after 0, 3, 6 and 48 h cold treatments with 4 °C, respectively), then used for library construction and sequenced on the Illumina Hiseq™ 4000 platform. Passing quality assessments, 500794 transcripts, and 206137 unigenes were de novo assembly out in Trinity v2.4.0, holding contig N50 of 2566 bp and unigene mean length of 754 bp. 44.20% of assembled unigenes were annotated to the well-known public protein database on a basis of sequence similarity. Using statistical comparison of the fragments per kilo base of transcript per million reads mapped (FPKM) values between conditions, 6082 group-specific differentially expressed genes (DEGs) were identified and considered as cold-responsive genes, which contained copious transcription factors and active secondary metabolism. Among them, 43 unigenes were constantly up-regulated expression along with cold time, which mainly implicated in the biosynthesis of secondary metabolites, carbon metabolism, RNA and DNA metabolism. Conversely, 21 unigenes involved in photosynthesis, cell wall, protein degradation, and transporters were downregulated continually with cold timescale. Experimentally, MtEF1α was chosen as the best housekeeping gene. Functional enrichments found that damaging of cold stress on M. tenacissima may be ascribed to inability of photosynthesis, ribsome processing, flavonoid biosynthesis and terpenoids degradation. Correlation analysis between cold induced transcription factors and tenacissoside biosynthesis-related genes indicated that 3ß-HSD significant positively correlated with bHLH51, and 4-MSO with NF-YB, GRAS3, Trihelix, FAR1, MYB60, MYBS1, bZIP43. Further promoter clone found MYB-binding site in the promoter of 4-MSO. In view of the reported cold tolerance of MYB60, it is recommended as a potential candidate suitable for future molecular design of exaptation cultivation with high bioactive constituents.

Correlation Between Dual-Energy Computed Tomography Single Scan and Computed Tomography Perfusion for Pancreatic Cancer Patients: Initial Experience.

OBJECTIVE: The objective of this study was to evaluate the role and limit of iodine maps by dual-energy computed tomography (CT) single scan for pancreatic cancer. METHODS: Thirty patients with suspected solitary pancreatic cancer were enrolled in this study and underwent CT perfusion and iodine maps. The parameters of pancreatic cancer and normal pancreatic tissue were calculated. Pearson correlation and paired t test were used for evaluating 2 techniques. RESULTS: Iodine concentration had a moderate positive correlation with blood flow or blood volume (P < 0.05 for both). All values of iodine concentration and blood flow, iodine concentration, and blood volume had significant positive correlations (P < 0.001 for both). The mean effective dose for CT perfusion and iodine maps had significant difference (8.61 ± 0.00 mSv vs 1.13 ± 0.14 mSv, P < 0.001). CONCLUSIONS: Iodine maps had the potential to replace routine CT perfusion for pancreatic cancer with low radiation dose.

Carbon emission intensity of electricity generation in Belt and Road Initiative countries: a benchmarking analysis.

The scope of this study is to analyze the carbon emissions intensity of electricity generation in "Belt and Road Initiative" (BRI) countries. The total CO2 emissions from electricity generation in BRI nations increases from 4232.34 Mt in 2013 to 4402.38 Mt in 2015, accounting for 34.45% of global CO2 emissions from electricity generation. Logarithmic mean Divisia index methodology is applied to analyze the drivers of carbon emissions intensity in BRI nations. The decomposition results revealed that the regional carbon emissions intensity in BRI nations increases during 2013-2015 and the power generation efficiency is the essential factor to improve carbon emissions performance in BRI developing countries. For BRI developing countries, promoting clean and efficient thermal power is a pragmatic priority for green power development.

Image-guided cancer therapy using aptamer-functionalized cross-linked magnetic-responsive Fe3O4@carbon nanoparticles.

The excellent anticancer effect of combined differential cancer therapies has been observed in the last few decades. Efficient theragnostic nanoparticles (NPs) for malignancy treatment have received considerable research attention and widely investigated today. This study presents our results on the development of aptamer-functionalized Fe3O4@carbon@doxorubicin NPs (Apt-Fe3O4@C@DOX) and their application in the synergetic chemo-photothermal therapy (PTT) of cancer. The Apt-Fe3O4@C@DOX NPs displayed high photothermal conversion efficiency and extensive pH/heat-induced drug release. In vitro (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium) bromide experiments indicated that the combined chemo-PTT is much more toxic toward lung adenocarcinoma cells (A549) than PTT or chemotherapy alone. In addition, the Apt-Fe3O4@C@DOX NPs demonstrated decreasing contrast enhancement of magnetic resonance (MR) signals, which means they may be potentially applied as a contrast agent and serve as a critical component of T2-weighted MR imaging of tumor tissues. Taking the results together, the Apt-Fe3O4@C@DOX NPs show great potential for cancer therapy.

Efficacy and safety of recombinant human parathyroid hormone (1-34) are similar to those of alendronate in the treatment of postmenopausal osteoporosis.

The study evaluates efficacy and safety of recombinant human parathyroid hormone (1-34) [rhPTH (1-34)] and alendronate (ALN) in the treatment of postmenopausal osteoporosis.Totally 65 postmenopausal women with osteoporosis were divided into 2 groups. PTH group received daily subcutaneous injection of rhPTH (1-34), and ALN group were treated orally with ALN per week. Bone mineral density (BMD) of lumbar spine (1-4), femoral neck, and total hip, serum levels of calcium, phosphorus, total cholesterol, triglyceride, alkaline phosphatase (ALP), N-terminal propeptide of type I collagen (PINP), and C-telopeptide of type I collagen (CTX) were tested before treatment and at week 24 and 48 after treatment. Serum levels of vascular endothelial growth factor (VEGF) and platelet-derived growth factor-BB (PDGF-BB) were measured before treatment and at week 48 after treatment.The rhPTH (1-34) increased BMD of lumbar spine (1-4), but decreased BMD of femoral neck and total hip at week 48 after treatment. By contrast, ALN enhanced BMD of lumbar spine (1-4) and femoral neck, but reduced BMD of total hip at week 48 after treatment. In PTH group, serum levels of PINP, ALP, and ß-CTX were significantly elevated above baseline at week 24 and 48 after treatment. Treatment with ALN decreased levels of PINP, ALP, and ß-CTX compared with baseline at week 24 and 48 after treatment. rhPTH (1-34) and ALN significantly decreased levels of PDGF-BB, but not levels of VEGF. rhPTH (1-34) increased levels of calcium, phosphorus and triglyceride, but decreased levels of total cholesterol. ALN increased levels of calcium and triglyceride, but reduced levels of phosphorus and total cholesterol. rhPTH (1-34) and ALN were safe in the treatment of postmenopausal osteoporosis.The study demonstrates that efficacy of rhPTH (1-34) on BMD of lumbar spine (1-4) is similar to that of alendronate in the treatment of postmenopausal osteoporosis. The effect of rhPTH (1-34) on BMD of femoral neck or total hip is weaker than that of ALN. In addition, rhPTH (1-34) increases BMD of lumbar spine (1-4) maybe by raising serum levels of VEGF, but reduces BMD of femoral neck and total hip maybe by decreasing serum levels of PDGF-BB.

Numerical investigation of narrowband infrared absorber and sensor based on dielectric-metal metasurface.

Metasurfaces are investigated intensively for biophotonics applications due to their resonant wavelength flexibly tuned in the near infrared region specially matching biological tissues. Here, we present numerically a metasurface structure combining dielectric resonance with surface plasmon mode of a metal plane, which is a perfect absorber with a narrow linewidth 10 nm wide and quality factor 120 in the near infrared regime. As a sensor, its bulk sensitivity and bulk figure of merit reach respectively 840 nm/RIU and 84/RIU, while its surface sensitivity and surface figure of merit are respectively 1 and 0.1/nm. For different types of adsorbate layers with the same thickness of 8 nm, its surface sensitivity and figure of merit are respectively 32.3 and 3.2/RIU. The enhanced electric field is concentrated on top of dielectric patch ends and in the patch ends simultaneously. Results show that the presented structure has high surface (and bulk) sensing capability in sensing applications due to its narrow linewidth and deep modulation depth. This could pave a new route toward dielectric-metal metasurface in biosensing applications, such as early disease detections and designs of neural stem cell sensing platforms.

Enhanced therapeutic effect of an antiangiogenesis peptide on lung cancer in vivo combined with salmonella VNP20009 carrying a Sox2 shRNA construct.

BACKGROUND: HM-3 is a polypeptide inhibiting angiogenesis. Recent reports suggest that the antitumor effect of angiogenesis inhibitors administered alone might be limited. Cancer stem cells can survive the lack of oxygen and nutrients. To achieve better anti-tumor effect, HM-3 was administered in combination with the attenuated Salmonella typhimurium VNP20009 transformed with a shRNA construct against sex determining region Y-box 2 (Sox2). METHODS: Cell invasion assay and soft agar colony formation assay were used to assess the migration and growth capability of A549 cells once Sox2 was knocked down with the shRNA construct. The shRNA construct targeting Sox2 was transformed into VNP20009. After the mouse xenograft model of A549 was established, HM-3 was co-administered with VNP20009 carrying the shRNA construct. The growth of tumor was checked to compare the effectiveness of different therapies. Western blotting assay and immunohistochemistry staining of the tumor tissue were used to measure the levels of proteins associated with the apoptosis pathway. RESULTS: Sox2 was necessary for the migration and growth of A549 cells. The expression of Sox2 was down regulated in the tumor tissue of the combined treatment group of HM-3 with VNP20009 carrying the Sox2 shRNA construct. Together with the accumulation of salmonella in tumor and the inhibition of angiogenesis by HM-3, more tumor cells went through cell apoptosis with increased expression of Bax, cleaved Caspase 3 and decreased expression of Bcl2. CONCLUSIONS: The results suggest the combination of antiangiogenesis agent HM-3 with gene therapy targeting Sox2 delivered by salmonella as a promising strategy for the treatment of lung cancer.

Lispro administered by the QS-M Needle-Free Jet Injector generates an earlier insulin exposure.

OBJECTIVE: The aim of this study is to evaluate the pharmacokinetic and pharmacodynamic (PK-PD) profiles of lispro administered by the QS-M needle-free jet injector in Chinese subjects. RESEARCH DESIGN AND METHODS: A randomized, double-blind, double-dummy, cross-over study was performed. Eighteen healthy volunteers were recruited. Lispro (0.2 units/kg) was administered by the QS-M needle-free jet injector or by conventional pen. Seven-hour euglycemic clamp tests were performed. RESULTS: A larger area under the curve (AUCs) of insulin concentration and glucose infusion rate (GIR) during the first 20 minutes after lispro injection by the jet injector compared to the insulin pen was observed (24.91 ± 15.25 vs. 12.52 ± 7.60 mg. kg(-1), P < 0.001 for AUCGIR,0-20 min; 0.36 ± 0.24 vs. 0.10 ± 0.04 U min L(-1), P < 0.001 for AUCINS, 0-20 min). Needle-free injection showed a shorter time to reach maximum insulin concentration (37.78 ± 11.14 vs. 80.56 ± 37.18 min, P < 0.001) and GIR (73.24 ± 29.89 vs. 116.18 ± 51.89 min, P = 0.006). There were no differences in total insulin exposure and hypoglycemic effects between the two devices. CONCLUSION: Lispro administered by QS-M needle-free injector results in earlier and higher insulin exposure than conventional pen, and a greater early glucose-lowering effect with similar overall potency.