Cellular Uptake Ability Research Articles

Synergistic cytotoxicity of irinotecan combined with polysaccharide-based nanoparticles for colorectal carcinoma

Functional polymeric nanoparticles (NPs) with antitumor potential were combined with the topoisomerase I inhibitor, irinotecan (IRT), to enhance cytotoxicity against colorectal cancers. The negatively charged γ-polyglutamic acid (γ-PGA) or fucoidan (FCD) was complexed with the positively charged chitosan (CS) to encapsulate IRT. The size of the γ-PGA/CS/IRT NPs and FCD/CS/IRT NPs were 146.0 ± 8.0 nm and 230.8 ± 2.5 nm, respectively, with polydispersity index ≤0.3. The cellular uptake ability of FCD/CS-FITC NPs was better than that of γ-PGA/CS-FITC NPs, especially in p-selectin positive HCT116 colorectal cancer cells (4.8 ± 0.8 μg/mL vs 11.4 ± 2.2 μg/mL). The IC50 of FCD/CS/IRT NPs was 2.4 times lower than that of γ-PGA/CS/IRT NPs in HCT116 cells (4.8 ± 0.8 μg/mL vs 11.4 ± 2.2 μg/mL), indicating its superior antitumor potential. The combination of irinotecan and fucoidan-based NPs exhibited a synergistic effect (CI <1), resulting in better anticancer activity of FCD/CS/IRT NPs than irinotecan alone. The apoptosis-related proteins, caspase 3, caspase 9, and poly(ADP-ribose) polymerase (PARP), were prominently increased in FCD/CS/IRT NPs-treated HCT116 cells by 2.3 folds, 3.5 folds, and 6.3 folds, respectively. All results support that fucoidan-based irinotecan-loaded nanoparticles possess the ability to effectively enhance cellular uptake and induce synergistic apoptosis of colorectal cancer cells.

Exosome-coated polydatin nanoparticles in the treatment of radiation-induced intestinal damage.

This study aimed to develop an exosome-coated polydatin (PD) nanoparticles (exo-PD) for improving the water solubility and bioavailability of polydatin and explore its salutary effects on intestinal radiation injury. Exosomes (exo) were extracted from the medium of human amniotic fluid stem cells (hAFSc). Mice were divided into control group, irradiation (IR) group, irradiation+PD (IR+PD) group, irradiation+exo (IR+exo) group and irradiation+exo-PD (IR+exo-PD) group. The results of characterization of protein markers, particle size, morphology and cellular uptake ability confirmed that exosomes were effectively isolated using ultracentrifugation. Compared with the IR group, exo-PD improved cell viability, prolonged survival of mice, improved leukocyte count and reduced diarrhea rate. Histological results showed that the exo-PD group had significant improvements in small intestinal villus length and crypt number and less crypt cell damage. exo-PD could reduce IL-1α and IL-6 levels, reduced γ-H2AX expression, increased mitochondrial membrane potential, enhanced oxidative phosphorylation, and delayed cellular senescence. exo-PD could alleviate intestinal injury by improving mitochondrial function through PI3K-AKT pathway. The exo-PD was able to reduce radiation damage to intestinal cells and could be a potential candidate for salvage of intestinal radiation damage.

Oral liposomes encapsulating ginsenoside compound K for rheumatoid arthritis therapy

Ginsenoside compound K (GCK) can efficiently treat rheumatoid arthritis (RA) due to its immune and anti-inflammatory functions. However, GCK exists some shortcomings such as poor aqueous solubility, low permeability to the intestinal cell membrane, and serious P-gp efflux, thus limiting its application. In order to solve these problems, a folic acid-targeted drug delivery system based on liposomes (FA-LP-GCK) was developed. The prepared FA-LP-GCK had a uniform size distribution and spherical structure, the particle size was 249.13 ± 1.40 nm. Meanwhile, they had high encapsulation efficiency (93.33 ± 0.05 %). FA-LP-GCK also presented good stability in artificial gastric juice, so they can be absorbed into the intestine and enter the blood circulation. The activated RAW 264.7 cells were chosen to evaluate the cytotoxicity and cellular uptake capacity of FA-LP-GCK. FA-LP-GCK showed stronger growth inhibition and cellular uptake ability against activated macrophages. Finally, the efficacy of FA-LP-GCK in vivo was evaluated in the adjuvant arthritis rat model. The results showed that FA-LP-GCK can significantly reduce joint swelling. Furthermore, it can significantly inhibit the expression of pro-inflammatory cytokines and improve synovial hyperplasia of joints and pathological changes in the spleen. Therefore, FA-LP-GCK may be a potential therapeutic approach for RA.

Positively Charged-Amylose-Entangled Au-Nanoparticles Acting as Protein Carriers and Potential Adjuvants to SARS-CoV-2 Subunit Vaccines

The COVID-19 pandemic continues to spread worldwide. To protect and control the spread of SARS-CoV-2, varieties of subunit vaccines based on spike (S) proteins have been approved for human applications. Here, we report a new subunit vaccine design strategy that functions as both an antigen carrier and an adjuvant in immunization to elicit high-level immune responses. The complex of 2-hydroxypropyl-trimethylammonium chloride chitosan and amylose entangles Au nanoparticles (HTCC/amylose/AuNPs) forming 40 nm nanocarriers with a positive charge. The obtained positively charged nanoparticles reveal many merits, including the larger S protein loading capacity in PBS buffer, higher cellular uptake ability, and lower cell cytotoxicity, supporting their potential as safe vaccine nanocarriers. Two functionalized nanoparticle subunit vaccines are prepared via loading full-length S proteins derived from SARS-CoV-2 variants. In mice, both prepared vaccines elicit high specific IgG antibodies, neutralize antibodies, and immunoglobulin IgG1 and IgG2a. The prepared vaccines also elicit robust T- and B-cell immune responses and increase CD19+ B cells, CD11C+ dendritic cells, and CD11B+ macrophages at the alveoli and bronchi of the immunized mice. Furthermore, the results of skin safety tests and histological observation of organs indicated in vivo safety of HTCC/amylose/AuNP-based vaccines. Summarily, our prepared HTCC/amylose/AuNP have significant potential as general vaccine carriers for the delivery of different antigens with potent immune stimulation.

A novel deformable liposomal hydrogel loaded with a SREBP-1-inhibiting polypeptide for reducing sebum synthesis in golden hamster model

Excessive sebum is the major factor involved in the pathophysiology of seborrheic diseases. Chemical medicines can result in mild to severe side effects. Polypeptides with much less side effects make them ideal for reducing sebum synthesis. Sterol regulatory element-binding proteins-1 (SREBP-1) is necessary for the biosynthesis of sterols. A SREBP-1-inhibiting polypeptide (SREi), which competitively inhibits the ubiquitination of Insig-1 so as to suppress the activation of SREBP-1 was selected as an active ingredient and formulated into skin topical preparations. The SREi anionic deformable liposomes contained sodium deoxycholate (SDCh) at the concentration of 4.4 mg/mL (SREi-ADL3) and SREi-ADL3 in 0.3% (w/v) carbomer hydrogel (SREi-ADL3-GEL) were prepared and characterized. The SREi-ADL3 presented a high entrapment efficiency of 92.62 ± 6.32%, a particle size of 99.54 ± 7.56 nm and a surface charge of -19.18 ± 0.45 mV. SREi-ADL3-GEL exhibited a sustained release behavior, a higher stability, a much more cellular uptake ability and transdermal absorption. In vivo golden hamster model confirmed that SREi-ADL3-GEL presented the strongest inhibitory effect on sebaceous gland growth and sebum synthesis by down-regulating the mRNA and protein expression of SREBP-1, fatty acid synthase (FAS) and acetyl–coenzyme A carboxylase 1 (ACC1). As confirmed by histological analysis, only a small amount of sebaceous gland lobes with the lightest staining intensity and the smallest dyeing area could be observed in the SREi-ADL3-GEL group. Taken together, SREi-ADL3-GEL displayed potential applications in sebum excessive production related diseases.

Coordination-Driven Self-Assembly of Biomedicine to Enhance Photodynamic Therapy by Inhibiting Proteasome and Bcl-2.

Tumor cells resist oxidative damage and apoptosis by activating defense mechanisms. Herein, a self-delivery biomedicine (designated as BSC) is developed by the self-assembly of Bortezomib (BTZ), Sabutoclax (Sab) and Chlorin e6 (Ce6). Interestingly, BTZ can be coordinated with Sab to promote the assembly of uniform ternary biomedicine through non-covalent intermolecular interactions. Moreover, BTZ as a proteasome inhibitor can prevent tumor cells from scavenging damaged proteins to reduce their oxidative resistance. Sab can downregulate B-cell lymphoma 2 (Bcl-2) to decrease the antiapoptotic protein. Both the proteasome and Bcl-2 inhibitions contribute to increasing cell apoptosis and amplifying photodynamic therapy (PDT) efficacy of Ce6. Encouragingly, carrier-free BSC receives all biological activities of these assembly elements, including photodynamic performance as well as inhibitory capabilities of proteasome and Bcl-2. Besides, BSC has a preferable cellular uptake ability and tumor retention property, which increase the drug delivery efficiency and bioavailability. In vitro and in vivo research demonstrate the superior PDT efficiency of BSC by proteasome and Bcl-2 inhibitions. Of special note, the coordination-driven self-assembly of BSC is pH-responsive, which can be disassembled for controlled drug release upon tumor acidic microenvironment. This study will expand the applicability of self-delivery nanomedicine with sophisticated mechanisms for tumor treatment.

Differential Blood-Brain Barrier Transport and Cell Uptake of Cyclic Peptides In Vivo and In Vitro.

The blood-brain barrier (BBB) poses major challenges to drug delivery to the CNS. SFTI-1 and kalata B1 are cyclic cell-penetrating peptides (cCPPs) with high potential to be used as scaffolds for drug delivery. We here studied their transport across the BBB and distribution within the brain to gauge the potential of these two cCPPs as scaffolds for CNS drugs. In a rat model, SFTI-1 exhibited, for a peptide, high extent of BBB transport with a partitioning of unbound SFTI-1 across the BBB, Kp,uu,brain, of 13%, while only 0.5% of kalata B1 equilibrated across the BBB. By contrast, kalata B1, but not SFTI-1, readily entered neural cells. SFTI-1, but not kalata B1, could be a potential CNS delivery scaffold for drugs directed to extracellular targets. These findings indicate that differences between the BBB transport and cellular uptake abilities of CPPs are crucial in the development of peptide scaffolds.

Tetrahedral DNA Nanostructure-modified Gold Nanorod-based Anticancer Nanomaterials for Combined Photothermal Therapy and Chemotherapy

ObjectiveTo develop an effective treatment strategy to simultaneously avoid fatal adverse effects in the treatment of oral cancer, combination therapy has been explored because of its multiple functions. This work aims to develop a novel type of gold-nanorod-based nanomaterials decorated with tetrahedral DNA nanostructures (TDN) carrying antitumor drugs, namely, GNR@TDN-DOX nanocomposites. MethodsIn the designed structure, TDN, with a three-dimensional geometry composed of DNA strands, can provide GC base pairs for binding with the anticancer drug doxorubicin (DOX). The photothermal heating properties, biocompatibility properties, and antitumor performance of obtained GNR@TDN-DOX nanocomposites were investigated to assess their application potential in tumor treatment. ResultsSystematic studies have shown that the obtained GNR@TDN-DOX nanocomposites have high photothermal conversion under the illumination of an 808-nm infrared laser, leading to effective antitumor applications. In addition, the cell viability study shows that GNR@TDN-DOX nanocomposites have good biocompatibility. In vitro studies based on A375 cells show that the GNR@TDN-DOX nanocomposites can effectively eliminate cancer cells because of the combination of photothermal therapy induced by GNRS and chemotherapy induced by TDN-carrying DOX. The result shows that the obtained GNR@TDN-DOX nanocomposites have efficient cellular uptake and lysosome escape ability, together with their nuclear uptake behavior, which results in a significant antitumor effect. ConclusionThis work has demonstrated a potential nanoplatform for anticancer applications.

Targeting EGFR and Monitoring Tumorigenesis of Human Lung Cancer Cells In Vitro and In Vivo Using Nanodiamond-Conjugated Specific EGFR Antibody.

Nanoprobes provide advantages for real-time monitoring of tumor markers and tumorigenesis during cancer progression and development. Epidermal growth factor receptor (EGFR) is a key protein that plays crucial roles for tumorigenesis and cancer therapy of lung cancers. Here, we show a carbon-based nanoprobe, nanodiamond (ND), which can be applied for targeting EGFR and monitoring tumorigenesis of human lung cancer cells in vitro and in vivo. The optimal fluorescent intensities of ND particles were observed in the human lung cancer cells and nude mice under in vivo imaging system. The fluorescence signal of ND particles can be real-time detected in the xenografted human lung tumor formation of nude mice. Moreover, the ND-conjugated specific EGFR antibody cetuximab (Cet) can track the location and distribution of EGFR proteins of lung cancer cells in vitro and in vivo. ND-Cet treatment increased cellular uptake ability of nanocomposites in the EGFR-expressed cells but not in the EGFR-negative lung cancer cells. Interestingly, single ND-Cet complex can be directly observed on the protein G bead by immunoprecipitation and confocal microscopy. Besides, the EGFR proteins were transported to lysosomes for degradation. Together, this study demonstrates that ND-conjugated Cet can apply for targeting EGFR and monitoring tumorigenesis during lung cancer progression and therapy.

Fluorination Effects on the Drug Delivery Property of Cylindrical Polymer Brushes.

Fluorination has been widely applied to improving the properties of small-molecule drugs. However, relatively little is known about the effects of fluorination on the drug delivery property of nanomaterials. In this paper, we synthesized a fluoroalkane-modified cylindrical polymer brush (CPB) BCPB-F and an alkane-modified analogue BCPB-H. Doxorubicin (DOX) was used as a model drug and was loaded onto the CPBs through a pH-responsive acylhydrazone linkage. High drug loading and good water solubility were achieved. The in vitro and in vivo experiments suggested that fluorination played an important role in improving the cellular uptake, blood circulation, tissue permeability, and tumor targeting ability of CPBs. Due to these superiorities, the DOX-loaded BCPB-F exhibited excellent antitumor efficacy and eradicated the tumors of mice after five-dose treatments. The well-defined structures of the drug-free and drug-loaded CPBs guaranteed the accuracy of the results. This work demonstrates that fluorination is a promising strategy to improve the overall properties of nanomedicines.

Selinexor-Loaded Polymeric Micelles for Multiple Myeloma Therapy

Introduction Multiple myeloma (MM) is characterized by the clonal proliferation of abnormal plasma cells in the bone marrow. Selinexor (SEL) is an XPO1 inhibitor, and in a pivotal clinical trial, the SEL and dexamethasone regimen showed a 26% of partial response rate or better, with two patients achieving stringent complete response. However, the single-agent efficacy of SEL was modest, with systemic toxicities including thrombocytopenia and gastrointestinal symptoms that negatively impacted the quality of life. Nanomedicine refers to the ingenious design of nanoscale biomaterials for drug delivery. Polymeric micelles are made up of self-assembled amphiphilic block polymers and act as an effective strategy to address the challenge of free drug administration. To reduce side effects and improve therapeutic efficacy, we reported our work on SEL delivery using mPEG-PCL micelles for the treatment of MM. Materials and Methods The SEL-loaded micelles were developed through thin-film hydration. The mean particle size, zeta potential, and polydispersity index of micelles were assessed by a Malvern Nano-ZS 90. The release behavior of the mPEG-PCL-SEL micelle was determined by a dialysis method in vitro. The cytotoxicity and apoptosis rate of the mPEG-PCL-SEL micelle were assessed on the RPMI-8226 cell line and the ARD cell line. The ARD orthotopic MM model was developed by intravenous administration of ARD-luc cells into 6-week-old B-NDG mice. Four groups were treated with saline, blank micelles, or mPEG-PCL-SEL micelles (SEL concentrations: 2.5 and 5 mg/kg) via intravenous injection, and the other four groups were given free-SEL via oral gavage (SEL concentrations: 2.5, 5, 10, and 15 mg/kg), respectively. All of the treatments were given twice a week for two weeks. To evaluate the tumor burden, bioluminescence imaging was monitored. Brain samples were collected for assessment of brain penetration ability of the micellar formulation. In addition, the animal weight, peripheral blood counts, and condition of mice were measured to investigate the side effects. Results The particle size of the mPEG-PCL-SEL micelle was 31.3 nm, the PDI was 0.11-0.16, and the zeta potential was −4.52 mV. The encapsulation efficacy was 90.56%. The micelles remained stable for a long period and exhibited a controlled release behavior. In addition, the mPEG-PCL-SEL micelle exhibited enhanced cellular uptake ability and efficient cytotoxicity toward MM cells. Most importantly, in the orthotopic MM model, this micelle system exhibited impressive therapeutic efficacy. The 5 mg/kg mPEG-PCL-SEL micelle group demonstrated better treatment efficacy than the 10 mg/kg free-SEL group according to the quantitative analysis of tumor bioluminescence, indicating the superior therapeutic activity, although there was no significant difference. Surprisingly, the SEL-loaded micelle efficiently prolonged the survival of myeloma-bearing mice. Besides, the micellar formulation possessed a reduced brain penetration property which may contribute to improved tolerability. And mice in the SEL-micelle groups did not show abnormal situation of hematopoietic cells and weight loss. The micelle demonstrated a favorable safety profile. Discussion and conclusions In this work, we developed mPEG-PCL-SEL micelles with thin-film hydration. To the best of our knowledge, no relevant studies of SEL delivery have been reported. The micelle formulation showed good stability and controlled release manner. Besides, the mPEG-PCL-SEL micelle induced comparable or even better levels of cytotoxicity compared with the free-SEL in vitro. Most importantly, the mPEG-PCL-SEL micelle exhibited improved therapeutic efficacy compared with the free-SEL at the same dose level and showed similar or better therapeutic outcomes than the high-dose free-SEL, performed with survival benefit. Meanwhile, the micelle formulation possessed acceptable tolerability and safety profile. It is worth noting that none of the treatment groups achieved complete remission. This may be due to the limited treatment efficacy of a single agent. Hence, nanomedicine-based combination therapy containing SEL can be studied to further improve the efficacy of MM treatment.

ROS-responsive chlorin e6 and silk fibroin loaded ultrathin magnetic hydroxyapatite nanorods for T1-magnetic resonance imaging guided photodynamic therapy in vitro

Magnetite hydroxyapatite nanoparticles show notable multifunctional therapeutic features in nanomedicine. However, designing MHAp nanoparticles with optimum dimensions, good stability and biocompatibility for specific biomedical applications is still in its infancy. Herein, a facile approach was employed to prepare ROS-responsive chlorin e6 and silk fibroin-loaded ultrathin magnetic hydroxyapatite nanorods for T1-magnetic resonance imaging and photodynamic therapy. Specifically, the Fe3O4-HAp nanorods were synthesized by the hydrothermal method, and then Pluronic® F-127 was used to improve the aqueous dispersion, biocompatibility, and loading capacity. Moreover, silk fibroin protein was encapsulated by a tri-block copolymer with good loading efficiency. Finally, the theranostic nano-assembly MHNRs-SF-Ce6 was completed by the addition of Ce6. The prepared MHNRs demonstrated excellent biocompatibility, cellular uptake, and ROS generation ability in in vitro after 660 nm laser irradiation, leading to the apoptosis of 4T1 mouse breast cancer cells. Notably, the designed MHNRs exhibited excellent r1 relaxivity value and T1 magnetic resonance imaging in vitro due to their minimal width (2 nm) of nanorods. Therefore, the obtained MHNRs-SF-Ce6 self-assembled nanoparticles provide an effective strategy for cancer diagnosis and photodynamic therapy.

Nanoparticles for Near-Infrared Light-Driven Singlet Oxygen and CO Gas Cogeneration for Pancreatic Adenocarcinoma Therapy

Developing photocatalytic medicine for targeted therapy is intriguing but still remains a great challenge. Herein, we developed a nanophotosensitizer (c-PDMS) decorated with pancreatic adenocarcinoma (PAC)-targeting DNA aptamer Xq-2D (abbreviated as Xq-2D/c-PDMS) for enhanced photodynamic–gas synergistic therapy of PAC. c-PDMS is constructed by poly[2,6-(4,4-bis-(2-ethylhexyl)-4H-cyclopenta[2,1-b/3,4-b′]dithiophene)-alt-4,7-(2,1,3-benzothiadiazole)] (OSP) integrated into dendritic mesoporous silica (DMS) through a one-step method and further loaded with the CORM-401 prodrug as the CO donor. Our prepared c-PDMS can produce 1O2 and then oxidate the CORM-401 prodrug to release CO gas under near infrared (NIR) laser irradiation. After being decorated by Xq-2D aptamer-HS with MAL-PEG-NHS, the resultant Xq-2D/c-PDMS showed good biocompatibility, active targeting, and high cellular uptake ability by PAC cells compared to c-PDMS alone, which led to an efficient killing effect to fight against PAC cancer cells through 1O2 oxidization and CO-mediated mitochondrial respiration inhibition. Furthermore, the excellent antitumor efficiency of Xq-2D/c-PDMS in vivo with minimized side effects was clarified by the analysis of tumor volume and weight, H&E staining of tumors, biochemical indexes, and weight loss after NIR laser irradiation. This study provides an efficient synergistic strategy for PAC therapy.

Colon-specific delivery of isoliquiritigenin by oral edible zein/caseate nanocomplex for ulcerative colitis treatment.

Although a natural anti-inflammatory ingredient, isoliquiritigenin (ISL), plays an effective role in ulcerative colitis (UC) treatment, a series of drawbacks still limit its clinical application, including the poor solubility, instability in gastrointestinal tract, and rapid elimination rate of ISL. Zein-based NPs display the benefits on drug loading and delivery, whereas with the poor stability. In this study, an edible nano-system composed by zein/caseinate complex was fabricated for the colon-targeting delivery of ISL, to improve its colon retention and anti-UC effects. The optimized ISL loaded zein/caseinate NPs (ISL@NPs) were prepared by single-factor design by anti-solvent precipitation method, and then characterized. The improved cellular uptake of ISL@NPs on NCM460 and RAW 264.7 cells was evaluated in vitro. The colon tissue permeability and retention capacity in vivo, and the anti-UC efficacy of ISL@NPs in DSS-induce UC were implemented. As a result, ISL@NPs with the high drug loading efficiency of 9.39% ± 0.26%, the average particle diameter of 137.32 ± 2.54 nm, exhibited the pH-sensitive stability in the different simulated gastrointestinal buffer. Compared with free ISL, ISL@NPs showed significantly higher cellular uptake ability in NCM460 and RAW 264.7 cells. Based on in vivo imaging system, zein/caseinate NPs showed the prolonged colonic retention and the enhanced penetration into the colonic epithelium. Finally, the oral administration of ISL@NPs could effectively alleviate the UC-related symptoms, down-regulate the production of pro-inflammatory factors, and reduce the infiltration of macrophages and neutrophils in colon tissues. In this study, an oral colon-specific nano-system, composed with the natural compound and edible materials, was developed as the promising alternatives in the prevention and treatment of UC.

Referential modification strategy based on phenolic hydroxyl-containing KSA luminogens for ER-targeting probe construction

The endoplasmic reticulum (ER) plays essential roles in various physiological processes and is intimately connected to kinds of diseases. The development of ER-targeting theranostic agents is highly demanded for precise treatments, however, the effective and referential strategies for the construction of ER-targeting probes are limited. Herein, we developed series of ER-targeting luminogens based on keto-salicylaldehyde azine (KSA) framework by introducing phenolic hydroxyl group, which present good theranostic performance with selective enrichment in ER. Under systematical structure modulation, the key role of phenolic hydroxyl group at K-terminal in ER-targeting was experimentally confirmed. Besides, the cyanobenzyl moiety at S-terminal can enhance the luminous efficiency and improve cellular uptake ability. Moreover, the generated reactive oxygen species (ROS) of these KSA derivatives can efficiently trigger ER stress to induce the apoptosis of cancer cells, resulting in the effective inhibition of tumor cells both in vitro and in vivo. Therefore, this feasible modification strategy of inserting phenolic hydroxyl group to common multi-aryl-based luminogens provides a reliable and referential approach for ER-targeting probe establishment.

Functional Au nanoparticles for engineering and long-term CT imaging tracking of mesenchymal stem cells in idiopathic pulmonary fibrosis treatment

Idiopathic pulmonary fibrosis (IPF) therapy has always been a big and long-standing challenge in clinical practice due to the lack of miraculous medicine. Mesenchymal stem cells (MSCs)-based therapy has recently emerged as a promising candidate for redefining IPF therapy. Enhancing the therapeutic efficacy of MSCs and understanding of their growth, migration and differentiation in harsh lung microenviroments are two keys to improving the stem cell-based IPF treatment. Herein, a non-viral dual-functional nanocarrier is fabricated by a one-pot approach, using protamine sulfate stabilized Au nanoparticles (AuPS), to genetically engineer MSCs for simultaneous IPF treatment and monitoring the biological behavior of the MSCs. AuPS exhibits superior cellular uptake ability, which results in efficient genetic engineering of MSCs to overexpress hepatocyte growth factor for enhanced IPF therapy. In parallel, the intracellular accumulation of AuPS improves the CT imaging contrast of MSCs, allowing visual tracking of the therapeutic engineered MSCs up to 48 days. Overall, this work has described for the first time a novel strategy for enhanced therapeutic efficacy and long-term CT imaging tracking of transplanted MSCs in IPF therapy, providing great prospect for stem cell therapy of lung disease.

Dual-miRNA-Propelled Three-Dimensional DNA Walker for Highly Specific and Rapid Discrimination of Breast Cancer Cell Subtypes in Clinical Tissue Samples

Dual-miRNA-Propelled Three-Dimensional DNA Walker for Highly Specific and Rapid Discrimination of Breast Cancer Cell Subtypes in Clinical Tissue Samples

Rationally designed monoamine oxidase A‐activatable AIE molecular photosensitizer for the specific imaging and cellular therapy of tumors

AbstractDue to both the requirements of repeated complex organic synthesis and tedious biochemical verification experiments for the screening of new photosensitizers, the development of a satisfactory photosensitizer with excellent photosensitivity and highly specific response ability is still a great challenge for the accurate imaging localization and the precise photodynamic therapy (PDT) of tumors. Herein, under the help of theoretical calculations, a high‐efficient target‐activatable aggregation‐induced emission (AIE) molecular photosensitizer, TPE‐TThPy, is rationally designed and synthesized by the conjugation of tetraphenylethylene (TPE, which is used as the electron donor) and tetrahydropyridine (ThPy, which can be converted to methylpyridine salts as the electron acceptor) using thiophene (T) as the π‐bridge. This TPE‐TThPy molecule exhibits not only good cellular uptake and mitochondrial targeting ability but also ultra‐high monoamine oxidase A (MAO‐A) response specificity and excellent photosensitivity when oxidized under the action of MAO‐A. The specifically imaging ability and cellular PDT performance of the MOA‐A‐activatable AIE photosensitizer of TPE‐TThPy is demonstrated by using different cell lines and mouse tumor models. The successful development of this MOA‐A‐activatable AIE photosensitizer also provides insight for the development of single‐molecule PDT therapeutic drugs with excellent photosensitivity and highly specific targeting‐response ability.

Self-assembled Cu2−xS nanochains network with tunable diameters for efficient photothermal conversion

Cu 2−x S nanochains network (NCNW) with tunable diameter in the range of 5–9 nm is prepared by a self-assembly strategy. Control experiments reveal that poly (sodium 4-styrenesulfonate) plays a key role in guiding the assembly of the nanochains. The Cu 2−x S NCNW demonstrates a broad localized surface plasmon resonance (LSPR) band in the near-infrared-Ⅱ region, which matches the optical window of biological tissues. The LSPR band of the Cu 2−x S NCNW red-shifts and intensifies with the increase of diameter. The Cu 2−x S NCNW with an average diameter of 8.7 nm exhibits a high photothermal conversion efficiency of 80.7% under 808 nm laser (0.75 W cm −2 ). Furthermore, the thermal effect stability of the Cu 2−x S NCNW is also good. In vitro experiments demonstrate that all the nanochains possess low cell cytotoxicity. The 8.7 nm Cu 2−x S NCNW own the maximum cellular uptake, and can cause> 90% apoptosis rate of Hela cells under low power density laser (808 nm, 0.75 W cm −2 ), demonstrating its promising application in photothermal therapy. • Cu 2−x S nanochains network with tunable diameter is synthesized. • The Cu 2−x S NCNW exhibits strong LSPR in the Near-Infrared region. • The 8.7 nm Cu 2−x S NCNW exhibits high PCE of 80.7% under 808 nm laser. • The 8.7 nm NCNW has highest cellular uptake and photothermal cell ablation ability.

Multifunctional peptide carrier-modified polymer micelle accelerates oral siRNA-delivery to the colon and improves gene silencing-mediated therapeutic effects in ulcerative colitis

In the treatment of inflammatory bowel diseases such as ulcerative colitis (UC), siRNAs are expected to enable fundamental suppression of the expression of pathogenic genes. Oral administration is considered the most desirable route of drug-administration as it can act directly on the affected area and improve the patient's quality of life. However, when orally administered, naked siRNA is easily degraded in the gastrointestinal tract; therefore, it is necessary to use a carrier to protect the siRNA from degradation. We have previously shown that systemic administration of the multifunctional peptide carrier (CH2R4H2C)-modified methoxy polyethylene glycol-polycaprolactone polymer micelles (MPEG-PCL-CH2R4H2C)/siRNA has high therapeutic efficacy against inflammatory diseases. In the present study, we aimed to apply MPEG-PCL-CH2R4H2C nano-micelles to apply MPEG-PCL-CH2R4H2C nano-micelles for oral delivery of siRNA to treat dextran sodium sulfate-induced UC model mice. Agarose gel electrophoresis and cell viability and cytotoxicity assays were performed. The therapeutic effects of siRelA in UC mice were assessed. MPEG-PCL-CH2R4H2C/siRNA complexes with an N/P ratio of more than 50 were not degraded at the gastrointestinal pH environment of 1.2 and 6.8, and showed high cellular uptake ability without showing cytotoxicity in macrophages. In addition, oral administration of the MPEG-PCL-CH2R4H2C/siRNA to mice showed improved delivery to the colon compared to naked siRNA. Finally, RelA-targeted siRNA suppressed the RelA mRNA expression and deterioration of clinical symptoms, such as bloody stool, diarrhea, weight loss, and colonic shortening, by complexation with MPEG-PCL-CH2R4H2C micelles. These results suggest that MPEG-PCL-CH2R4H2C micelles are useful as novel siRNA carriers for oral administration.