Active Delivery of VLPs Promotes Anti-Tumor Activity in a Mouse Ovarian Tumor Model.

Virus-like nanoparticles (VLPs) have been used as an attractive means in cancer immunotherapy because of their unique intrinsic immunostimulatory properties. However, for treating metastatic tumors in the peritoneal cavity, such as ovarian cancer, multiple injections of therapy are needed due to the large peritoneal space and fast excretion of therapy. Here, it is reported on the development of active VLP delivery vehicles for the treatment of peritoneal ovarian tumors using biocompatible Qß VLPs-loaded Mg-based micromotors. The autonomous propulsion of such Qß VLPs-loaded Mg-micromotors in the peritoneal fluid enables active delivery of intact immunostimulatory Qß VLPs to the peritoneal space of ovarian tumor bearing mice, greatly enhancing the local distribution and retention of Qß VLPs. Such improved distribution and longer retention time of Qß in the peritoneal cavity leads to enhanced immunostimulation and therefore increased survival rate of tumor-bearing mice compared to a passive Qß treatment. For clinical translation, the active delivery of VLPs holds great promise for tumor immunotherapy toward the treatment of different types of primary and metastatic tumors in the peritoneal cavity.

Impact of a selective use of episiotomy combined with Couder's maneuver for the perineal protection.

PURPOSE: To evaluate the impact of a selective use of episiotomy combined with Couder's maneuver on the incidence of perineal tears in spontaneous term deliveries. METHODS: A comparative, retrospective, mono-centric study in a university maternity unit was designed and included all primiparous women who delivered spontaneously after 37 weeks of gestation in cephalic presentation. Two cohorts were studied, before and after the practice of Couder's maneuver. In the first cohort, the ''OSE cohort'' only selective episiotomies were performed from January 2009 to December 2010. In the second cohort, from January 2016 to December 2017, the ''SEC cohort'' selective episiotomies combined with Couder's maneuver were performed by midwives and obstetricians. The primary outcome was the type of perineal tears, according to the Royal College of Obstetricians and Gynaecologists (RCOG) classification. RESULTS: A total of 2081 patients were included: 909 patients in the OSE cohort and 1172 patients in the SEC cohort. Couder's maneuver was performed in 59% of the SEC cohort. In the SEC cohort, there were an increase in the number of intact perinea (55% versus 63%, p < 0.001), a decrease in second-degree perineal tears (18% versus 11%, p < 0.001) and a decrease in labia minora tears (48% versus 37%, p < 0.001). The rate of obstetrical anal sphincter injuries was less than 1% in both cohorts (0.3% versus 0.5%, p = 0.7). CONCLUSION: A selective use of episiotomy combined with Couder's maneuver could reduce the incidence of perineal tears, particularly second-degree perineal tears, without increasing the rate of obstetrical anal sphincter injuries.

Micromotors for Active Delivery of Minerals toward the Treatment of Iron Deficiency Anemia.

As the most common nutritional disorder, iron deficiency represents a major public health problem with broad impacts on physical and mental development. However, treatment is often compromised by low iron bioavailability and undesired side effects. Here, we report on the development of active mineral delivery vehicles using Mg-based micromotors, which can autonomously propel in gastrointestinal fluids, aiding in the dynamic delivery of minerals. Iron and selenium are combined as a model mineral payload in the micromotor platform. We demonstrate the ability of our mineral-loaded micromotors to replenish iron and selenium stores in an anemic mouse model after 30 days of treatment, normalizing hematological parameters such as red blood count, hemoglobin, and hematocrit. Additionally, the micromotor platform exhibits no toxicity after the treatment regimen. This proof-of-concept study indicates that micromotor-based active delivery of mineral supplements represents an attractive approach toward alleviating nutritional deficiencies.

Liposomes of Quantum Dots Configured for Passive and Active Delivery to Tumor Tissue.

The majority of developed and approved anticancer nanomedicines have been designed to exploit the dogma of the enhanced permeability and retention (EPR) effect, which is based on the leakiness of the tumor's blood vessels accompanied by impeded lymphatic drainage. However, the EPR effect has been under scrutiny recently because of its variable manifestation across tumor types and animal species and its poor translation to human cancer therapy. To facilitate the EPR effect, systemically injected NPs should overcome the obstacle of rapid recognition and elimination by the mononuclear phagocyte system (MPS). We hypothesized that circulating monocytes, major cells of the MPS that infiltrate the tumor, may serve as an alternative method for achieving increased tumor accumulation of NPs, independent of the EPR effect. We describe here the accumulation of liposomal quantum dots (LipQDs) designed for active delivery via monocytes, in comparison to LipQDs designed for passive delivery (via the EPR effect), following IV administration in a mammary carcinoma model. Hydrophilic QDs were synthesized and entrapped in functionalized liposomes, conferring passive ("stealth" NPs; PEGylated, neutral charge) and active (monocyte-mediated delivery; positively charged) properties by differing in their lipid composition, membrane PEGylation, and charge (positively, negatively, and neutrally charged). The various physicochemical parameters affecting the entrapment yield and optical stability were examined in vitro and in vivo. Biodistribution in the blood, various organs, and in the tumor was determined by the fluorescence intensity and Cd analyses. Following the treatment of animals (intact and mammary-carcinoma-bearing mice) with disparate formulations of LipQDs (differing by their lipid composition, neutrally and positively charged surfaces, and hydrophilic membrane), we demonstrate comparable tumor uptake of QDs delivered by the passive and the active routes (mainly by Ly-6Chi monocytes). Our findings suggest that entrapping QDs in nanosized liposomal formulations, prepared by a new facile method, imparts superior structural and optical stability and a suitable biodistribution profile leading to increased tumor uptake of fluorescently stable QDs.

Layered Double Hydroxide-Based Functional Nanohybrids as Controlled Release Carriers of Pharmaceutically Active Ingredients.

The chemical stability, degradation and penetration ability of pharmaceutically active ingredients in topical formulations are the greatest challenges because of problems with the protection of actives for long times and with delivery. Therefore, the development of unique and efficient substrate material is vital for their protection and controlled drug release. Layered double hydroxides (LDHs) known as hydrotalcite like compounds possess positive charges due to isomorphic substitutions, which are counterbalanced by hydrated exchangeable anions located in the interlayer region. Some of the active ingredient molecules can be intercalated into the inner region of the LDHs through ionic bonding, hydrogen bonding or van der Waals interaction to form nanohybrids, which are more potent for their protection and controlled-release. This account focuses on our recent research efforts and key scientific and technical challenges in the development of LDH based nanohybrids for commercial use in advanced controlled release carriers of active ingredients in topical formulations.

Properties of Native High-Density Lipoproteins Inspire Synthesis of Actively Targeted In Vivo siRNA Delivery Vehicles.

Efficient systemic administration of therapeutic short interfering RNA (siRNA) is challenging. High-density lipoproteins (HDL) are natural in vivo RNA delivery vehicles. Specifically, native HDLs: 1) Load single-stranded RNA; 2) Are anionic, which requires charge reconciliation between the RNA and HDL, and 3) Actively target scavenger receptor type B-1 (SR-B1) to deliver RNA. Emphasizing these particular parameters, we employed templated lipoprotein particles (TLP), mimics of spherical HDLs, and self-assembled them with single-stranded complements of, presumably, any highly unmodified siRNA duplex pair after formulation with a cationic lipid. Resulting siRNA templated lipoprotein particles (siRNA-TLP) are anionic and tunable with regard to RNA assembly and function. Data demonstrate that the siRNA-TLPs actively target SR-B1 to potently reduce androgen receptor (AR) and enhancer of zeste homolog 2 (EZH2) proteins in multiple cancer cell lines. Systemic administration of siRNA-TLPs demonstrated no off-target toxicity and significantly reduced the growth of prostate cancer xenografts. Thus, native HDLs inspired the synthesis of a hybrid siRNA delivery vehicle that can modularly load single-stranded RNA complements after charge reconciliation with a cationic lipid, and that function due to active targeting of SR-B1.

Engineered platelet cell motors for boosted cancer radiosensitization.

Design of engineered cells to target and deliver nanodrugs to the hard-to-reach regions has become an exciting research area. However, the limited penetration and retention of cell-based carriers in tumor tissue restricted their therapeutic efficiency. Inspired by the enhanced delivery behavior of mobile micro/nanomotors, herein, urease-powered platelet cell motors (PLT@Au@Urease) capable of active locomotion, tumor targeting, and radiosensitizers delivery were designed for boosting radiosensitization. The engineered platelet cell motors were constructed by in situ synthesis and loading of radiosensitizers gold nanoparticles in platelets, and then conjugation with urease as the engine. Under physiological concentration of urea, thrust around PLT@Au@Urease motors can be generated via the biocatalytic reactions of urease, leading to rapid tumor cell targeting and enhanced cellular uptake of radiosensitizers. Encouragingly, in comparison with engineered PLT without propulsion capability (PLT@Au), the self-propelled PLT@Au@Urease motors could significantly increase intracellular ROS level and exacerbate nuclear DNA damage induced by γ-radiation, resulting in a remarkably high sensitization enhancement rate (1.89) than that of PLT@Au (1.08). In vivo experiments with 4 T1-bearing mice demonstrated that PLT@Au@Urease in combination with radiation therapy possessed good antitumor performance. Such an intelligent cell motor would provide a promising approach to enhance radiosensitization and broaden the applications of cell motor-based delivery systems.

Using a Knowledge-Based Clinical Decision Support System to Reduce the Time to Appropriate Antimicrobial Therapy in Hospitalized Patients With Bloodstream Infections: A Single-Center Observational Study.

Background: Inappropriate antimicrobial use is a crucial determinant of mortality in hospitalized patients with bloodstream infections. Current literature reporting on the impact of clinical decision support systems on optimizing antimicrobial prescription and reducing the time to appropriate antimicrobial therapy is limited. Methods: Kaohsiung Veterans General Hospital implemented a hospital-wide, knowledge-based, active-delivery clinical decision support system, named RAPID (Real-time Alert for antimicrobial Prescription from virtual Infectious Diseases experts), to detect whether there was an antimicrobial agent-pathogen mismatch when a blood culture result was positive. Once RAPID determines the current antimicrobials as inappropriate, an alert text message is immediately sent to the clinicians in charge. This study evaluated how RAPID impacted the time to appropriate antimicrobial therapy among patients with bloodstream infections. Results: During the study period, 633 of 11 297 recorded observations (5.6%) were determined as inappropriate antimicrobial prescriptions. The time to appropriate antimicrobial therapy was significantly shortened after the implementation of RAPID (1.65 vs 2.45 hours, P < .001), especially outside working hours (1.24 vs 6.43 hours, P < .001), in the medical wards (1.40 vs 2.14 hours, P < .001), in participants with candidemia (0.74 vs 5.36 hours, P < .001), and for bacteremia due to non-multidrug-resistant organisms (1.66 vs 2.49 hours, P < .001). Conclusions: Using a knowledge-based clinical decision support system to reduce the time to appropriate antimicrobial therapy in a real-world scenario is feasible and effective. Our results support the continued use of RAPID.

Cell nucleus as endogenous biological micropump.

Micropumps can generate directional microflows in blood vessels or bio-capillaries for targeted transport of nanoparticles and cells in vivo, which is highly significant for biomedical applications from active drug delivery to precision clinical therapy. Meanwhile, they have been extensively used in the biosensing fields with their unique features of autonomous motion, easy surface functionalization, dynamic capture and effective isolation of analytes in complex biological media. However, synthetic devices for actuating microflows, including pumps and motors, generally exhibit poor or limited biocompatibility with living organisms as a result of the invasive implantation of exogenous materials into blood vessels. Here we demonstrate a method of constructing endogenous micropumps by extracting nuclei from red blood cells, thus making them intrinsically and completely biocompatible. The nuclei are extracted and then driven by a scanning optical tweezing system. By a precise actuation of the microflows, nanoparticles and cells are navigated to target destinations, and the transport velocity and direction is controlled by the multifunctional dynamics of the micropumps. With the targeted transport of functionalized micro/nanoparticles followed by a dynamic mixing in microliter blood samples, the micropumps provide considerable promises to enhance the target binding efficiency and improve the sensitivity and speed of biological assays in vivo. Furthermore, multiplexing by simultaneously driving an array of multiple nuclei is demonstrated, thus confirming that the micropumps could provide a bio-friendly high-throughput in vivo platform for the treatment of blood diseases, microenvironment monitoring, and biomedical analysis.

The impact of active delivery of the anterior arm during vacuum-assisted vaginal delivery on perineal tears: a clinical practice evaluation.

Objective: Our purpose was to evaluate the impact of active delivery of the anterior arm with Couder's Maneuver (CM) during vacuum-assisted vaginal delivery (VAVD) on perineal tears. This maneuver can be beneficial because it has the advantage of reducing fetal biacromial diameter.Methods: This monocentric retrospective study compared two non-concurrent cohorts of nulliparous women before and after implementation of a systematic CM during VAVD: Cohort 1 from 1 January to 31 December 2006 without CM and Cohort 2 from 1 January to 31 December 2016 with systematic CM. This study reviewed all births during these two periods. All live-born singleton pregnancies where VAVD occurred after 37 weeks of gestation were included. The principal endpoint was the type of perineal tear.Results: In total, there were 179 VAVD in the Cohort 1 and 267 VAVD in the Cohort 2. In the Cohort 2, 233 VAVD (87.3%) were performed with systematic CM. No episiotomy was performed in both cohorts. There was a significant decrease in the rate of second-degree perineal tears between the two cohorts (42.4 versus 15%, p < .001) and a significant increase in the rate of intact perineum (34.1 versus 54.7%, p < .001). There was no influence of CM on the rate of obstetrical anal sphincter injury (3.9 versus 2.6%, p = .44).Conclusions: Practicing this maneuver could improve the perineal prognosis during VAVD in nulliparous women.

Fantastic Voyage of Nanomotors into the Cell.

Richard Feynman's 1959 vision of controlling devices at small scales and swallowing the surgeon has inspired the science-fiction Fantastic Voyage film and has played a crucial role in the rapid development of the microrobotics field. Sixty years later, we are currently witnessing a dramatic progress in this field, with artificial micro- and nanoscale robots moving within confined spaces, down to the cellular level, and performing a wide range of biomedical applications within the cellular interior while addressing the limitations of common passive nanosystems. In this review article, we discuss key recent advances in the field of micro/nanomotors toward important cellular applications. Specifically, we outline the distinct capabilities of nanoscale motors for such cellular applications and illustrate how the active movement of nanomotors leads to distinct advantages of rapid cell penetration, accelerated intracellular sensing, and effective intracellular delivery toward enhanced therapeutic efficiencies. We finalize by discussing the future prospects and key challenges that such micromotor technology face toward implementing practical intracellular applications. By increasing our knowledge of nanomotors' cell entry and of their behavior within the intracellular space, and by successfully addressing key challenges, we expect that next-generation nanomotors will lead to exciting advances toward cell-based diagnostics and therapy.

Multicompartment Tubular Micromotors Toward Enhanced Localized Active Delivery.

A tubular micromotor with spatially resolved compartments is presented toward efficient site-specific cargo delivery, with a back-end zinc (Zn) propellant engine segment and an upfront cargo-loaded gelatin segment further protected by a pH-responsive cap. The multicompartment micromotors display strong gastric-powered propulsion with tunable lifetime depending on the Zn segment length. Such propulsion significantly enhances the motor distribution and retention in the gastric tissues, by pushing and impinging the front-end cargo segment onto the stomach wall. Once the micromotor penetrates the gastric mucosa (pH ≥ 6.0), its pH-responsive cap dissolves, promoting the autonomous localized cargo release. The fabrication process, physicochemical properties, and propulsion behavior are systematically tested and discussed. Using a mouse model, the multicompartment motors, loaded with a model cargo, demonstrate a homogeneous cargo distribution along with approximately four-fold enhanced retention in the gastric lining compared to monocompartment motors, while showing no apparent toxicity. Therapeutic payloads can also be loaded into the pH-responsive cap, in addition to the gelatin-based compartment, leading to concurrent delivery and sequential release of dual cargos toward combinatorial therapy. Overall, this multicompartment micromotor system provides unique features and advantages that will further advance the development of synthetic micromotors for active transport and localized delivery of biomedical cargos.

A Nanomotor-Based Active Delivery System for Intracellular Oxygen Transport.

Active transport of gas molecules is critical to preserve the physiological functions of organisms. Oxygen, as the most essential gas molecule, plays significant roles in maintaining the metabolism and viability of cells. Herein, we report a nanomotor-based delivery system that combines the fast propulsion of acoustically propelled gold nanowire nanomotors (AuNW) with the high oxygen carrying capacity of red blood cell membrane-cloaked perfluorocarbon nanoemulsions (RBC-PFC) for active intracellular delivery of oxygen. The oxygen delivery capacity and kinetics of the AuNW nanomotors carrying RBC-PFC (denoted as "Motor-PFC") are examined under ultrasound field. Specifically, the fast movement of the Motor-PFC under an acoustic field accelerates intracellular delivery of oxygen to J774 macrophage cells. Upon entering the cells, the oxygen loaded in the Motor-PFC is sustainably released, which maintains the cell viability when cultured under hypoxic conditions. The acoustically propelled Motor-PFC leads to significantly higher cell viability (84.4%) over a 72 h period, compared to control samples with free RBC-PFC (44.4%) or to passive Motor-PFC (32.7%). These results indicate that the Motor-PFC can act as an effective delivery vehicle for active intracellular oxygen transport. While oxygen is used here as a model gas molecule, the Motor-PFC platform can be readily expanded to the active delivery of other gas molecules to various target cells.

Red Blood Cell-Mimicking Micromotor for Active Photodynamic Cancer Therapy.

Photodynamic therapy (PDT) is a promising cancer therapeutic strategy, which typically kills cancer cells through converting nontoxic oxygen into reactive oxygen species using photosensitizers (PSs). However, the existing PDTs are still limited by the tumor hypoxia and poor targeted accumulation of PSs. To address these challenges, we here report an acoustically powered and magnetically navigated red blood cell-mimicking (RBCM) micromotor capable of actively transporting oxygen and PS for enhanced PDT. The RBCM micromotors consist of biconcave RBC-shaped magnetic hemoglobin cores encapsulating PSs and natural RBC membrane shells. Upon exposure to an acoustic field, they are able to move in biological media at a speed of up to 56.5 µm s-1 (28.2 body lengths s-1). The direction of these RBCM micromotors can be navigated using an external magnetic field. Moreover, RBCM micromotors can not only avoid the serum fouling during the movement toward the targeted cancer cells but also possess considerable oxygen- and PS-carrying capacity. Such fuel-free RBCM micromotors provide a new approach for efficient and rapid active delivery of oxygen and PSs in a biofriendly manner for future PDT.

Next-Generation Noncompetitive Nanosystems Based on Gambogic Acid: In silico Identification of Transferrin Receptor Binding Sites, Regulatory Shelf Stability, and Their Preliminary Safety in Healthy Rodents.

A major challenge in drug delivery is to enhance the transport of drugs across biological barriers, such as the small intestine, the blood-brain barrier, and the blood-retinal/ocular barrier, and to effectively reach the site of action while minimizing the systemic impact. In recent years, piggybacking cell surface receptors have been considered a viable strategy for active drug delivery across the biological barriers. However, the ligands used to target drugs to plasma membrane receptors often have to compete against endogenous ligands, thereby limiting their binding to the cell surface and their transport across barriers. To address this problem, gambogic acid (GA) was identified as a noncompetitive ligand specific to the transferrin receptor (TfR), a receptor present on various barriers. However, the binding sites of the GA on TfR remain unknown, an essential step toward establishing structure-activity relationships. In silico binding site prediction tools, blind docking, and molecular docking simulation confirm that the GA binding site on the TfR is independent of the transferrin-bound iron binding sites. The GA-conjugated polyesters were processed into nanoparticles suitable for drug delivery applications that possess excellent storage stability under regulatory conditions. Traditionally, GA has been used as an anticancer compound that warrants safety assessment. The preliminary studies in healthy rodents on 10-repeated oral doses show no adverse effects. This work will generate paradigm shifting, new knowledge in the field of nanomedicines using unique noncompetitive nanosystems that do not compete with endogenous transferrin.

Neutrophil-mediated delivery of nanotherapeutics across blood vessel barrier.

Nanotherapeutics, nanoparticles (NPs) loaded with drugs, show the ability of tissue targeting, long circulation and low toxicity compared with free drugs. Endothelium lying the lumen of a blood vessel is a barrier to restrain tissue deposition of nanotherapeutics. Neutrophils, a type of white blood cells, migrate across endothelium during inflammation. There is an emerging concept that in situ targeting of neutrophils allows delivery of nanotherapeutics into deep tissues at disease sites. Here we summarize the recent advances in delivery of nanotherapeutics to inflammatory tissues or tumor microenvironments via neutrophil infiltration. The studies would shift the current paradigm of nanomedicine to biology-driven design of nanotherapeutics. [Formula: see text].

Ex Vivo Rat Eye Model for Investigating Transport of Next Generation Precision-Polyester Nanosystems.

We present for the first time a robust ex vivo rat eye model for investigating the transport of precision-polyester nanosystems (P2Ns) across the blood-retinal barrier, intended for systemic administration. The P2Ns-GA actively transport exploiting transferrin receptors present in the inner retinal barrier and colocalize in ganglion cells. Such delivery approaches have the potential to deliver drugs to posterior segments of the eye, which is still a major challenge in treating posterior ocular disorders.

Enteric Micromotor Can Selectively Position and Spontaneously Propel in the Gastrointestinal Tract.

The gastrointestinal (GI) tract, which hosts hundreds of bacteria species, becomes the most exciting organ for the emerging microbiome research. Some of these GI microbes are hostile and cause a variety of diseases. These bacteria colonize in different segments of the GI tract dependent on the local physicochemical and biological factors. Therefore, selectively locating therapeutic or imaging agents to specific GI segments is of significant importance for studying gut microbiome and treating various GI-related diseases. Herein, we demonstrate an enteric micromotor system capable of precise positioning and controllable retention in desired segments of the GI tract. These motors, consisting of magnesium-based tubular micromotors coated with an enteric polymer layer, act as a robust nanobiotechnology tool for site-specific GI delivery. The micromotors can deliver payload to a particular location via dissolution of their enteric coating to activate their propulsion at the target site toward localized tissue penetration and retention.