Nanomaterial-related hemoglobin-based oxygen carriers, with emphasis on liposome and nano-capsules, for biomedical applications: current status and future perspectives.

Oxygen is necessary for life and plays a key pivotal in maintaining normal physiological functions and treat of diseases. Hemoglobin-based oxygen carriers (HBOCs) have been studied and developed as a replacement for red blood cells (RBCs) in oxygen transport due to their similar oxygen-carrying capacities. However, applications of HBOCs are hindered by vasoactivity, oxidative toxicity, and a relatively short circulatory half-life. With advancements in nanotechnology, Hb encapsulation, absorption, bioconjugation, entrapment, and attachment to nanomaterials have been used to prepare nanomaterial-related HBOCs to address these challenges and pend their application in several biomedical and therapeutic contexts. This review focuses on the progress of this class of nanomaterial-related HBOCs in the fields of hemorrhagic shock, ischemic stroke, cancer, and wound healing, and speculates on future research directions. The advancements in nanomaterial-related HBOCs are expected to lead significant breakthroughs in blood substitutes, enabling their widespread use in the treatment of clinical diseases.

Bioinspired Polydopamine-Coated Hemoglobin as Potential Oxygen Carrier with Antioxidant Properties.

Oxidative side reaction is one of the major factors hindering the development of hemoglobin-based oxygen carriers (HBOCs). To avoid the oxidative toxicity, we designed and synthesized polydopamine-coated hemoglobin (Hb-PDA) nanoparticles via simple one-step assemblage without any toxic reagent. Hb-PDA nanoparticles showed oxidative protection of Hb by inhibiting the generation of methemoglobin (MetHb) and ferryl (Fe IV) Hb, as well as excellent antioxidant properties by scavenging free radicals and reactive oxygen species (ROS). Interestingly, the scavenging rate of Hb-PDA nanoparticles for ABTS+ radical is at most 89%, while for DPPH radical it reaches 49%. In addition, Hb-PDA efficiently reduced the intracellular H2O2-induced ROS generation. Moreover, Hb-PDA nanoparticles exhibited high oxygen affinity, low effect on blood constituents, and low cytotoxicity. The results indicate that polydopamine-coated hemoglobin might be a promising approach for constructing novel oxygen carriers with the capacity to reduce oxidative side reaction.

[Yimusake Tablet: safe and efficacious for premature ejaculation].

OBJECTIVE: To objectively evaluate the efficacy and safety of Yimusake Tablet in the treatment of premature ejaculation (PE) through a multi-centered large-sample trial. METHODS: We conducted a multi-centered, open, fixed-dose, and self-compared clinical trial among 300 patients with diagnosed PE. The trial lasted 12 weeks, including 4 weeks without any medication and 8 weeks of treatment with Yimusake Tablet, 2 pills (1 g) per night. We observed the intravaginal ejaculation latency time (IELT) before and after treatment, evaluated the safety of medication, and performed a questionnaire investigation on the patients' satisfaction. RESULTS: Of the 300 PE patients, 288 accomplished the clinical trial. The patients ranged in age from 22 to 60 years, averaging at 31.6 years. The mean IELT of the patient was 62.5 seconds at baseline, 168.9 seconds after 4 weeks of treatment with Yimusake Tablet, and 222.2 seconds after 8 weeks of medication. Among the 157 patients with normal erectile function (IIEF >21), the mean IELT was 71.4 seconds before treatment, 147.4 seconds after 4 weeks of medication, and 172.5 seconds after 8 weeks of medication. The patients' satisfaction was significantly increased after treatment. Those complicated by mild to moderate erectile dysfunction achieved different degrees of improvement in the IIEF-5 score, with a mean increase of 3.8. Only a few patients experienced mild adverse events, including constipation, dry mouth, nose bleeding, abdominal pain, and lumbosacral pain, which were all relieved without drug withdrawal. CONCLUSION: Yimusake Tablet is a safe and effective medicine for the treatment of PE.

Polydopamine-based surface modification of hemoglobin particles for stability enhancement of oxygen carriers.

Templated assembly techniques have been extensively used to develop various types of hemoglobin (Hb) loaded particles with improved performance. However, several instability issues must still be solved, including Hb exposure, enhanced Hb auto-oxidation, and the relatively weak binding of Hb to cross-linkers. Herein, to meet the stability requirements for novel hemoglobin-based oxygen carriers (HBOCs), hemoglobin-polydopamine particles (Hb-PDA) were fabricated using a mild process that combines the co-precipitation of Hb and an inorganic template with the spontaneous adhesion of PDA. The Hb-PDA showed uniform size distribution, chemical integrity of both Hb and PDA, high biocompatibility, and robust oxygen delivery. Our results demonstrated that the use of polydopamine as a biocompatible coating material reduced Hb leakage from the particles under both static and flow conditions, thus mitigating the toxicity associated with free Hb and strengthening the stability of Hb particles. In addition, Hb-PDA reduced HUVEC (Human Umbilical Vein Cells) oxidative injury and scavenged 85% of the available hydroxyl radicals, exhibiting its potential to act as an antioxidant for encapsulated Hb. Hb-PDA therefore shows significant promise as a cell-like structurally and functionally stable HBOCs.

Characterization and Biosafety Evaluation of Hemoglobin-Based Oxygen Carriers Coated with Polydopamine.

Hemoglobin-polydopamine particles (Hb-PDA) have shown high stability, with polydopamine (PDA) serving as a protective layer and antioxidant. However, the effects of the PDA coating on the properties and in vivo biosafety of Hb-PDA remain unclear. This work was conducted to characterize Hb-PDA and evaluate its biosafety. Hb-PDA exhibited negative surface charge and their infusion did not cause blood immunotoxicity or significant tissue injury. Hb-PDA were not phagocyted after co-incubation with macrophages for 3 h. Moreover, the particles showed the highest accumulation in the lungs, and a prolonged retention in major organs. It was also found that the particles were cleared by macrophages in splenic tissue and Kupffer cells in hepatic tissue. In summary, this research showed that Hb-PDA has high dispersion stability, low in vivo toxicity, and extended retention, illustrating its potency as a biosafe oxygen carrier.

Clinical significance of 4 patients with chronic hepatitis B achieving HBsAg clearance by treated with pegylated interferon alpha-2a for less than 1 year: a short report.

We report 4 chinese patients with hepatitis B e antigen-positive chronic hepatitis B achieving clearance of HBsAg by using pegylated interferon alpha-2a for less than 1 year, to provide one clinical clue for the treatment of chronic hepatitis B.

Improved flowing behaviour and gas exchange of stored red blood cells by a compound porous structure.

Storage lesions in red blood cells (RBCs) hinder efficient circulation and tissue oxygenation. The absence of flow mechanics and gas exchange may contribute to this problem. To test if in vitro compensation of flow mechanics and gas exchange helps RBC recovery, three-dimensional polydimethylsiloxane (PDMS) porous structures were fabricated with a sugar mould, simulating lung alveoli. RBC suspensions were passed through the porous structure cyclically, simulating in vivo blood circulation. Acid-base indices, partial gas pressures, ions, glucose and RBC indices were analyzed. An atomic force microscope was used to investigate local mechanical properties of intact RBCs. RBCs suspensions that passed through the porous structures had a higher pH and oxygen partial pressure, and a lower potassium concentration and carbon dioxide partial pressure. Meantime they had better biochemical properties relative to static samples, namely, they exhibited a more homogenous distribution of Young's Modulus. RBCs that passed through a PDMS porous structure were healthier than static ones, giving hints to prevent RBC storage lesions.

Antioxidative protection of haemoglobin microparticles (HbMPs) by PolyDopamine.

Clinically applicable haemoglobin-based oxygen carriers (HBOCs) should neither induce immunological nor toxic reactions. Additionally, Hb should be protected against oxidation. In the absence of protective enzymes (superoxide dismutase (SOD) and catalase (CAT)) Hb is oxidized to MetHb and thus losing its function of oxygen delivery. Alternatively, polydopamine (PD), a scavenger of free radicals, could be used for Hb protection against oxidation Therefore, we synthetized HbMPs modified with PD. The content of functional haemoglobin in these PD-HbMPs was twice higher than that in the control HbMPs due to the protective antioxidant effect of PD. In addition, the PD-HbMPs exhibited a high scavenging activity of free radicals including H2O2 and excellent biocompatibility. In contrast to monomeric dopamine, which has been shown to produce toxic effects on neurons due to formation of H2O2, hydroxyl radicals and superoxide during the process of auto-oxidation, PD-HbMPs are not neurotoxic. Consequently, the results presented here suggest a great potential of PD-HbMPs as HBOCs.

Influence of polydopamine-mediated surface modification on oxygen-release capacity of haemoglobin-based oxygen carriers.

Oxidative toxicity has impeded the development of haemoglobin-based oxygen carriers (HBOCs) by causing methaemoglobin (MetHb) formation and inducing oxidative stress. In our previous work, polydopamine-coated haemoglobin (Hb-PDA) nanoparticles have been designed and synthesized with the capacity to reduce oxidative toxicity. In this investigation, the mass ratio of dopamine (DA) to haemoglobin (Hb) and the pH value are found to be the primary factors that influence preparation of Hb-PDA nanoparticles. X-ray photoelectron spectroscopy showed that the catechol groups of DA play a crucial role in the modification of Hb surface. Hb-PDA nanoparticles were found to exhibit oxidative protection from hydrogen peroxide (H2O2) and the change of mitochondrial membrane potential showed that the Hb-PDA nanoparticles reduced H2O2-induced apoptosis. It is demonstrated that modification of PDA could maintain the oxygen-release capacity of Hb. These findings confirm that Hb-PDA nanoparticles possess restrained oxidative toxicity and preserve oxygen-release capacity.

Reactive oxygen species-responsive polymeric nanoparticles for alleviating sepsis-induced acute liver injury in mice.

Sepsis-associated acute liver injury contributes to the pathogenesis of multiple organ dysfunction syndrome and is associated with increased mortality. Currently, no specific therapeutics for sepsis-associated liver injury are available. With excess levels of reactive oxygen species (ROS) being implicated as key players in sepsis-induced liver injury, we hypothesize that ROS-responsive nanoparticles (NPs) formed via the self-assembly of diblock copolymers of poly(ethylene glycol) (PEG) and poly(propylene sulfide) (PPS) may function as an effective drug delivery system for alleviating sepsis-induced liver injury by preferentially releasing drug molecules at the disease site. However, there are no reports available on the biocompatibility and effect of PEG-b-PPS-NPs in vivo. Herein, this platform was tested for delivering the promising antioxidant therapeutic molecule melatonin (Mel), which currently has limited therapeutic efficacy because of its poor pharmacokinetic properties. The mPEG-b-PPS-NPs efficiently encapsulated Mel using the oil-in-water emulsion technique and provided sustained, on-demand release that was modulated in vitro by the hydrogen peroxide concentration. Animal studies using a mouse model of sepsis-induced acute liver injury revealed that Mel-loaded mPEG-b-PPS-NPs are biocompatible and much more efficacious than an equivalent amount of free drug in attenuating oxidative stress, the inflammatory response, and subsequent liver injury. Accordingly, this work indicates that mPEG-b-PPS-NPs show potential as an ROS-mediated on-demand drug delivery system for improving Mel bioavailability and treating oxidative stress-associated diseases such as sepsis-induced acute liver injury.

A PEGylated bovine hemoglobin as a potent hemoglobin-based oxygen carrier.

Hemoglobin (Hb)-based oxygen carriers (HBOCs) have been used as blood substitutes in surgery medicine and oxygen therapeutics for ischemic stroke. As a potent HBOC, the PEGylated Hb has received much attention for its oxygen delivery and plasma expanding ability. Two PEGylated Hbs, Euro-Hb, and MP4 have been developed for clinical trials, using human adult hemoglobin (HbA) as the original substrate. However, HbA was obtained from outdated human blood and its quantity available from this source may not be sufficient for mass production of PEGylated HbA. In contrast, bovine Hb (bHb) has no quantity constraints for its ample resource. Thus, bHb is of potential to function as an alternative substrate to obtain a PEGylated bHb (bHb-PEG). bHb-PEG was prepared under the same reaction condition as HbA-PEG, using maleimide chemistry. The structural, functional, solution and physiological properties of bHb-PEG were determined and compared with those of HbA-PEG. bHb-PEG showed higher hydrodynamic volume, colloidal osmotic pressure, viscosity and P50 than HbA-PEG. The high P50 of bHb can partially compensate the PEGylation-induced perturbation in the R to T state transition of HbA. bHb-PEG was non-vasoactive and could efficiently recover the mean arterial pressure of mice suffering from hemorrhagic shock. Thus, bHb-PEG is expected to function as a potent HBOC for its high oxygen delivery and strong plasma expanding ability. © 2016 American Institute of Chemical Engineers Biotechnol. Prog., 33:252-260, 2017.