Blood Circulation Time Research Articles

Polysarcosine-Coated liposomes attenuating immune response induction and prolonging blood circulation

HypothesisLiposomes coated with long polysarcosine (PSar) chains at a high density might enable long blood circulation and attenuate accelerated blood clearance (ABC) phenomenon. ExperimentsIn this study, we controlled the length (23, 45, 68 mers) and density (5, 10, 15 mol%) of PSar on liposomal coatings and, furthermore, investigated the effects of PSar length and density on the blood circulation time, biodistribution, immune response, and ABC phenomenon induction. Length-controlled PSar-bound lipids (PSar-PEs) were synthesized using a click reaction and inserted into bare liposomes at different combinations of chain lengths and proportions. FindingsAlthough all PSar-coated liposomes (PSar-lipos) had similar morphological, physical, and chemical properties, they had different blood circulation times and biodistribution, and exerted varied effects on the immune system. All PSar-lipos with different PSar length and density showed a similar anti-PSar IgM response. Liposomes modified with the longest PSar chain (68 mers) at a high density (15 mol%) showed the longest blood circulation time and, additionally, attenuated ABC phenomenon compared with PEG-lipo. The ex vivo analysis of the biodistribution of liposomes revealed that a thick PSar layer enhanced the blood circulation time of liposomes due to the reduction of the accumulation of liposomes in the liver and spleen. These findings provide new insights into the relationship between IgM expression and ABC phenomenon inhibition.

A near-infrared bacteriochlorin nanomedicine for enhanced photodynamic therapy

Photodynamic therapy (PDT) is a greatly promising treatment for cancers due to non-invasiveness and low biotoxicity, but its efficacy is limited by poor water solubility, low selectivity, and short therapeutic wavelength of photosensitizers (PSs). Herein, we construct a near-infrared (NIR) nanomedicine (PEO-PDLA@FBC) by co-assembly of tetrafluorophenyl bacteriochlorin (FBC) with an amphiphilic block copolymer (PEO-b-PDLA). The hydrophobic FBC PS can realize the long blood circulation time by the formation of nano-assemblies, which is conducive to the efficient accumulation of the nanomedicine in tumor. Meanwhile, PEO-PDLA@FBC achieves deeper tissue penetration and higher singlet oxygen generation capability than the control (PEO-PDLA@HP) formed by clinically approved PS hematoporphyrin (HP). Based on the results of in vitro and in vivo experiments, PEO-PDLA@FBC demonstrates superior phototoxicity and anti-tumor efficacy, respectively. Moreover, PEO-PDLA@FBC has almost no side effects and toxicity to normal tissues. Therefore, PEO-PDLA@FBC would be a promising nanomedicine for the clinical PDT.

Protein corona formation on lipidic nanocapsules: Influence of the interfacial PEG repartition

The parameters currently used for characterization of nanoparticles, such as size and zeta potential, were not able to reflect the performance of a nanocarrier in the biological environment. Therefore, more thorough in vitro characterization is required to predict their behavior in vivo, where nanoparticles acquire a new biological identity due to interactions with biomolecules. In this present study, we performed in vitro characterization in biological fluids for lipid nanocapsules (LNCs) with varying means sizes (50 nm and 100 nm), different electrical surface charges and different Poly Ethylene Glycol (PEG) compositions. Then, different methods were applied to show the impact of the protein corona formation on LNCs. Even if all formulations attached to plasmatic proteins, a higher thickness of corona and highest protein binding was observed for certain LNC50 formulations. A better knowledge of the phenomenon of protein adsorption over NPs in the plasmatic media is a cornerstone of clinical translation. In fact, after short blood circulation time, it is not the initially designed nanoparticle but the complex nanoparticle bearing its protein corona which circulates to reach its target.

Oxygen-Generating Organic/Inorganic Self-Assembled Nanocolloids for Tumor-Activated Dual-Model Imaging-Guided Photodynamic Therapy.

Tumor phototheranostics is usually compromised by the hypoxic tumor microenvironment and poor theranostic efficiency. The interplay between organic polymers and inorganic nanoparticles in novel nanocomposites has proven to be advantageous, overcoming previous limitations and harnessing their full potential through activation via the tumor microenvironment. This study successfully fabricated hypoxia-activated nanocolloids called HOISNDs through a process of self-assembly involving superparamagnetic iron oxide nanoparticles (SPIONs) and an organic polymer ligand called tetrakis(4-carboxyphenyl) porphyrin (TCPP)-engineered organic polymer ligand [methoxy poly(ethyleneglycol)-block-poly(dopamine-ethylenediamine-conjugated-4-nitrobenzyl chloroformate)-l-glutamate, mPEG-b-P(Dopa-EDA-co-NBCF)LG-TCPP)]. The SPIONs act as an oxygen generator to overcome the challenges posed by hypoxic tumors and enable the use of hypoxic-activatable MR/fluorescence dual-modal imaging-guided photodynamic therapy (PDT). The colloid stability of these HOISNDs proved to be exceptional in diverse biomimetic environments. Furthermore, they not only augment T2-weighted contrast capability as an MRI contrast agent but also function as an oxygen-producing device to amplify the generation and release of reactive oxygen species (ROS). The HOISNDs can significantly target to tumor sites through the enhanced permeability and retention (EPR) effect with prolonged blood circulation time and subsequently are effectively endocytosed into a hypoxic intracellular environment that "turn on" the imaging function and photodynamic activity. Moreover, HOISNDs possess the ability to effectively decompose naturally occurring H2O2 into oxygen (O2) within the tumor utilizing the Fenton reaction. This method can mitigate the impact of hypoxia on oxygen-dependent PDT. The outcomes of in vivo diagnostic and therapeutic evaluations indicated that HOISNDs are a highly promising tool for dual-model imaging-guided cancer theranosis by ameliorating hypoxic conditions and augmenting PDT efficiency.

Transport by circulating myeloid cells drives liposomal accumulation in inflamed synovium.

The therapeutic potential of liposomes to deliver drugs into inflamed tissue is well documented. Liposomes are believed to largely transport drugs into inflamed joints by selective extravasation through endothelial gaps at the inflammatory sites, known as the enhanced permeation and retention effect. However, the potential of blood-circulating myeloid cells for the uptake and delivery of liposomes has been largely overlooked. Here we show that myeloid cells can transport liposomes to inflammatory sites in a collagen-induced arthritis model. It is shown that the selective depletion of the circulating myeloid cells reduces the accumulation of liposomes up to 50-60%, suggesting that myeloid-cell-mediated transport accounts for more than half of liposomal accumulation in inflamed regions. Although it is widely believed that PEGylation inhibits premature liposome clearance by the mononuclear phagocytic system, our data show that the long blood circulation times of PEGylated liposomes rather favours uptake by myeloid cells. This challenges the prevailing theory that synovial liposomal accumulation is primarily due to the enhanced permeation and retention effect and highlights the potential for other pathways of delivery in inflammatory diseases.

Aptamer-grafted, cell membrane-coated dendrimer loaded with doxorubicin as a targeted nanosystem against epithelial cellular adhesion molecule (EpCAM) for triple negative breast cancer therapy

The major issue associated with chemotherapeutics is the non-specific distribution, extended range of toxicity, and low intratumoral accumulation. Targeted therapy using aptamers could be a ground-breaking approach in cancer treatment. Poly(amidoamine) PAMAM dendrimers are a type of nanocarriers with a well-defined structure, higher encapsulation efficiency and modification surface groups. However, the toxicity of cationic dendrimers and non-targetability poses a great risk to patients' health. Considering this, we developed a EpCAM aptamer-functionalized, red blood cell (RBC) membrane-camouflaged PAMAM dendrimer loaded with doxorubicin to selectively target EpCAM-positive triple-negative breast cancer (TNBC) cells. An increase in size of doxorubicin (Dox) loaded PAMAM was observed from 11.34 nm to 108.4 nm post coating with RBC membrane and aptamer, respectively. The biocompatibility and blood circulation time were enhanced by the coating of the RBC membrane on the surface of the dendrimers while functionalization with aptamers improved its cancer cell internalization. The results obtained suggested that the coating with RBC provided controlled and sustained release during the 140 h of study. In vitro cell viability study showed enhanced apoptosis and significantly elevated uptake by the cancer cells as compared with the non-targeted preparation. Furthermore, the volume of the tumor was significantly reduced in groups treated with aptamer-modified, cell membrane-coated dendrimer due to selective internalization in the cancer cells only. This novel, personalized, and targeted therapy could be a potent platform for TNBC therapy.

Polyphosphazene nanodrugs for targeting delivery and inflammation responsive release of curcumin to treat acute lung injury by effectively inhibiting cytokine storms

An excessive inflammatory response induced by cytokine storms is the primary reason for the deterioration of patients with acute lung injury (ALI). Though natural polyphenols such as curcumin (CUR) have anti-inflammation activity for ALI treatment, they often have limited efficacy due to their poor solubility in water and oxidising tendency. This study investigates a highly cross-linked polyphosphazene nano-drug (PHCH) developed by copolymerisation of CUR and acid-sensitive units (4-hydroxy-benzoic acid (4-hydroxy-benzylidene)-hydrazide, D-HBD) with hexachlorotripolyphosphonitrile (HCCP) for improved treatment of ALI. PHCH can prolong the blood circulation time and targeted delivery into lung inflammation sites by enhancing CUR's water dispersion and anti-oxidant properties. PHCH also demonstrates the inflammation-responsive release of CUR in an inflammation environment due to the acid-responsive degradation of hydrazine bonds and triphosphonitrile rings in PHCH. Therefore, PHCH has a substantial anti-inflammation activity for ALI treatment by synergistically improving CUR's water-solubility, bioavailability and biocompatibility. As expected, PHCH attenuates the cytokine storm syndrome and alleviates inflammation in the infected cells and tissues by down-regulating several critical inflammatory cytokines (TNF-α, IL-1β, and IL-8). PHCH also decreases the expression of p-p65 and C-Caspase-1, inhibiting NLRP3 inflammasomes and suppressing NF-κB signalling pathways. The administrated mice experiments confirmed that PHCH accumulation was enhanced in lung tissue and showed the efficient scavenging ability of reactive oxygen species (ROS), effectively blocking the cytokine storm and alleviating inflammatory damage in ALI. This smart polyphosphazene nano-drug with targeting delivery property and inflammation-responsive release of curcumin has excellent potential for the clinical treatment of various inflammatory diseases, including ALI.

Research Progress of Neutrophil-Mediated Drug Delivery Strategies for Inflammation-Related Disease.

As the most abundant white blood cells in humans, neutrophils play a key role in acute and chronic inflammation, suggesting that these cells are a key component of targeted therapies for various inflammation-related diseases. Specific enzyme-responsive or specific ligand-modified polymer nanoparticles are beneficial for improving drug efficacy, reducing toxicity, and enhancing focal site retention. However, there remain significant challenges in biomedical applications of these synthetic polymer nanoparticles, mainly due to their rapid clearance by the reticuloendothelial system. In recent years, biomimetic drug delivery systems such as neutrophils acting directly as drug carriers or neutrophil-membrane-coated nanoparticles have received increasing attention due to the natural advantages of neutrophils. Thus, neutrophil-targeted, neutrophil-assisted, or neutrophil-coated nanoparticles exhibit a prolonged blood circulation time and improved accumulation at the site of inflammation. Despite recent advancements, further clinical research must be performed to evaluate neutrophil-based delivery systems for future biomedical application in the diagnosis and treatment of related inflammatory diseases. In this review, we have summarized new exciting developments and challenges in neutrophil-mediated drug delivery strategies for treating inflammation-related diseases.

Formulation and Evaluation of PLGA Nanoparticulate-Based Microneedle System for Potential Treatment of Neurological Diseases.

The tight structure of the blood-brain barrier severely limits the level of drug therapy for central nervous system disorders. In this study, a novel composite delivery system combining nanocarrier and microneedle technology was prepared to explore the possibility of transdermal delivery of drugs to work in the brain. Nanoparticle solutions containing paroxetine and rhodamine-B were prepared using PLGA as a carrier by the emulsification-solvent volatilization method. Then, they were mixed with hyaluronic acid and the PLGA nanoparticulate-based microneedle system (Rh-NPs-DMNs) was prepared by a multi-step decompression-free diffusion method. The particle size, zeta potential, and micromorphology of the nano solution were measured; the appearance, mechanical strength, dissolution properties, and puncture effect of the Rh-NPs-DMNs were evaluated; also, it was evaluated for in vivo live imaging properties and in vitro skin layer transport and distribution properties. The mean particle size of Rh-NPs was 96.25 ± 2.26 nm; zeta potential of 15.89 ± 1.97 mV; PDI of 0.120 ± 0.079. Rh-NPs-DMNs had a high needle content of 96.11 ± 1.27% and a tip height of 651.23 ± 1.28 μm, with excellent mechanical properties (fracture force of 299.78 ± 1.74 N). H&E skin tissue staining showed that Rh-NPs-DMNs produced micron-sized mechanical pores approximately 550 μm deep immediately after drug administration, allowing for efficient circulation of the drug; and the results of in vivo imaging showed that Rh-B NPs DMNs had a faster transport rate than Rh-B DMNs, with strong fluorescent signals in both brain (P<0.01) and hippocampus (P<0.05) 48 h after drug administration. Nanoparticles can prolong blood circulation time and intracerebral retention time and have certain brain-targeting properties due to their excellent physical properties. The use of microneedle technology combined with nanocarriers provides new ideas for delivery systems for the treatment of central neurological diseases.

Identification of the Proteins Determining the Blood Circulation Time of Nanoparticles.

The therapeutic efficacy and adverse impacts of nanoparticles (NPs) are strongly dependent on their systemic circulation time. The corona proteins adsorbed on the NPs determine their plasma half-lives, and hence, it is crucial to identify the proteins shortening or extending their circulation time. In this work, the in vivo circulation time and corona composition of superparamagnetic iron oxide nanoparticles (SPIONs) with different surface charges/chemistries were analyzed over time. SPIONs with neutral and positive charges showed the longest and shortest circulation times, respectively. The most striking observation was that corona-coated NPs with similar opsonin/dysopsonin content showed different circulation times, implying these biomolecules are not the only contributing factors. Long-circulating NPs adsorb higher concentrations of osteopontin, lipoprotein lipase, coagulation factor VII, matrix Gla protein, secreted phosphoprotein 24, alpha-2-HS-glycoprotein, and apolipoprotein C-I, while short-circulating NPs adsorb higher amounts of hemoglobin. Therefore, these proteins may be considered to be determining factors governing the NP systemic circulation time.

The D-amino acid oxidase-carbon nanotubes: evaluation of cytotoxicity and biocompatibility of a potential anticancer nanosystem

The ‘enzyme prodrug therapy’ represents a promising strategy to overcome limitations of current cancer treatments by the systemic administration of prodrugs, converted by a foreign enzyme into an active anticancer compound directly in tumor sites. One example is D-amino acid oxidase (DAAO), a dimeric flavoenzyme able to catalyze the oxidative deamination of D-amino acids with production of hydrogen peroxide, a reactive oxygen species (ROS), able to favor cancer cells death. A DAAO variant containing five aminoacidic substitutions (mDAAO) was demonstrated to possess a better therapeutic efficacy under low O2 concentration than wild-type DAAO (wtDAAO). Recently, aiming to design promising nanocarriers for DAAO, multi-walled carbon nanotubes (MWCNTs) were functionalized with polyethylene glycol (PEG) to reduce their tendency to aggregation and to improve their biocompatibility. Here, wtDAAO and mDAAO were adsorbed on PEGylated MWCNTs and their activity and cytotoxicity were tested. While PEG-MWCNTs-DAAOs have shown a higher activity than pristine MWCNTs-DAAO (independently on the DAAO variant used), PEG-MWCNTs-mDAAO showed a higher cytotoxicity than PEG-MWCNTs-wtDAAO at low O2 concentration. In order to evaluate the nanocarriers’ biocompatibility, PEG-MWCNTs-DAAOs were incubated in human serum and the composition of protein corona was investigated via nLC-MS/MS, aiming to characterize both soft and hard coronas. The mDAAO variant has influenced the bio-corona composition in both number of proteins and presence of opsonins and dysopsonins: notably, the soft corona of PEG-MWCNTs-mDAAO contained less proteins and was more enriched in proteins able to inhibit the immune response than PEG-MWCNTs-wtDAAO. Considering the obtained results, the PEGylated MWCNTs conjugated with the mDAAO variant seems a promising candidate for a selective antitumor oxidative therapy: under anoxic-like conditions, this novel drug delivery system showed a remarkable cytotoxic effect controlled by the substrate addition, against different tumor cell lines, and a bio-corona composition devoted to prolong its blood circulation time, thus improving the drug’s biodistribution.

Bavachinin selectively modulates PPAR γ and maintains bone homeostasis in Type 2 Diabetes.

Full peroxisome proliferator-activated receptor (PPAR) γ agonists, Thiazolidinediones (TZDs), effectively prevent the process of Type 2 Diabetes Mellitus (T2DM), but their side effects have curtailed use in the clinic, including weight gain and bone loss. Here, we identified that a selective PPAR γ modulator, Bavachinin (BVC), isolated from the seeds of Psoralea Corylifolia L., could potently regulate bone homeostasis. MC3T3-E1 pre-osteoblast cells and C3H10T1/2 mesenchymal stem cells were assessed for osteogenic differentiation activities, and receptor activator of NF-κB ligand (RANKL)-induced RAW 264.7 cells were assessed osteoclasts formation. Leptin receptor-deficient mice and diet-induced obesity mice were applied to evaluate the effect of BVC on bone homeostasis in vivo. Compared to full PPAR γ agonist rosiglitazone, BVC significantly increased the osteogenesis differentiation activities under normal and high glucose conditions in MC3T3-E1 cells. Moreover, BVC could alleviate osteoclast differentiation in RANKL-induced RAW 264.7 cells. In vivo, synthesized BVC prodrug (BN) has been applied to improve water solubility, increase the extent of oral absorption of BVC and prolong its residence time in blood circulation. BN could prevent weight gain, ameliorate lipid metabolism disorders, improve insulin sensitivity, and maintain bone mass and bone biomechanical properties. BVC, a unique PPAR γ selective modulator, could maintain bone homeostasis, and its prodrug (BN) exhibits insulin sensitizer activity while circumventing the side effects of the TZDs, including bone loss and undesirable weight gain.

Preclinical evaluation of PEG-Multiwalled carbon nanotubes: Radiolabeling, biodistribution and toxicity in mice

Multiwalled carbon nanotubes (MWCNTs) have been integrated into many recent biomedical studies since their cylindrical architecture, high aspect ratio, and specific functionalization could allow carbon nanotubes (CNTs) to penetrate into the cells through the plasma membrane. However, one of the main challenges in the in vivo applications of these nanoparticles is their reduced biocompatibility and poor dispersibility. Furthermore, even today, there are still some knowledge gaps concerning CNTs toxicity and their behavior considering in vivo tumor-bearing mice models. In this sense, herein, polyethylene glycol chains were covalently bound to MWCNTs (PEG-MWCNTs) through an aliphatic nucleophilic substitution chemical reaction and radiolabeled with [99 mTc]Tc, yielding a high radiochemical rate. The physicochemical characterization procedures showed that the PEG chains were successfully covalently attached to the MWCNT surface. Biodistribution studies were carried out in tumor-bearing mice, and the results revealed that a produced system displays prolonged blood circulation time and relevant tumor uptake rates. Toxicological data were obtained from testing on healthy animals, and the data obtained revealed that PEG-MWCNTs did not induce an important toxicity profile. Considering all the results obtained in this work, the PEG-coated MWCNTs can be considered a potential candidate for future oncologic applications.

“Y-type” PEG modified liposomes could eliminate the accelerated blood clearance (ABC) phenomenon and improved tumor therapy

Poly(ethylene glycol) (PEG) is widely applied to decorate nanocarriers due to its “long circulation” characteristics. However, the applications of linear PEG-modified nanocarriers have been hindered by severe adverse effects due to the accelerated blood clearance (ABC) phenomenon. It was universally known that anti-PEG antibodies (APAs) were main culprits in ABC phenomenon which induced the significant change in pharmacokinetics, biological distributions of the second injection and triggered complement activation-related pseudoallergies (CARPA). Recent studies have illustrated that APAs triggered the ABC phenomenon of PEGylated protein drug and even related to the CARPA of COVID-19 vaccine. Therefore, it is urgent to inhibit the generation of APAs and eliminate the ABC phenomenon. Here, “Y-type” PEG was chosen to replace linear PEG due to its weak immunogenicity. “Y-type” PEG-lipid derivatives [DSPE-mPEG2,n (n = 2, 10, and 20 kDa)]-modified doxorubicin liposomes (DOX-PL2,n) and topotecan liposomes (TP-PL2,n) induced lower levels of APAs and could avoid activating complement system. In further research, we found that liposomes decorated with DSPE-mPEG2,n could avoid the ABC phenomenon after duplicate injections. Furthermore, pharmacodynamic tests indicated that DOX-PL2,n and TP-PL2,n improved the curative effect of S180 tumor than DOX-PL2k and TP-PL2k (linear PEGylated liposomes). For the first time, DOX-PL2,n and TP-PL2,n were used for in vivo pharmacokinetic and pharmacodynamic experiments. Liposomes ornamented with “Y-type” PEG may provide new approaches to maintaining long blood circulation time, eliminating the ABC phenomenon of encapsulated active compounds, and also could weaken CARPA and improve tumor therapeutic effect. Our research aims to promote the research and development of “Y-type” PEG-decorated nanocarriers and provide a substantial academic basis for its clinical application.

Functional Ligand-Enabled Particle Assembly for Bio-Nano Interactions.

ConspectusFunctional ligands consist of a wide range of small or large molecules that exhibit a spectrum of physical, chemical, and biological properties. A suite of small molecules (e.g., peptides) or macromolecular ligands (e.g., antibodies and polymers) have been conjugated to particle surfaces for specific applications. However, postfunctionalization of ligands often presents challenges in controlling the surface density and may require the chemical modification of ligands. As an alternative option to postfunctionalization, our work has focused on using functional ligands as building blocks to assemble particles while maintaining their intrinsic (functional) properties. Through self-assembly or template-mediated assembly strategies, we have developed a range of protein-, peptide-, DNA-, polyphenol-, glycogen-, and polymer-based particles. This Account discusses the assembly of such nanoengineered particles, which includes self-assembled nanoparticles, hollow capsules, replica particles, and core-shell particles, according to three categories of functional ligands (i.e., small molecules, polymers, and biomacromolecules) that are used as building blocks for their formation. We discuss a range of covalent and noncovalent interactions among ligand molecules that have been explored to facilitate the assembly of particles. The physicochemical properties of the particles, including size, shape, surface charge, permeability, stability, thickness, stiffness, and stimuli-responsiveness, can be readily controlled by varying the ligand building block or by tuning the assembly method. By selecting specific ligands as building blocks, the bio-nano interactions (i.e., stealth, targeting, and cell trafficking) can also be modulated. For instance, particles composed mainly of low-fouling polymers (i.e., poly(ethylene glycol)) exhibit an extended blood circulation time (half-life > 12 h), while antibody-based nanoparticles demonstrate that a trade-off between stealth and targeting may be required when designing targeting nanoparticle systems. Small molecular ligands, such as polyphenols, have been used as building blocks for particle assembly as they can interact with various biomacromolecules through multiple noncovalent interactions, retain the function of biomacromolecules within the assembly, enable pH-responsive disassembly when coordinating with metal ions, and facilitate endosomal escape of nanoparticles. A perspective is provided on the current challenges associated with the clinical translation of ligand-based nanoparticles. This Account is also expected to serve as a reference to guide the fundamental research and development of functional particle systems assembled from various ligands for diverse applications.

Development of Edaravone Ionic Liquids and Their Application for the Treatment of Cerebral Ischemia/Reperfusion Injury.

Preparation of the ionic liquid (IL) form of active pharmaceutical ingredients (APIs), termed API-IL, has attracted attention because it can improve upon certain disadvantages of APIs, such as poor water solubility and low stability. Edaravone (3-methyl-1-phenyl-2-pyrazolin-5-one) is a clinically approved cerebroprotective agent against ischemic stroke and amyotrophic lateral sclerosis, while new formulations that enable improvement of its physicochemical properties and biodistribution are desired. Herein, we report a newly developed API-IL of edaravone (edaravone-IL), in which edaravone is used as an anionic molecule. We investigated the physicochemical properties of edaravone-IL and its therapeutic effect against cerebral ischemia/reperfusion (I/R) injury, a secondary injury after an ischemic stroke. Among the cationic molecules used for edaravone-IL preparation, the IL prepared with tetrabutylphosphonium cation existed as a liquid at room temperature, and significantly increased the water solubility of edaravone without decreasing its antioxidative activity. Importantly, edaravone-IL formed negatively charged nanoparticles upon suspension in water. Intravenous administration of edaravone-IL showed significantly higher blood circulation time and lower distribution in the kidney compared with edaravone solution. Moreover, edaravone-IL significantly suppressed brain cell damage and motor functional deficits in model rats of cerebral I/R injury and showed comparable cerebroprotective effect to edaravone. Taken together, these results suggest that edaravone-IL could be a new form of edaravone with superior physicochemical properties and could be useful for the treatment of cerebral I/R injury.

Recent Developments of Inorganic Nano-sensitizers for Sonodynamic Therapy.

As a noninvasive treatment, sonodynamic therapy (SDT) has been widely used in the treatment of tumors because of its ability to penetrate deep tissue with few side effects. As the key factor of SDT, it is meaningful to design and synthesize efficient sonosensitizers. Compared with organic sonosensitizers, inorganic sonosensitizers can be easily excited by ultrasound. In addition, inorganic sonosensitizers with stable properties, good dispersion, and long blood circulation time, have great development potential in SDT. This review summarizes possible mechanisms of SDT (sono-excitation and ultrasonic cavitation) in detail. Based on these mechanisms, the design and synthesis of inorganic nano sonosensitizers can be divided into three categories: traditional inorganic semiconductor sonosensitizers, enhanced inorganic semiconductor sonosensitizers, and cavitation-enhanced sonosensitizers. Subsequently, the current efficient construction methods of sonosensitizers are summarized including accelerated semiconductor charge separation and enhanced production of reactive oxygen species through ultrasonic cavitation. Furthermore, we systematically discuss the advantages and disadvantages of different inorganic sonosensitizers and detailed strategies on how to enhance SDT. Hopefully, this review could provide new insights into the design and synthesis of efficient inorganic nano-sonosensitizers for SDT. This article is protected by copyright. All rights reserved.

A cascade-responsive nanoplatform with tumor cell-specific drug burst release for chemotherapy.

Most of the nanomedicines can reduce the side effects of anti-tumor chemical drugs but do not have good enough therapeutic efficacy, largely due to the sustained drug release profile. It might be a promising alternative strategy to develop a cascade-responsive nanoplatform against tumor with the burst release of chemotherapeutics based on the highly efficient tumor cell targeting delivery. In this work, we constructed innovative nanoparticles (PMP/WPH-NPs) consisting of two functional polymers. PMP contained the MMP-2 enzyme sensitive linker and disulfide bond, which could respond to the tumor-overexpressing enzyme MMP-2 and high-level glutathione. While WPH promoted tumor penetration and acid-responsive drug release by modifying cellular penetrating peptides and polymerizing L-histidine. PMP/WPH-NPs exhibited outstanding features including longer blood circulation time, promoted tumor-specific accumulation, enhanced tumor penetration and efficient escape from lysosomes. Subsequently, the model drug paclitaxel (PTX), widely used in the tumor chemotherapy, was encapsulated into PMP/WPH-NPs via an emulsion solvent evaporation method. Within a short period of time, PTX-PMP/WPH-NP in simulated tumor cellular microenvironment could release 8 times more PTX than that in the physiological environment, demonstrating a good potential in tumor cell-specific burst drug release. In addition, PTX-PMP/WPH-NPs exhibited stronger anti-tumor activity than PTX in vitro and in vivo, which also had good biocompatibility according to the hemolysis assay and H&E staining. In summary, our work has succeeded in designing an original polymeric nanoplatform for programmed burst drug release based on the tailored tumor targeting delivery system. This new approach would facilitate the clinical translation of more anti-tumor nanomedicines. STATEMENT OF SIGNIFICANCE: Biomaterials responsive to the tumor-specific stimulus has conventionally used in the targeted-delivery of anti-tumor drugs. However, the levels of common stimulus are not uniformly distributed and not high enough to effectively trigger drug release. In an effort to achieve a better specific drug release and promote the chemotherapeutic efficacy, we constructed a cascade responsive nanoplatform with tumor cell-specific drug burst release profile. The tailored biomaterial could overcome the bio-barriers in vivo and succeeded in the programmed burst drug release based on the tumor cell-specific delivery of chemotherapeutics.

Metal-Organic Framework in Pharmaceutical Drug Delivery.

Metal-organic frameworks (MOFs) are porous, crystalline materials made up of organic ligands and metal ions/metal clusters linked by coordinative bonds. This large family is becoming increasingly popular for drug delivery due to their tuneable porosity, chemical composition, size and shape, and ease of surface functionalization. There has been a growing interest over the last decades in the design of engineered MOFs with controlled sizes for a variety of biomedical applications. Starting with the MOFs classification adapted for drug delivery systems (DDSs) based on the types of constituting metals and ligands. MOFs are appealing drug delivery vehicles because of their substantial drug absorption capacity and slow-release processes, which protect and convey sensitive drug molecules to target areas. Other guest materials have been incorporated into MOFs to create MOF-composite materials, which have added additional functionalities such as externally triggered drug release, improved pharmacokinetics, and diagnostic aids. Magnetic nanoparticles in MOFs for MRI image contrast and polymer coatings that increase blood circulation time are examples of synthetically adaptable MOF-composites. By including photosensitizers, which exert lethal effects on cancer cells by converting tumour oxygen into reactive singlet oxygen (1O2), metalorganic frameworks have been employed for photodynamic treatment (PDT) of malignancies among a multitude of nanosized therapies. Importantly, a variety of representative MOF applications are described from the perspectives of pharmaceutics, disease therapy, and advanced drug delivery systems. However, because of their weak conductivity, selectivity, and lack of modification sites, MOF materials' uses in electrochemical biosensing are restricted. MOF-based composites provide excellent electrical conductivity and robust catalytic activity by adding functionalized nanoparticles into MOF structures, which process benefits over single component MOFs.

Erythrocytes Nanoparticle Delivery: A Boon for Targeting Tumor.

Although nanoparticles (NPs) have many advantages as drug delivery systems, their poor stability in circulation, premature drug release, and nonspecific uptake in non-target organs have prompted biomimetic approaches to camouflage nano vehicles using natural cell membranes. Among them, which are extensively studied in erythrocytes, are the most abundant circulating blood cells. They are specially used for biomimetic coating on artificial NPs due to their excellent properties of good biocompatibility, biodegradability, non-immunogenicity, and long-term blood circulation. Erythrocyte-mimicking nanoparticles (EM-NPs) are prepared by combining nanoparticle cores with naturally derived erythrocyte (red blood cell or RBC) membranes. Compared with conventional nanosystems, EM-NPs hold the preferable characteristics of prolonged blood circulation time and immune evasion. In this review, the biomimetic platform of erythrocyte membrane-coated NPs is described in various aspects, with particular focus placed on the coating mechanism, preparation methods, characterization method, and recent advances in the biomedical applications of EM-NPs concerning cancer and targeted delivery.