Journal articles on the topic 'Long-circulation drug carriers'

Recently, drug delivery using natural biological carriers has emerged as one of the most widely investigated topics of research. Erythrocytes, or red blood cells, can act as potential carriers for a wide variety of drugs, including anticancer, antibacterial, antiviral, and anti-inflammatory, along with various proteins, peptides, enzymes, and other macromolecules. The red blood cell-based nanocarrier systems, also called nanoerythrosomes, are nanovesicles poised with extraordinary features such as long blood circulation times, the ability to escape immune system, the ability to release the drug gradually, the protection of drugs from various endogenous factors, targeted and specified delivery of drugs, as well as possessing both therapeutic and diagnostic applications in various fields of biomedical sciences. Their journey over the last two decades is escalating with fast pace, ranging from in vivo to preclinical and clinical studies by encapsulating a number of drugs into these carriers. Being biomimetic nanoparticles, they have enhanced the stability profile of drugs and their excellent site-specific targeting ability makes them potential carrier systems in the diagnosis and therapy of wide variety of tumors including gliomas, lung cancers, breast cancers, colon cancers, gastric cancers, and other solid tumors. This review focuses on the most recent advancements in the field of nanoerythrosomes, as an excellent and promising nanoplatform for the novel drug delivery of various drugs particularly antineoplastic drugs along with their potential as a promising diagnostic tool for the identification of different tumors.

The possibility of targeted drug delivery to a specific tissue, organ, or cell has opened new promising avenues in treatment development. The technology of targeted delivery aims to create multifunctional carriers that are capable of long circulation in the patients organism and possess low toxicity at the same time. The surface of modern synthetic carriers has high structural similarity to the cell membrane, which, when combined with additional modifications, also promotes the transfer of biological properties in order to penetrate physiological barriers effectively. Along with artificial nanocages, further efforts have recently been devoted to research into extracellular vesicles that could serve as natural drug delivery vehicles. This review provides a detailed description of targeted delivery systems that employ lipid and lipid-like nanocages, as well as extracellular vesicles with a high level of biocompatibility, highlighting genetically encoded drug delivery vehicles.

Liposomes are highly advantageous platforms for drug delivery. To improve the colloidal stability and avoid rapid uptake by the mononuclear phagocytic system of conventional liposomes while controlling the release of encapsulated agents, modification of liposomes with well-designed polymers to modulate the physiological, particularly the interfacial properties of the drug carriers, has been intensively investigated. Briefly, polymers are incorporated into liposomes mainly using “grafting” or “coating”, defined according to the configuration of polymers at the surface. Polymer-modified liposomes preserve the advantages of liposomes as drug-delivery carriers and possess specific functionality from the polymers, such as long circulation, precise targeting, and stimulus-responsiveness, thereby resulting in improved pharmacokinetics, biodistribution, toxicity, and therapeutic efficacy. In this review, we summarize the progress in polymer-modified liposomes for drug delivery, focusing on the change in physiological properties of liposomes and factors influencing the overall therapeutic efficacy.

Aim: In the present work, folic acid-modified human serum albumin conjugated to cationic solid lipid nanoparticles were synthesized as nanocarriers of mitoxantrone for the treatment of breast cancer. Background: Dual-targeted drug delivery is a new drug dosing strategy that is frequently used to enhance the therapeutic efficacy of anticancer drugs. Objective: Dual targeting of the cancer cells was achieved by dual tagging of human serum albumin and folic acid on the surface of the lipid nanoparticles. Methods: The targeted drug-loaded nanocomplexes were synthesized and characterized using transmission electron microscopy along with photon-correlation and Fourier-transform infrared spectroscopic techniques. The anti-cancer activity of the nanocomplexes was screened against an in-vitro model of MCF-7 and MDA-MB-231 breast cancer cell lines to examine drug efficacy. Results: The entrapment efficiency and drug loading values for mitoxantrone were calculated to be 97 and 8.84%, respectively. The data from the drug release studies for the system indicated the release profile did not significantly change within a pH range of 5.5-7.4. The hemolysis ratio of the hybrid carrier was less than 5% even at the upper doses of 3 mg/mL, demonstrating its safety for intravenous injection with limited hemolysis and a long blood circulation time. Conclusion: The cell cytotoxicity results confirmed that the drug hybrid nanocomplex was more toxic to breast cancer cells compared with the free drug. Furthermore, the weakly cationic and small size particles prevented opsonin binding of nanocomplexes, improving blood circulation time and cancer tissue uptake.

Drug carriers based on polyelectrolyte microcapsules remotely controlled with an external magnetic field are a promising drug delivery system. However, the influence of capsule parameters on microcapsules’ behavior in vivo is still ambiguous and requires additional study. Here, we discuss how the processes occurring in the blood flow influence the circulation time of magnetic polyelectrolyte microcapsules in mouse blood after injection into the blood circulatory system and their interaction with different blood components, such as WBCs and RBCs. The investigation of microcapsules ranging in diameter 1–5.5 μm allowed us to reveal the dynamics of their filtration by vital organs, cytotoxicity, and hemotoxicity, which is dependent on their size, alongside the efficiency of their interaction with the magnetic field. Our results show that small capsules have a long circulation time and do not affect blood cells. In contrast, the injection of large 5.5 μm microcapsules leads to fast filtration from the blood flow, induces the inhibition of macrophage cell line proliferation after 48 h, and causes an increase in hemolysis, depending on the carrier concentration. The obtained results reveal the possible directions of fine-tuning microcapsule parameters, maximizing capsule payload without the side effects for the blood flow or the blood cells.

Nanoparticles are explored as drug carriers with the promise for the treatment of diseases to increase the efficacy and also reduce side effects sometimes seen with conventional drugs. To accomplish this goal, drugs are encapsulated in or conjugated to the nanocarriers and selectively delivered to their targets. Potential applications include immunization, the delivery of anti-cancer drugs to tumours, antibiotics to infections, targeting resistant bacteria, and delivery of therapeutic agents to the brain. Despite this great promise and potential, drug delivery systems have yet to be established, mainly due to their limitations in physical instability and rapid clearance by the host’s immune response. Recent interest has been taken in using red blood cells (RBC) as drug carriers due to their naturally long circulation time, flexible structure, and direct access to many target sites. This includes coating of nanoparticles with the membrane of red blood cells, and the fabrication and manipulation of liposomes made of the red blood cells’ cytoplasmic membrane. The properties of these erythrocyte liposomes, such as charge and elastic properties, can be tuned through the incorporation of synthetic lipids to optimize physical properties and the loading efficiency and retention of different drugs. Specificity can be established through the anchorage of antigens and antibodies in the liposomal membrane to achieve targeted delivery. Although still at an early stage, this erythrocyte-based platform shows first promising results in vitro and in animal studies. However, their full potential in terms of increased efficacy and side effect minimization still needs to be explored in vivo.

Cell-based drug delivery systems have shown tremendous advantages in cancer treatment due to their distinctive properties. For instance, delivery of therapeutics using tumor-tropic cells like neutrophils, lymphocytes and mesenchymal stem cells can achieve specific tumor targeting due to the “Trojan Horse” effect. Other circulatory cells like erythrocytes and platelets can greatly improve the circulation time of nanoparticles due to their innate long circulation property. Adipocytes, especially cancer-associated adipocytes, play key roles in tumor development and metabolism, therefore, adipocytes are regarded as promising bio-derived nanoplatforms for anticancer targeted drug delivery. Nanomaterials are important participants in cell-based drug delivery because of their unique physicochemical characteristics. Therefore, the integration of various nanomaterials with different cell types will endow the constructed delivery systems with many attractive properties due to the merits of both. In this review, a number of strategies based on nanomaterial-involved cell-mediated drug delivery systems for cancer treatment will be summarized. This review discusses how nanomaterials can be a benefit to cell-based therapies and how cell-derived carriers overcome the limitations of nanomaterials, which highlights recent advancements and specific biomedical applications based on nanomaterial-mediated, cell-based drug delivery systems.

1. Adsorption of the block copolymer non-ionic surfactant poloxamine-908 on to the surface of polystyrene nanospheres (60 nm in diameter) produced ‘phagocyte-resistant’ particles (otherwise known as long-circulating particles). This was reflected by a profound reduction in uptake of such engineered nanospheres by macrophages of the reticuloendothelial system and extended blood circulation time, after intravenous administration to rats. 2. A single intravenous administration of poloxamine-908-coated particles dramatically affected the circulation half-life and body distribution of a second subsequent dose. The degree of alteration depended on the interval between the two doses. At 3 days after a single intravenous injection of poloxamine-coated particles, Kupffer cells and spleen macrophages could clear a second dose of long-circulating beads from the blood. When tested at day 14, the second dose of intravenously injected poloxamine-coated particles avoided rapid uptake by liver and spleen macrophages and remained in the blood. 3. The coating polymer (poloxamine-908) apparently triggered bead clearance by resident Kupffer cells and certain sub-populations of spleen macrophages, since a single intravenous dose of an endotoxin-free solution of poloxamine 3 days before the administration of long-circulating particles induced similar effects. When the interval between the two injections was 2 weeks, poloxamine-coated particles again exhibited long circulation half-life. This cycle could be repeated after intravenous administration of a second poloxamine dose 2 weeks after the first poloxamine injection. 4. The mechanism of particle recognition by resident tissue macrophages was found to be independent of opsonization processes. 5. These studies could have important implications in biomedical application, design and engineering of poloxamine-based long-circulating drug carriers for repeated intravenous administration.

Nano-delivery systems represent one of the most studied fields, thanks to the associated improvement in the treatment of human diseases. The functionality of nanostructures is a crucial point, which the effectiveness of nanodrugs depends on. A hybrid approach strategy using synthetic nanoparticles (NPs) and erythrocytes offers an optimal blend of natural and synthetic materials. This, in turn, allows medical practitioners to exploit the combined advantages of erythrocytes and NPs. Erythrocyte-based drug delivery systems have been investigated for their biocompatibility, as well as the long circulation time allowed by specific surface receptors that inhibit immune clearance. In this review, we will discuss several methods—whole erythrocytes as drug carriers, red blood cell membrane-camouflaged nanoparticles and nano-erythrosomes (NERs)—while paying attention to their application and specific preparation methods. The ability to target cells makes erythrocytes excellent drug delivery systems. They can carry a wide range of therapeutic molecules while also acting as bioreactors; thus, they have many applications in therapy and in the diagnosis of many diseases.

Abstract Surface engineering of synthetic carriers is an essential and important strategy for drug delivery in vivo. However, exogenous properties make synthetic nanosystems invaders that easily trigger the passive immune clearance mechanism, increasing the retention effect caused by the reticuloendothelial systems and bioadhesion, finally leading to low therapeutic efficacy and toxic effects. Recently, a cell membrane cloaking technique has been reported as a novel interfacing approach from the biological/immunological perspective, and has proved useful for improving the performance of synthetic nanocarriers in vivo. After cell membrane cloaking, nanoparticles not only acquire the physiochemical properties of natural cell membranes but also inherit unique biological functions due to the presence of membrane-anchored proteins, antigens, and immunological moieties. The derived biological properties and functions, such as immunosuppressive capability, long circulation time, and targeted recognition integrated in synthetic nanosystems, have enhanced their potential in biomedicine in the future. Here, we review the cell membrane-covered nanosystems, highlight their novelty, introduce relevant biomedical applications, and describe the future prospects for the use of this novel biomimetic system constructed from a combination of cell membranes and synthetic nanomaterials.

e14076 Background: We report a biomimetic delivery platform based on human cytotoxic T-lymphocyte membranes. In this platform, T-lymphocyte membranes were camouflaged to the surface of poly-lactic-co-glycolic acid nanoparticles, with local low-dose irradiation (LDI) as a chemoattractant. These carriers were further anchored with the recombinant protein anti-EGFR-iRGD, improving tumor accumulation, facilitating tumor uptake. Methods: The T-lymphocyte membrane coating was verified by dynamic light scattering, transmission electron microscopy and confocal laser scanning microscopy. The particle phagocytosis study was performed using a human phagocytic cell line. In vivo NIR fluorescence imaging was performed to monitor the route of nanoparticles. EGFR expression of tumor cells was tested before and after LDI. Results: This new platform reduced phagocytosis of macrophages by 23.99% (p = 0.002). iRGD-EGFR anchored T-lymphocyte membrane-encapsulated nanoparticles accumulated in tumor site more than unfunctionalized groups, while LDI significantly enhanced the targeting ability. LDI could up-regulate EGFR expression on tumor cells, which was important in the process of localization of iRGD-EGFR anchored T-lymphocyte membrane-encapsulated nanoparticles in tumors. Conclusions: This new platform included both the long circulation time and tumor sites accumulation ability while LDI could significantly enhance the tumor accumulation ability.

✓ Anthracyclines entrapped in small-sized, sterically stabilized liposomes have the advantage of long circulation time, reduced systemic toxicity, increased uptake into systemic tumors, and gradual release of their payload. To date, there is no information on the behavior of these liposomes in brain tumors. The objective of this study was to compare the biodistribution and clinical efficacy of free doxorubicin (F-DOX) and stealth liposome—encapsulated DOX (SL-DOX) in a secondary brain tumor model. Nine days after tumor inoculation Fischer rats with a right parietal malignant sarcoma received an intravenous dose of 6 mg/kg of either F-DOX or SL-DOX for evaluation of drug biodistribution. For therapeutic trials a single dose of 8 mg/kg was given 6 or 11 days after tumor induction, or alternatively, weekly doses (5 mg/kg) were given on Days 6,13, and 20. Liposome—encapsulated DOX was slowly cleared from plasma with a t1/2 of 35 hours. Free-DOX maximum tumor drug levels reached a mean value of 0.8 µg/g and were identical in the adjacent brain and contralateral hemisphere. In contrast, SL-DOX tumor levels were 14-fold higher at their peak levels at 48 hours, declining to ninefold increased levels at 120 hours. A gradual increase in drug levels in the brain adjacent to tumor was noted between 72 and 120 hours (up to 4 µg/g). High-performance liquid chromatography analysis identified a small amount of aglycone metabolites within the tumor mass from 96 hours and beyond, after SL-DOX injection. Cerebrospinal fluid levels were barely detectable in tumor-bearing rats treated with F-DOX up to 120 hours after drug injection (≥ 0.05 µg/ml), whereas the levels found after SL-DOX were 10- to 30-fold higher. An F-DOX single-dose treatment given 6 days after tumor inoculation increased the rats' life span (ILS) by 135% over controls (p < 0.05) but was not effective if given on Day 11. In contrast, SL-DOX treatment resulted in an ILS of 168% (p< 0.0003) with no difference when given after 6 or 11 days. Treatment with three weekly doses of SL-DOX produced an ILS of 189% compared to 126% by F-DOX (p < 0.0002). The authors conclude that the use of long-circulating liposomes as cytotoxic drug carriers in brain tumor results in enhanced drug exposure and improved therapeutic activity, with equal effectiveness against early small- and large-sized brain tumors.

To develop a drug delivery system with long circulation and controlled drug release in cancer cells, polymeric micelles based on PEGylated chitosan-g-lipoic acid were prepared to use as a drug delivery platform. These micelles possessed good stability and were stable in physiological environment and high salt concentrations. The in vitro drug release results implied that the drug carrier could maintain their stability and minimize the payload leakage in systemic circulation, but release drugs faster under intracellular redox condition. Furthermore, the cellular uptake and therapeutic efficacy of the drug carrier were evaluated in vitro, and the results demonstrated that the drug carrier could escape from the endo/lysosomes of tumor cells effectively and present high cytotoxicity to tumor cells. Therefore, this drug delivery system has the potential to serve as a drug carrier for cancer therapy.

Nanohydrogels based on natural polymers, such as polysaccharides, are gaining interest as vehicles for therapeutic agents, as they can modify the pharmacokinetics and pharmacodynamics of the carried drugs. In this work, hyaluronan-riboflavin nanohydrogels were tested in vivo in healthy rats highlighting their lack of toxicity, even at high doses, and their different biodistribution with respect to that of native hyaluronan. They were also exploited as carriers of a hydrophobic model drug, the anti-inflammatory piroxicam, that was physically embedded within the nanohydrogels by an autoclave treatment. The nanoformulation was tested by intravenous administration showing an improvement of the pharmacokinetic parameters of the molecule. The obtained results indicate that hyaluronan-based self-assembled nanohydrogels are suitable systems for low-soluble drug administration, by increasing the dose as well as the circulation time of poorly available therapeutic agents.

Chemotherapy is the most commonly used treatment for cancer. However, due to their short circulation time and lack of specific biological distribution, chemotherapeutic drugs cause severe systemic toxicity. Using the agents specifically binding to the targeted molecules might resolve this dilemma. Aptamers can directly connect with the drugs or couple with the nano-carrier to reduce systemic toxicity. In this review, we elucidated the definition, characteristics and screening process of aptamers. The methods of drug delivery by aptamers were illustrated in details. Furthermore, clinical application of aptamers in recent years was briefly summarized and its long-term prospects were put forward.

Albumin, the most abundant protein in plasma, possesses some inherent beneficial structural and physiological characteristics that make it suitable for use as a drug delivery agent, such as an extraordinary drug-binding capacity and long blood retention, with a high biocompatibility. The use of these characteristics as a nanoparticle drug delivery system (DDS) offers several advantages, including a longer circulation time, lower toxicity, and more significant drug loading. To date, many innovative liposome preparations have been developed in which albumin is involved as a DDS. These novel albumin-containing liposome preparations show superior deliverability for genes, hydrophilic/hydrophobic substances and proteins/peptides to the targeting area compared to original liposomes by virtue of their high biocompatibility, stability, effective loading content, and the capacity for targeting. This review summarizes the current status of albumin applications in liposome-based DDS, focusing on albumin-coated liposomes and albumin-encapsulated liposomes as a DDS carrier for potential medical applications.

Extranodal nasal NK/T-cell lymphoma is highly aggressive and malignant. Owing to the lack of multi-center prospective controlled studies, there is not a unified standard for the current clinical best treatment model. In recent years, new nano-drug delivery systems have made great progress in the field of tumor treatment. However, research on ENKTL is still in its infancy. The authors' previous research has proven that the dextran nano-drug delivery system can optimize and improve the in vivo pharmacokinetic behavior and anti-tumor effects of doxorubicin through interaction with the reticuloendothelial system and the complex tumor microenvironment. At the same time, gemcitabine, which is commonly used in the clinical treatment of ENKTL, and cisplatin, which is a radiosensitizer, both contain free amino groups, which can be successfully grafted to aldehyde-based natural polysaccharides. Therefore, based on the natural nano-drug carrier, we constructed a smart long-circulation drug delivery system that co-loaded gemcitabine and cisplatin and targeted ENKTL to achieve effective treatment of ENKTL under the dual treatment mode of chemotherapy and radiosensitization. This project improves the radiosensitivity of ENKTL and overcomes the multi-drug resistance of chemotherapeutics through the radiotherapy-cooperative natural nano-drug delivery system and provides a new idea for the further development and optimization of ENKTL treatment programs.

To promote chemotherapeutic efficacy and easier clinical transformation, a series of pH-sensitive and dynamic drug delivery systems with facile two-step synthesis and simple structure have been successfully constructed by the tunable grafting reaction between pH-sensitive ortho ester and poly(vinyl alcohol). The amphipathic graft macromolecules (PVA- g-OE x, x represents the percentage of feed between ortho esters and hydroxyl groups of polyvinyl alcohol) could self-assemble into micelles and doxorubicin was embedded. These micelles exhibited pH-sensitivity to both extracellular and intracellular pH and demonstrated the following characteristics: (i) maintaining long-term storage and blood circulation stability at pH 7.4; (ii) responding to tumoral extracellular pH value following gradually larger nanoparticles for improved drug accumulation and retention; (iii) being sensitive to tumoral intracellular pH value following disintegration for rapid drug release to improve toxicity to tumor cells. Moreover, the doxorubicin-loaded micelle (PVA- g-OE30-DOX) showed similar cytotoxicity to free doxorubicin in vitro, but stronger tumor penetration and inhibition ability in vitro human liver carcinoma cell line multicellular tumor spheroids. In vivo biodistribution and tumor inhibition examinations demonstrated that PVA- g-OE30-DOX had more superior efficacy in significantly enhancing drug accumulation in tumor, restraining tumor growth while decreasing drug concentration in normal tissues. The pH-sensitive, dynamic graft polymer micelles via simple synthesis could be considered as a promising and effective drug carrier in tumor therapy.

Polymer nanoparticles are a promising approach for cancer treatment and detection, due to their biocompatibility, biodegradability, targeting capabilities, capacity for drug loading and long blood circulation time. This study aims to evaluate the impact of poly (styrene–acrylic acid) latex particles on colorectal and cervical cancer cells for anti-tumor efficiency. Latex particles were synthesized by a surfactant-free radical emulsion polymerization process and the obtained polymer particles were characterized in terms of size, size distribution, morphology using scanning electron microscopy (SEM) and transmission electron microscopy (TEM), and electrokinetic property (i.e., zeta potential). Human colorectal and cervical cancer, and normal cell lines, were then treated with different concentrations of poly (styrene–acrylic acid) latex particles. The cell morphology changes were pointed out using an optical microscope and the nanoparticles’ (NPs) cell cytotoxicity was evaluated using MTT assay. The obtained results showed that poly (styrene–acrylic acid) latex particles are effective against colorectal and cervical cancer cells if treated with an appropriate particle concentration for 48 h. In addition, it showed that normal cells are the least affected by this treatment. This indicates that these NPs are safe as a drug delivery carrier when used at a low concentration.

Object. Intrathecal bolus administration of (Z)-1-[N-(2-aminoethyl)-N-(2-ammonioethyl)aminio]diazen-1-ium-1,2-diolate (DETA/NO), a long half-life diazeniumdiolate-class nitric oxide (NO) donor, was evaluated for safety and efficacy in the treatment of delayed cerebral vasospasm in a canine model of subarachnoid hemorrhage (SAH). Methods. The baseline basilar artery (BA) diameter of 25 dogs was measured with the aid of angiography on Day 0. Vasospasm was then induced by intracisternal injection of autologous arterial blood on Days 0 and 2. Repeated arteriography on Day 7 revealed an average BA diameter of 58% of baseline. Each dog was then randomized to one of four groups: a pathology control group (SAH only, four animals); a treatment control group (SAH plus 2 µmol of the inactive drug carrier DETA, eight animals); a low-dose treatment group (SAH plus 0.2 µmol DETA/NO, six animals); or a high-dose treatment group (SAH plus 2 µmol DETA/NO, six animals). The drugs were administered in a 2-ml intrathecal bolus via the cisterna magna. Arterial caliber was monitored by angiography over the subsequent 4 hours. A 2-µmol dose of the drug was then given and serial arteriography continued for an additional hour to screen for tachyphylaxis. Intracranial pressure and respiratory and hemodynamic parameters were continuously monitored. Histopathological analyses of the animals' brains were performed after the dogs were killed on Day 8. The drug DETA/NO produced reversal of vasospasm in a dose-dependent fashion that roughly followed a double exponential time course. Doses of 2 µmol DETA/NO resulted in restoration of the angiographically monitored BA diameter to the prevasospasm size at 1.5 hours posttreatment, and this was sustained at 88% of baseline at 4 hours (p < 0.01, independent samples t-test). By contrast, the treatment control group remained on average at 54% of baseline diameter. The low-dose treatment group achieved only partial and more transitory relaxation. Histopathological analyses showed findings consistent with chronic SAH but did not demonstrate any toxicity associated with the NO donor. No adverse physiological changes were seen. Conclusions. This study indicates that long-acting NO donors are potentially useful as agents to restore circulation in patients suffering from cerebral vasospasm.

ABSTRACTConsideration of existing compounds always simplifies and shortens the long and difficult process of discovering new drugs specifically for diseases of developing countries, an approach that may add to the significant potential cost savings. This study focused on improving the biological characteristics of the already-existing antischistosomal praziquantel (PZQ) by incorporating it into montmorillonite (MMT) clay as a delivery carrier to overcome its known bioavailability drawbacks. The oral bioavailability of a PZQ-MMT clay nanoformulation and itsin vivoefficacy againstSchistosoma mansoniwere investigated. The PZQ-MMT clay nanoformulation provided a preparation with a controlled release rate, a decrease in crystallinity, and an appreciable reduction in particle size. Uninfected and infected mice treated with PZQ-MMT clay showed 3.61- and 1.96-fold and 2.16- and 1.94-fold increases, respectively, in area under the concentration-time curve from 0 to 8 h (AUC0–8) and maximum concentration of drug in serum (Cmax), with a decrease in elimination rate constant (kel) by 2.84- and 1.35-fold and increases in the absorption rate constant (ka) and half-life (t1/2e) by 2.11- and 1.51-fold and 2.86- and 1.34-fold, respectively, versus the corresponding conventional PZQ-treated groups. This improved bioavailability has been expressed in higher efficacy of the drug, where the dose necessary to kill 50% of the worms was reduced by >3-fold (PZQ 50% effective dose [ED50] was 20.25 mg/kg of body weight for PZQ-MMT clay compared to 74.07 mg/kg for conventional PZQ), with significant reduction in total tissue egg load and increase in total immature, mature, and dead eggs in most of the drug-treated groups. This formulation showed better bioavailability, enhanced antischistosomal efficacy, and a safer profile despite the longer period of residence in the systemic circulation. Although the conventional drug's toxicity was not examined, animal mortality rates were not different between groups receiving the test PZQ-clay nanoformulation and conventional PZQ.

Many attempts have been made to achieve good selectivity to targeted tumor cells by preparing specialized carrier agents that are therapeutically profitable for anticancer therapy. Among these, liposomes are the most studied colloidal particles thus far applied in medicine and in particular in antitumor therapy. Although they were first described in the 1960s, only at the beginning of 1990s did the first therapeutic liposomes appear on the market. The first-generation liposomes (conventional liposomes) comprised a liposome-containing amphotericin B, Ambisome (Nexstar, Boulder, CO, USA), used as an antifungal drug, and Myocet (Elan Pharma Int, Princeton, NJ, USA), a doxorubicin-containing liposome, used in clinical trials to treat metastatic breast cancer. The second-generation liposomes (“pure lipid approach”) were long-circulating liposomes, such as Daunoxome, a daunorubicin-containing liposome approved in the US and Europe to treat AIDS-related Kaposi's sarcoma. The third-generation liposomes were surface-modified liposomes with gangliosides or sialic acid, which can evade the immune system responsible for removing liposomes from circulation. The fourth-generation liposomes, pegylated liposomal doxorubicin, were called “stealth liposomes” because of their ability to evade interception by the immune system, in the same way as the stealth bomber was able to evade radar. Actually, the only stealth liposome on the market is Caelyx/Doxil (Schering-Plough, Madison NJ, USA), used to cure AIDS-related Kaposi's sarcoma, resistant ovarian cancer and metastatic breast cancer. Pegylated liposomal doxorubicin is characterized by a very long-circulation half-life, favorable pharmacokinetic behavior and specific accumulation in tumor tissues. These features account for the much lower toxicity shown by Caelyx in comparison to free doxorubicin, in terms of cardiotoxicity, vesicant effects, nausea, vomiting and alopecia. Pegylated liposomal doxorubicin also appeared to be less myelotoxic than doxorubicin. Typical forms of toxicity associated to it are acute infusion reaction, mucositis and palmar plantar erythrodysesthesia, which occur especially at high doses or short dosing intervals. Active and cell targeted liposomes can be obtained by attaching some antigen-directed monoclonal antibodies (Moab or Moab fragments) or small proteins and molecules (folate, epidermal growth factor, transferrin) to the distal end of polyethylene glycol in pegylated liposomal doxorubicin. The most promising therapeutic application of liposomes is as non-viral vector agents in gene therapy, characterized by the use of cationic phospholipids complexed with the negatively charged DNA plasmid. The use of liposome formulations in local-regional anticancer therapy is also discussed. Finally, pegylated liposomal doxorubicin containing radionuclides are used in clinical trials as tumor-imaging agents or in positron emission tomography.

Boron neutron capture therapy is a unique form of adjuvant cancer therapy for various malignancies including malignant gliomas. The conjugation of boron compounds and human serum albumin (HSA)—a carrier protein with a long plasma half-life—is expected to extend systemic circulation of the boron compounds and increase their accumulation in human glioma cells. We report on the synthesis of fluorophore-labeled homocystamide conjugates of human serum albumin and their use in thiol-‘click’ chemistry to prepare novel multimodal boronated albumin-based theranostic agents, which could be accumulated in tumor cells. The novelty of this work involves the development of the synthesis methodology of albumin conjugates for the imaging-guided boron neutron capture therapy combination. Herein, we suggest using thenoyltrifluoroacetone as a part of an anticancer theranostic construct: approximately 5.4 molecules of thenoyltrifluoroacetone were bound to each albumin. Along with its beneficial properties as a chemotherapeutic agent, thenoyltrifluoroacetone is a promising magnetic resonance imaging agent. The conjugation of bimodal HSA with undecahydro-closo-dodecaborate only slightly reduced human glioma cell line viability in the absence of irradiation (~30 μM of boronated albumin) but allowed for neutron capture and decreased tumor cell survival under epithermal neutron flux. The simultaneous presence of undecahydro-closo-dodecaborate and labeled amino acid residues (fluorophore dye and fluorine atoms) in the obtained HSA conjugate makes it a promising candidate for the combination imaging-guided boron neutron capture therapy.

In the post-epidemic period, the circulation of the causative agent of diphtheria in the population is maintained due to the carrier of bacteria. Entering an organism with a high level of antitoxic immunity, the pathogen enters into intermicrobial interactions with representatives of the opportunistic microflora inhabiting the respiratory tract and forms a biofilm. Materials and methods. Modeling of the biofilm formation process was carried out using the strains C.diphtheriae gravis tox+№. 665, C.pseudodiphtheriticum, S.aureus. Biofilm samples were placed on the stage of a scanning electron microscope and gold-sputtered in an EicoIB-3 ioncoater vacuum deposition unit (Eico, Japan) at an ion current of 6-8 mA. The samples obtained were examined in a JEOL 6510LB scanning electronmicroscope. («JEOL» company, Japan) at an accelerating voltage of 30 kV. Results. Electron microscopic examination of samples of biofilms C. diphtheriae gravis tox+ № 665 and opportunistic microorganisms shows groups of 2-7 young bacterial cells packed into a single microcapsule. Much more voluminous accumulations of bacterial cells (more than 10-12) are typical for biofilm samples represented by C. diphtheriae gravis tox+№ 665 and S. aureus cells. On the surface of the biofilm, young bacterial cells with an intact structure are located at various stages of active division. The conglomerates of bacterial cells, covered with a common intermicrobial matrix, adhere tightly to each other and form a multilayer biofilm. Conclusion. Features of the ultrastructure of biofilms containing strains of C. diphtheriae and opportunistic bacteria, especially antibiotic-resistant bacteria inhabiting the respiratory tract, can contribute to long-term persistence of the pathogen of diphtheria in the body. They not only significantly complicate the access of antibacterial drugs, but also interfere with the isolation of C.diphtheriae during bacteriological research.

Abstract Peptides containing Arg-Gly-Asp (RGD) sequences are known to bind to integrins which mediate cell adhesion and therefore have been utilized in applications such as antithrombotics and tissue engineering. Although RGD and related peptides show promise, their unfavourable pharmacokinetic profiles and susceptibility to in vivo proteolysis hinder their clinical usefulness. Peptide-polymer conjugates can address one of these challenges by extending the peptide’s residence in plasma. Hyperbranched polyglycerols (HPGs) are biocompatible polyether polyols with very long plasma circulation half-lives (t1/2 ∼ 60h) and as such are ideally suited to be carriers in such conjugates. HPGs of three different molecular weights were conjugated with RGD peptides at various substitution levels. Some of the terminal hydroxyl groups of polyglycerols were converted to vinyl sulfone groups which were subsequently utilized to couple cysteine terminated RGD peptides. The following conjugates were made: 515 kDa with substitution levels of 100:1, 500:1 and 1000:1; 100 kDa with substitution levels of 100:1 and 1000:1; and 3 kDa with substitution levels of 1:1, and 10:1. RGD-coupled HPG inhibited fibrinogen binding to platelet glycoprotein IIb-IIIa as detected by flow cytometry using anti-fibrinogen. Compared to free RGD (Ic50 = 5 x 10-5 M), inhibition of fibrinogen binding increased with increasing HPG molecular weight and increasing RGD-substitution for the high MW conjugates: Ic50 for the 515 kDa conjugates were 6.3 x 10−8 M for the 100:1 substitution, 4.7 x 10-8 M for the 500:1 substitution, and 4.1 x 10−8 M for 1000:1 substitution; Ic50 for the 100 kDa conjugates were 7.0 x 10−7 M for the 100:1 substitution and 1.2 x 10−7 M for the 1000:1 substitution. Ic50 for the 3 kDa conjugates were 2 x 10−5 M for the 1:1 substitution, 2 x 10−4 M for 10:1 substitution. Similarly, platelet function, as demonstrated by MnCl2-initated aggregation was inhibited in a dose- and molecular weight-dependent manner by HPG-RGD conjugates. Platelet aggregate formation and aggregate size were confirmed by microscopy. However, unsubstituted HPG had no effect on platelet fibrinogen binding and neither conjugated nor unconjugated HPG increased platelet CD62 surface expression. Trypsin digestion (but not SBTI-treated trypsin) removed the inhibitory activity of the conjugates and thus confirmed that both fibrinogen binding and aggregation-inhibition were dependent on the RGD peptide sequence. Such multi-determinant peptide-HPG conjugates represent a new approach to the development of antithrombotic drugs.

Two conjugates of anticancer drug doxorubicin (Dox) covalently bound by the hydrolytically degradable hydrazone bond to the polymer carrier based on water-soluble N-(2-hydroxypropyl) methacrylamide (HPMA) copolymers were synthesized and their properties were compared, namely their behavior in vivo. The polymer carriers differed in dispersity due to different methods of synthesis; the carrier with relatively high dispersity (HD) was prepared by free radical polymerization (Mw = 29 900 g/mol, Ð = 1.75) and the carrier with low dispersity (LD) by controlled radical polymerization (Mw = 30 000 g/mol, Ð = 1.13). Both polymer-Dox conjugates showed prolonged blood circulation and tumor accumulation of the drug in comparison with the free drug; e.g. the tumor-to-blood ratio for the polymer-bound Dox was 3-5 times higher. The LD polymer-Dox conjugate exhibited moderately higher tumor accumulation than the HD one at a dose of 1 x 15 mg Dox (eq.)/kg. Also, their anti-tumor activity did not differ when injected at this dose. However, the increase of the dose to 1 x 25 mg Dox (eq.)/kg resulted in the enhanced therapeutic activity of the conjugates, especially of the LD one with 100 % of long-term survivals. The dispersity of polymer drug carriers influenced the tumor accumulation rate, which affected the overall anti-cancer activity of polymer-drug conjugates.

Amphiphilic polymer micellar carriers are the most commonly used nanocarriers for oral delivery of hydrophobic drugs because their hydrophilic shell can avoid the recognition of the reticuloendothelial system (RES), has excellent drug-carrying capacity, and protect the drug from inactivation in the gastrointestinal fluid. The polymer micelle shell can enter cancer cells by endocytosis, and autophagy in cells, degradation by lysosomal pathway, so as to release drugs, prolong the circulation time of drugs in vivo, and then achieve the effect of drug sustained release. In this study, the glutathione-responsive PLGA-ss-PEG loaded paclitaxel (PTX) micelles (PLGA-ss-PEG-PTX) were developed for anticancer therapy. With its long-term circulation and EPR (enhanced permeability and retention) effect, and the micelle had disulfide bond, which could be used as the recognition group of tumor microenvironment, so that the PLGA-ss-PEG-PTX could specifically accumulate at the tumor site, so as to produce better anti-tumor effect. The PLGA-ss-PEG-PTX was formulated by the emulsification method in this study. The drug loading was about 21.54%, the entrapment efficiency was about 94.2%, and the particle size range was about 90 nm with narrow particle size distribution. Cytotoxicity and embryonic toxicity experiments were carried out using mouse lung cancer cells (LLC) and zebrafish fertilized eggs. It was proved that the low concentration of blank micelles had little cytotoxicity, but high concentration of blank micelles had adverse effects on zebrafish embryonic development, resulting in embryonic malformation. The uptake of drugs by cancer cells was studied by a high connotation cell imaging analysis system. The experiments showed that the drug molecules encapsulated in micelles could achieve higher uptake by cells compared with free drug molecules. In addition, in the in vivo evaluation experiment of drugs, the PLGA-ss-PEG-PTX could significantly enhance the therapeutic effect of the PTX, improve its water solubility, and improve its oral bioavailability.

Biomacromolecules have gained much attention as biomedicine carriers in recent years due to their remarkable biophysical and biochemical properties including sustainability, non-toxicity, biocompatibility, biodegradability, long systemic circulation time and ability to target. Recent developments in a variety of biological functions of biomacromolecules and progress in the study of biological drug carriers suggest that these carriers may have advantages over carriers of synthetic materials in terms of half-life, durability, protection and manufacturing facility. Despite the full pledge advancements in the applications of biomacromolecules, its clinical use is hindered by certain factors that allow the pre-mature release of loaded cargos before reaching the target site. The delivery therapeutics are degraded by systemic nucleases, cleared by reticulo-endothelial system, cleared by pulmonary mucus cilia or engulfed by lysosome during cellular uptake that has led to the failure of clinical therapy. It clearly indicates that there is a wide range of gaps in the results of experimental work and clinical applications of biomacromolecules. This review focuses mainly on the barriers (intracellular/extracellular) and hurdles to the delivery of biomacromolecules with special emphasis on siRNA as well as the delivery of antisense oligos in multiple pulmonary diseases, particularly focusing on lung cancer. Also, the challenges posed to such delivery and possible solutions have been highlighted.

Plant virus nanoparticles (PVNPs) have been widely used for drug delivery, antibody development and medical imaging because of their good biodegradation and biocompatibility. Particles of pepper mild mottle virus (PMMoV) are elongated and may be useful as drug carriers because their shape favours long circulation, preferential distribution and increased cellular uptake. Moreover, its effective degradation in an acidic microenvironment enables a pH-responsive release of the encapsulated drug. In this study, genetic engineering techniques were used to form rod-shaped structures of nanoparticles (PMMoV) and folated-modified PMMoV nanotubes were prepared by polyethylene glycol (PEG) to provide targeted delivery of paclitaxel (PTX). FA@PMMoV@PTX nanotubes were designed to selectively target tumor cells and to release the encapsulated PTX in response to pH. Efficient cell uptake of FA@PMMoV@PTX nanotubes was observed when incubated with tumor cells, and FA@PMMoV@PTX nanotubes had superior cytotoxicity to free PTX, as reflected by cell survival and apoptosis. This system is a strong candidate for use in developing improved strategies for targeted treatment of tumors.

: Exosomes are nano structured (50-90 nm) vesicles that originate from endosomal compartment of eukaryotic cells and are secreted into extracellular matrix. In recent years there has been increased interest in exploring exosomes for diagnostic and therapeutic applications. Like many other diseases e.g. neurodegenerative disorders, autoimmune diseases exosomes have large significance in cancer too. Exosomes are known to prevail in large numbers and carry unique cargos in different types of cancers and thus are proving as versatile entities in understanding their biology of cancers and utilized as efficient diagnostic biomarkers in identification of cancer type. In addition to diagnostic applications there has been an increased interest in recent years to exploit exosomes as carriers for delivery of therapeutic agents to target sites as well. This is indebted to their exceptional non-immunogenic and biomimetic properties that prompted researchers to use exosomes as carriers for delivery of therapeutic agents e.g. drugs, genes and peptides. Exosomes also circumvent many drawbacks associated with other lipid or polymeric nanocarriers e.g. low circulation time, lipid toxicities, long term stability etc. However, in spite of many favorable aspects for exosome based therapy there have been a number of challenges too. This review will focus on the current status of the exosome based drug therapy for cancer, the challenges faced and its potential for future clinical use.

AbstractLung cancer is often diagnosed at an advanced stage and has a poor prognosis. Conventional treatments are not effective for metastatic lung cancer therapy. Although some of molecular targets have been identified with favorable response, those targets cannot be exploited due to the lack of suitable drug carriers. Lung cancer cell-derived exosomes (LCCDEs) receive recent interest in its role in carcinogenesis, diagnosis, therapy, and prognosis of lung cancer due to its biological functions and natural ability to carry donor cell biomolecules. LCCDEs can promote cell proliferation and metastasis, affect angiogenesis, modulate antitumor immune responses during lung cancer carcinogenesis, regulate drug resistance in lung cancer therapy, and be now considered an important component in liquid biopsy assessments for detecting lung cancer. Therapeutic deliverable exosomes are emerging as promising drug delivery agents specifically to tumor high precision medicine because of their natural intercellular communication role, excellent biocompatibility, low immunogenicity, low toxicity, long blood circulation ability, biodegradable characteristics, and their ability to cross various biological barriers. Several studies are currently underway to develop novel diagnostic and prognostic modalities using LCCDEs, and to develop methods of exploiting exosomes for use as efficient drug delivery vehicles. Current status of lung cancer and extensive applicability of LCCDEs are illustrated in this review. The promising data and technologies indicate that the approach on LCCDEs implies the potential application of LCCDEs to clinical management of lung cancer patients.

Docetaxel (DOX) is usually one of drugs used for breast cancer treatment. The key of targeted drug delivery therapy is to deliver effective drugs directly and safely to the tumor focus via an efficient targeting drug carrier with immunogenicity. In this study, Long-circulating targeted drug carrying microspheres (DOX-PEG-EpCAM-MNs) entrapping DOX were constructed. In addition, both cytotoxicity and magnetic resonance imaging (MRI) analyses were performed to establish a mouse model and further complete corresponding performance analysis.The results showed that the average particle size of DOX-PEG-EpCAM-MNs was 139.3 ± 1.6 nm. Morphological analysis proves that they are spherical and uniformly dispersed. The Corresponding entrapment rate and drug carrying capacity are 82.43% and 7.16% respectively. Additionally, MRI shows that they have the capability to track tumor cells within 5 days. This study established a safe and efficient breast cancer cells targeted long-circulating drug delivery system.

Background: How to achieve high targeting efficiency for drug delivery system is still one of the most important issues that tumor diagnosis and non-surgical therapies faced. Although nanoparticle-based drug delivery system made an amount of progress in extending circulation time, improving targetability, controlled drug release etc., yet the targeting efficiency remained low, and the development was limited to reduce side effects with overall survival rates unchanged or improved a little. Objective: This paper aims to review current researches on the cell-driven drug delivery systems, and discuss the potential obstacles and directions for cell-based cancer therapies and diagnosis. Methods: More than one hundred references were collected, and this paper focused on red blood cells, monocytes, macrophages, neutrophils, natural killer cells, T lymphocytes, mesenchymal stem cells, cell membrane, artificial cells and extracellular vesicles, then summarized 1) the utilizable properties, 2) balancing cargo-loading amounts and cell function, 3) cascade strategies for targetability improvement. Main findings: circulatory cells and their derivatives were featured by good biocompatibility, long circulation time in blood, unique chemo-migration and penetration ability. On the base of backpack and encapsulation approach, cargo loading amounts and cell function could be balanced through regulating membrane receptors, particle material/size/shape/structure and incubation temperature, etc. The cell-driven drug delivery system met most of the demands that nanoparticle-based delivery system failed to for effective tumortropic delivery. Conclusion: Despite of new challenges, cell-driven drug delivery system generally brought great benefits to and shed a light on for cancer therapy and diagnosis.

Abstract Background Photothermal therapy (PTT) has been extensively investigated as a tumor-localizing therapeutic modality for neoplastic disorders. However, the hyperthermia effect of PTT is greatly restricted by the thermoresistance of tumor cells. Particularly, the compensatory expression of heat shock protein 90 (HSP90) has been found to significantly accelerate the thermal tolerance of tumor cells. Thus, a combination of HSP90 inhibitor and photothermal photosensitizer is expected to significantly enhance antitumor efficacy of PTT through hyperthermia sensitization. However, it remains challenging to precisely co-deliver two or more drugs into tumors. Methods A carrier-free co-delivery nanoassembly of gambogic acid (GA, a HSP90 inhibitor) and DiR is ingeniously fabricated based on a facile and precise molecular co-assembly technique. The assembly mechanisms, photothermal conversion efficiency, laser-triggered drug release, cellular uptake, synergistic cytotoxicity of the nanoassembly are investigated in vitro. Furthermore, the pharmacokinetics, biodistribution and self-enhanced PTT efficacy were explored in vivo. Results The nanoassembly presents multiple advantages throughout the whole drug delivery process, including carrier-free fabrication with good reproducibility, high drug co-loading efficiency with convenient dose adjustment, synchronous co-delivery of DiR and GA with long systemic circulation, as well as self-tracing tumor accumulation with efficient photothermal conversion. As expected, HSP90 inhibition-augmented PTT is observed in a 4T1 tumor BALB/c mice xenograft model. Conclusion Our study provides a novel and facile dual-drug co-assembly strategy for self-sensitized cancer therapy. Graphic abstract

Abstract Chemo-thermotherapy, as a promising cancer combination therapy strategy, has attracted widespread attention. In this study, a novel aptamer functionalized thermosensitive liposome encapsulating hydrophobic drug quercetin was fabricated as an efficient drug delivery system. This aptamer-functionalized quercetin thermosensitive liposomes (AQTSL) combined the merits of high-loading yield, sustained drug release, long-term circulation in the body of PEGylated liposomes, passive targeting provided by 100-200 nm nanoparticles, active targeting and improved internalization effects offered by AS1411 aptamer, and temperature-responsive of quercetin release. In addition, AQTSL tail vein injection combined with 42℃ water bath heating on tumor site (AQTSL+42℃)treatment inhibited the tumor growth significantly compared with the normal saline administration (p<0.01), and the inhibition rate reached 75%. Furthermore, AQTSL+42℃ treatment also slowed down the tumor growth significantly compared with QTSL combined with 42℃ administration (p<0.05), confirming that AS1411 decoration on QTSL increased the active targeting and internalization effects of the drug delivery system, and AS1411 aptamer itself might also contribute to the tumor inhibition. These data indicate that AQTSL is a potential carrier candidate for different hydrophobic drugs and tumor targeting delivery, and this kind of targeted drug delivery system combined with temperature responsive drug release mode is expected to achieve an ideal tumor therapy effect.

IntroductionThe erythrocyte membranes used in nanovaccines include high membrane stability, long circulation life, adaptability and extremely good bio compatibility. Nanoparticles encapsulated by erythrocyte membranes are widely used as ideal drug delivery vehicles because of their high drug loading, long circulation time, and excellent biocompatibility. The mannose modification of delivery materials can help target mannose receptors (MRs) to deliver antigens to antigen-presenting cells (APCs).MethodsIn this study, the antigen gene gp90 of avian reticuloendotheliosis virus (REV) was encapsulated with carboxymethyl chitosan (CS) to obtain CSgp90 nanoparticles, which were coated with mannose-modied fowl erythrocyte membranes to yield CS-gp90@M-M nanoparticles. The physicochemical characterization and immune response of the CS-gp90@M-M nanoparticles were investigated in vitro and in vivo.ResultsCS-gp90@M-M nanoparticles were rapidly phagocytized in vitro by macrophages to induce the production of cytokines and nitric oxide. In vivo, CS-gp90@M-M nanoparticles increased cytokine levels, the CD4+/8+ ratio, REV-specific antibodies in the peripheral blood of chicks, and the mRNA levels of immune-related genes in the spleen and bursa of immunized chicks. CS-gp90@M-M nanoparticles could be targeted to lymphoid organs to prolong the retention time of the nanoparticles at the injection site and lymphatic organs, leading to a strong, sustained immune response. Moreover, the CS-gp90@M-M nano-vaccine showed a lasting immunoprotective effect and improved the body weight of chicks after the challenge.ConclusionOverall, CS-gp90@M-M nanoparticles can be used in vaccine designs as an effective delivery carrier with immune response-enhancing effects.

Vesicular systems (liposomes), one of several potential novel drug delivery systems, provide an advanced technology for delivering active compounds to the site of action, and numerous formulations are currently in clinical use. Liposome technology has developed from typical vesicles to sterically stabilised vesicles, which produce long-circulating liposomes by varying the lipid content, size, and charge of the vesicle. Several compounds, such as glycolipids, have been used to create liposomes with changed surfaces. The addition of the synthetic polymer poly-(ethylene glycol) (PEG) in liposome composition was a crucial milestone in the creation of long-circulating liposomes. PEG on the liposomal carrier's surface has been found to increase blood circulation time while decreasing mononuclear phagocyte system uptake (Stealth Liposomes). As a consequence of this technique, a vast variety of liposome formulations encapsulating active compounds have been developed, all of which have excellent target efficiency and activity. Stealth liposomes can also be actively targeted with monoclonal antibodies or ligands thanks to a synthetic alteration of the terminal PEG molecule. This article focuses on vesicular drug delivery as well as stealth technology and presents preclinical and clinical data for the most common liposome formulations, as well as discussing developing developments in this promising technology.

AbstractLiposomes hold great potential in anti-cancer drug delivery and the targeting treatment of tumors. However, the clinical therapeutic efficacy of liposomes is still limited by the complexity of tumor microenvironment (TME) and the insufficient accumulation in tumor sites. Meanwhile, the application of cholesterol and polyethylene glycol (PEG), which are usually used to prolong the blood circulation and stabilize the structure of liposomes respectively, has been questioned due to various disadvantages. Herein, we developed a ginsenoside Rh2-based multifunctional liposome system (Rh2-lipo) to effectively address these challenges once for all. Different with the conventional ‘wooden’ liposomes, Rh2-lipo is a much more brilliant carrier with multiple functions. In Rh2-lipo, both cholesterol and PEG were substituted by Rh2, which works as membrane stabilizer, long-circulating stealther, active targeting ligand, and chemotherapy adjuvant at the same time. Firstly, Rh2 could keep the stability of liposomes and avoid the shortcomings caused by cholesterol. Secondly, Rh2-lipo showed a specifically prolonged circulation behavior in the blood. Thirdly, the accumulation of the liposomes in the tumor was significantly enhanced by the interaction of glucose transporter of tumor cells with Rh2. Fourth, Rh2-lipo could remodel the structure and reverse the immunosuppressive environment in TME. When tested in a 4T1 breast carcinoma xenograft model, the paclitaxel-loaded Rh2-lipo realized high efficient tumor growth suppression. Therefore, Rh2-lipo not only innovatively challenges the position of cholesterol as a liposome component, but also provides another innovative potential system with multiple functions for anti-cancer drug delivery.

At present, the clinical diagnosis of and treatment methods for hepatic carcinoma still fail to fully meet the needs of patients. The integrated theranostic system, in which functional materials are used to load different active molecules, created a new developmental direction for the combination treatment of hepatic carcinoma, realizing the synchronization of diagnosis and treatment. In this study, polydopamine (PDA), which has the functions of self-assembly, encapsulation, photothermal conversion, and photoacoustic interaction, was used as the carrier material. The IR780, a near-infrared fluorescence imaging (NIFI), photoacoustic imaging (PAI), and photothermal therapy (PTT) agent, and paclitaxel (PTX), a broad-spectrum chemotherapy drug, were selected to build the NIF/PA dual-mode imaging and PTT/chemo synergistic theranostic nanoparticles (DIST NPs). The DIST NPs have a 103.4 ± 13.3 nm particle size, a weak negative charge on the surface, good colloidal stability, slow and controlled drug release, and high photothermal conversion ability. The experiments results showed that the DIST NPs have a long circulation in vivo, high bioavailability, high biocompatibility, and low effective dose. DIST NPs showed an excellent NIFI/PAI dual-mode imaging and significant synergistic antitumor effect in hepatic carcinoma models. DIST NPs met the initial design requirements. A set of fast and low-cost preparation methods was established. This study provides an experimental basis for the development of new clinical theranostic methods for hepatic carcinoma.

Background: Oral cancer is a deadly disease affecting worldwide. Despite developments of conventional cancer therapy, there has been little improvement in the survival rates. This culminated in the evolution of a targeted. New Drug Delivery System, discovering novel objectives for successful drug delivery and synergistic combination of anticancer agents to minimize side effects. Objective: The main focus was on understanding the various aspects of different targeted drug delivery vehicles used in the treatment of oral cancer including advantages, disadvantages, and future perspectives. Materials and Methods: A literature search was accomplished from 2005 to 2020 via Google scholar. PubMed, EBSCO, Embase, and Scopus databases along with Clinical trials registries using the terms oral buccal thin films, Hyperthermia and Thermoablation, Intra-tumoral, Photodynamic, Immunotherapy, photothermal, and ultrasound therapy in oral cancer. The articles were scrutinized and those which were not relevant to our search were omitted. Clinical trials on targeted drug delivery systems for Oral Cancer being conducted or completed around the world from various registries of clinical trials have also been searched out and the findings were tabulated in the end. The PRISMA 2020 guidelines were followed. Results: The treatment of oral squamous cell carcinoma (OSCC) mostly depends upon the location, type, and stage of the tumor. Vivid targeted drug delivery systems are being used in the therapeutic interventions of oral cancer as they aim for specific target site delivery and are the most appropriate treatment. Active Pharmacological Ingredient (API) is taken to the targeting site, sparing non-target organs or cells, triggering selective and efficient localization, thereby maximizing the therapeutic index with minimizing toxicity. The successful targeted drug delivery system works on four principles i.e. Retain, Evade, Target and Release, which means loading of sufficient drug into a suitable drug carrier, does not affect body secretions, long duration in circulation, reaching the targeted site and, drug release within the time for effective functioning of the drug. All techniques described in this paper have proven to show effective results. Conclusion: Oral Cancer is an emerging public health problem worldwide. Various conventional therapies are used for treating oral cancer, but they enclose variable degrees of side effects both on the body as well as the cellular microenvironment. With advanced technology, many other aids have been introduced in the field of oncology to treat oral cancer with minimal side effects. All techniques described in this paper have proven to show effective results in the therapeutic interventions of oral cancer. Moreover, they can be used even in combination with conventional drug therapy to show beneficial outcomes. Several clinical trials are being conducted and completed in this aspect to investigate definite results of these therapies, yet robust research is needed for further confirmation.

Background: There is a mechanistic link between QT prolongation and the development of TdP. Women with LQTS have an increased risk of serious cardiac arrhythmias during the postpartum period,however,there is limited data on the effects of pregnancy on those without a prolonged QT prior to delivery. Case Description: The patient is a 22 y/o female with no history of arrhythmia.During pregnancy she had three episodes of SVT,each prompting hospital admissions.ECG showed a heart rate of 148-163bpm,a QTc of 390 to 410ms,and laboratory data a magnesium level of 1.6.On day 3 after a scheduled cesarean section, she suffered a eclamptic seizure and then a Tdp induced cardiac arrest.Magnesium was immediately given.CPR was performed for 31 minutes until return of spontaneous circulation was achieved.The patient had an extended ICU course but was eventually discharged home with her newborn twins,a subcutaneous implantable cardiac defibrillator (S-ICD),multiple postpartum ECGs showing QTc of 493 to 524ms,and a diagnosis of LQTS. Discussion: Pregnancy increases or precipitate cardiac arrhythmias not previously present in otherwise healthy females. In women with LQTS, there have been studies that have shown significant increases in arrhythmias and SCD during the 9 months postpartum.Also recognized are silent forms of congenital LQTS in which patients are arrhythmia free until exposed to a precipitant.5-10% of patients who develop drug-induced TdP are silent carriers of gene mutations related to LQTS, suggesting a “second hit” can uncover the LQTS phenotype despite a “normal” QTc in the unprovoked state. This emphasizes the importance of other potential ‘hits’ that can uncover a LQTS, particularly relevant to this case, the postpartum period.To our knowledge,this is the first case of a simultaneously occurring eclamptic seizure and TdP induced cardiac arrest both successfully treated with IV magnesium.This is also the first report,to our knowledge,of multiple episodes of SVT occurring during pregnancy in a patient who subsequently developed postpartum eclampsia,TdP,SVT,and LQTS. Further studies are needed to identify patients at high risk for postpartum induced LQTS/TdP and if SVT during pregnancy is a risk factor, as well as twin births and Cesarian deliveries.

While the definition of high-dose corticosteroids depends on the indication, it is typically defined as greater than 15–20 mg for greater than 2–4 weeks. Corticosteroids have a variety of indications such as autoimmune, gastrointestinal, rheumatologic, respiratory, and hematologic conditions and after organ or hematopoietic stem cell transplantation. They can predispose these patients to infections such as pneumococcal pneumonia, Pneumocystis jirovecii (carinii) pneumonia (PJP), hepatitis B reactivation, active tuberculosis, and disseminated strongyloides infection. This article outlines ways to modify these risks in these patients. Prophylaxis is of utmost importance to those at risk for PJP with trimethoprim/sulfamethoxazole, lamivudine for those at risk of hepatitis B reactivation, isoniazid (INH) for latent tuberculosis and ivermectin for those with positive strongyloides serology. Equally important in mitigating disease risk is the appropriate timing of vaccines to elicit an adequate immune response as well as offering additional vaccines such as the pneumococcal vaccine.RésuméLa notion de dose élevée de corticostéroïdes varie selon les indications, mais elle est généralement définie comme correspondant à plus de 15‑20 mg sur une période de plus de deux à quatre semaines. Les corticostéroïdes sont indiqués dans nombre de conditions auto‑immunes, gastro-intestinales, rhumatologiques, respiratoires et hématologiques, ainsi qu’à la suite d’une transplantation d’organe ou de cellules souches hématopoïétiques. Ils peuvent toutefois prédisposer les patients à diverses infections comme la pneumonie pneumococcique et la pneumonie à Pneumocystis jirovecii (carinii) ou PCP, à une réactivation de l’hépatite B, à une tuberculose active et à une strongyloïdose disséminée. Le présent article passe en revue différentes façons de réduire ces risques chez les patients concernés. Voici des mesures de prophylaxie qui s’avèrent être de la plus haute importance pour les personnes à risque : le triméthoprime ou le sulfaméthoxazole pour celles à risque de PCP; la lamivudine pour celles à risque de réactivation de l’hépatite B; l’isoniazide (INH) dans les cas de tuberculose latente; et l’ivermectine pour les personnes montrant une sérologie positive aux strongyloïdes. De plus, pour réduire le risque de maladie, un calendrier de vaccination approprié est tout aussi important, en vue de susciter une réponse immunitaire adéquate et de pouvoir offrir d’autres vaccins comme le vaccin antipneumococcique.Corticosteroids were first used in clinical practice in 1949 for rheumatoid arthritis.1 The number of patients on high-dose corticosteroids is not well known but the use of corticosteroids is becoming increasingly common for a number of indications: An estimated 1% of the general population in the UK is treated with corticosteroids, and this rate increases with age to almost 2.5% in those aged 70–79. 4“High-dose corticosteroids” as a risk factor for infections is typically defined as greater than 15–20 mg of prednisone (or its’ equivalent) for greater than 2–4 weeks, although this definition does vary slightly depending on the infection considered. Notably, this definition is different from the standard definition of high-dose corticosteroids for treatment purposes used in the literature – which is usually defined as greater than 30 mg but less than 100 mg/day – as this dose results in almost complete cytosolic receptor saturation. 2Corticosteroids are used commonly for their anti-inflammatory effects in many conditions with an element of autoimmune disease. The mechanism is to induce transient lymphocytopenia by altering lymphocyte circulation, inducing lymphocyte death and inhibiting cytokines to prevent T-cell activation.3 For example, they are used to induce remission in inflammatory bowel disease (IBD) or to maintain symptom control in rheumatologic diseases like polymyalgia rheumatica. They are also used to prevent organ rejection in solid organ transplantation. Other indications include autoimmune hepatitis, other rheumatologic diseases such as rheumatoid arthritis, systemic lupus erythematous, vasculitis, respiratory conditions such as interstitial lung disease, sarcoidosis, hematologic disorders such as lymphoma, leukemia, idiopathic thrombocytopenic purpura, hemolytic anemia), endocrine disorders like Graves disease to prevent opthalmopathy and other conditions like multiple sclerosis.The relative risk of bacterial infections was found to be 5-fold higher in IBD patients on corticosteroids alone, 4-fold higher for other infections like strongyloides and tuberculosis, and only 1.5 fold higher for viral infections.5 However, the absolute individual risk of infectious complications from corticosteroid use remains fairly small. Nevertheless, the burden is significant at a population level due to the high frequency of corticosteroid use. 4 Thus, most practitioners eventually come across these complications during their career.VaccinationsOne of the first considerations in patients on high-dose corticosteroids is the timing of the administration of vaccines to be given to these patients. Immunizations with inactivated vaccines can be given up to 2 weeks before high-dose corticosteroids are initiated, whereas live vaccines need to be given 4 weeks before the high-dose corticosteroids are begun. If the vaccines cannot be given prior to the start of a corticosteroid treatment, both live and inactivated vaccines must wait for 4 weeks after the steroids are completed to elicit an adequate immune response and prevent infectious complications with live vaccines.6Equally important to the timing of the vaccines, patients on high-dose corticosteroids (defined as anyone receiving ³ 20 mg/day for 14 days or more) should receive additional vaccines. A single dose of an inactivated pneumococcal conjugate vaccine (Prevnar), at least one year after any previous dose of pneumococcal vaccine polyvalent (Pneumovax), followed by a single dose of Pneumovax 8 weeks later with a booster of Pneumovax 5 years later is recommended for those on high-dose corticosteroids.7,8 Pneumocystis jiroveci infectionThe following patient groups are considered to be at higher risk forPneumocystis jiroveci pneumonia (PJP; formerly known as Pneumocystis carinii pneumonia [PCP])if exposed to prednisone at doses as low as 20 mg/day for at least 4 weeks9: patients with an underlying immunosuppressive disorder (including autologous HSCT and malignancy), or those with chronic obstructive pulmonary disease and interstitial lung disease secondary to polymyositis/dermatomyositis. Also, patients receiving the same dose of prednisone plus TNF-alpha inhibitors, cyclophosphamide, methotrexate, or temsirolimus should also receive PJP prophylaxis. The first-line agent for prophylaxis is trimethoprim/sulfamethoxazole 80/400 mg (single strength) daily or 160/800 mg (double strength) three times per week (e.g., Monday/Wednesday/Friday). While adverse events are rare on such low doses, thrombocytopenia is possible given that this is an idiosyncractic reaction but pancytopenia is usually observed at much higher (i.e., treatment) doses. Also possible are hyperkalemia, increased serum creatinine and aseptic meningitis. A more rare but devastating adverse event is Stevens-Johnson syndrome. A second line agent for PJP prophylaxis is dapsone but this requires glucose-6-phosphate dehydrogenase (G6PD) testing first, as those who are deficient in this erythrocytic enzyme show a two-fold higher predisposition to dapsone-induced hemolytic anemia. Other alternatives for PJP prophylaxis are atovaquone 1500 mg daily, but this is a costly option, or inhaled pentamidine via a nebulizer at 300 mg every month. Correct administration of inhaled pentamidine is crucial and due to the route of administration, disseminated PCP disease is still possible. 9 Hepatitis B ReactivationFurthermore, patients on corticosteroids of at least 20 mg/day for at least 4 weeks, have an 11–20% chance of reactivation if they are hepatitis B surface Ag carriers. An inactive carrier is hepatitis B surface antigen positive for greater than 6 months without detectable hepatitis B e antigen (HbeAg), presence of anti-hepatitis B e antibodies (anti-Hbe), and undetectable or low levels of hepatitis B DNA, repeatedly normal ALT levels, and no or minimal liver fibrosis. Inactive carriers comprise the largest group of chronic hepatitis B infected individuals with an estimated 250 million people worldwide and can convert to active disease under such immunosuppression.Therefore, it is prudent to prescribe hepatitis B prophylaxis to these patients although no high-level evidence supporting this approach is available.11 Lamivudine is considered first choice for these patients if they do not otherwise meet treatment criteria for hepatitis B. Tenofovir is considered first line in areas highly prevalent for resistance to lamivudine, which tends to occur with prolonged lamivudine exposure. For example, lamivudine resistance develops in up to 90% of HBV-HIV co-infected individuals after 4 years of lamivudine therapy.12.In the setting of isolated anti-Hb-core antibody positivity, prophylaxis is not recommendedgiven that the rate of reactivation is less than 1%.10 Instead, patients should have serial measurements of liver function, hepatitis B serology and hepatitis B DNA every 1–3 months during the period of immunosuppressive treatment and if there is any elevation in these markers, antiviral prophylaxis or treatment (depending on the results) should be offered.So, when assessing patients for the need for PCP or hepatitis B prophylaxis, both the intended duration as well as the dose of the corticosteroids need to be considered.Strongyloides stercoralis InfectionStrongyloides stercoralis can persist for several decades and can reactivate with glucocorticoid exposure causing a severe and sometimes fatal disseminated infection. Strongyloides infection can be asymptomatic and can be acquired walking barefoot on soil in the developing world.13 Strongyloides serology is therefore recommended for refugees from low-income countries in Southeast Asia and Africa where strongyloides is endemic before starting high-dose corticosteroid treatement.14 If positive, patients should be treated with 2 doses of ivermectin to prevent the development of hyperinfection. TuberculosisPatients with latent tuberculosis on higher dose and/or longer duration of glucocorticoid use are also at risk of conversion to active disease. A one-step tuberculin skin test (TST) ³ 5 mm is considered positive when a patient is on prednisone doses ³ 15 mg/day for one month or more. First-line treatment for latent tuberculosis is isoniazid over 9 months. Patients should begin therapy ideally at least 4 weeks before starting such immunosuppression to prevent conversion to active disease.15,16. If this is not possible, the recommendation is to start isoniazid and the corticosteroids at the same time. ConclusionsSerious and potentially fatal infections are just one of the many potential complications of being on high-dose corticosteroids for a long period of time – others include diabetes, hypertension, psychosis, osteoporosis, adrenal insufficiency and the development of cushingoid features.17 Infectious diseases that are either latent or inactive may reactivate under high-dose corticosteroids including tuberculosis, pneumocystis jirovecii pneumonia, Strongyloides stercoralis, and hepatitis B. Screening and treatment for such conditions prior to starting high-dose corticosteroids, or at least once the corticosteroids are started, can prevent these complications. Furthermore, the timing of both inactivated and live vaccines is crucial for the patients’ ability to mount an appropriate immune response and to avoid complications from live vaccines. Finally, patients on high-dose corticosteroids are at higher risk for illnesses that may require additional vaccinations not otherwise given to such individuals – for example the pneumococcal vaccine.DisclosureThere are no conflicts of interest for either author on this manuscript. References1. Zoorob RJ and Cender D. A different look at corticosteroids. American Family Physician. 1998 Aug 1; 58(2): 443-450. 2. Buttgereit F, Da Silva JAP, Boers M et al. Standardised nomenclature for glucocorticoid dosages and glucocorticoid treatment regimens: current questions and tentative answers in rheumatology. Ann Rheum Dis 2002; 61: 718-722. 3.Hall BM and Hodgkinson SJ. Corticosteroids in autoimmune diseases. Aust Prescr 1999; 22: 9-11. 4. T.P. van Staa, H.G. Leufkens, L. Abenhaim, B. Begaud, B. Zhang, C. Cooper. Use of oral corticosteroids in the United Kingdom. QJM. 2000 Feb; 93(2): 105–111. 5. Paul Brassard, Alain Bitton, Alain Suissa, Liliya Sinyavskaya, Valerie Patenaude and Samy Suissa. 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