Showing papers in "Drug Delivery in 2018"
TL;DR: The focus then turns to the most difficult barrier to potential in vivo use of CRISPR/Cas9, delivery, and detail the various cargos and delivery vehicles reported for CRISpr/ Cas9, including physical delivery vehicles, viral delivery methods, and non-viral delivery methods.
Abstract: Gene therapy has long held promise to correct a variety of human diseases and defects. Discovery of the Clustered Regularly-Interspaced Short Palindromic Repeats (CRISPR), the mechanism of the CRISPR-based prokaryotic adaptive immune system (CRISPR-associated system, Cas), and its repurposing into a potent gene editing tool has revolutionized the field of molecular biology and generated excitement for new and improved gene therapies. Additionally, the simplicity and flexibility of the CRISPR/Cas9 site-specific nuclease system has led to its widespread use in many biological research areas including development of model cell lines, discovering mechanisms of disease, identifying disease targets, development of transgene animals and plants, and transcriptional modulation. In this review, we present the brief history and basic mechanisms of the CRISPR/Cas9 system and its predecessors (ZFNs and TALENs), lessons learned from past human gene therapy efforts, and recent modifications of CRISPR/Cas9 to provide functions beyond gene editing. We introduce several factors that influence CRISPR/Cas9 efficacy which must be addressed before effective in vivo human gene therapy can be realized. The focus then turns to the most difficult barrier to potential in vivo use of CRISPR/Cas9, delivery. We detail the various cargos and delivery vehicles reported for CRISPR/Cas9, including physical delivery methods (e.g. microinjection; electroporation), viral delivery methods (e.g. adeno-associated virus (AAV); full-sized adenovirus and lentivirus), and non-viral delivery methods (e.g. liposomes; polyplexes; gold particles), and discuss their relative merits. We also examine several technologies that, while not currently reported for CRISPR/Cas9 delivery, appear to have promise in this field. The therapeutic potential of CRISPR/Cas9 is vast and will only increase as the technology and its delivery improves.
688 citations
TL;DR: It was showed that hyaluronic acid would have broad prospects for drug delivery and had good biocompatibility, biodegradability, and nonimmunogenicity.
Abstract: Hyaluronic acid has good biocompatibility, biodegradability, and nonimmunogenicity. In addition, it has the ability to recognize specific receptors that are overexpressed on the surface of tumor cells, and cancer drugs can be targeted to the tumor cells to better kill them. Therefore, hyaluronic acid has attracted much attention as drug delivery vehicle. Herein, the application of hyaluronic acid as carrier in drug delivery was analyzed and summarized in detail. It showed that hyaluronic acid would have broad prospects for drug delivery.
249 citations
TL;DR: It is suggested that PLGA-PEG-B6/Cur nanoparticles would be of potential and promising use for the treatment of Alzheimer’s disease.
Abstract: Alzheimer's disease is a neurodegenerative disorder mainly characterized by β-amyloid deposit and tau hyperphosphorylation with no curative treatments. Curcumin (Cur) has been proved to have potential use in Alzheimer's disease with its anti-amyloid, anti-inflammatory, and anti-oxidant properties, etc. However, its hydrophobicity and low bioavailability hinder its application. In this paper, we designed a novel brain-target nanoparticle, poly(lactide-co-glycolide)-block-poly(ethylene glycol) (PLGA-PEG) conjugated with B6 peptide and was loaded with Cur (PLGA-PEG-B6/Cur) and administered it into HT22 cells and APP/PS1 Al transgenic mice. The in vitro assays including dynamic light scattering (DLS), flow cytometry (FCM), red blood cell (RBC) lysis, and thromboelastography (TEG) analysis indicated that this nanoparticle could narrow the diameter of Cur, increase its cellular uptake and possess good blood compatibility. The results from Morris water maze proved that PLGA-PEG-B6/Cur could tremendously improve the spatial learning and memory capability of APP/PS1 mice, compared with native Cur. The ex vivo assays including Bielschowsky silver staining, immunostaining, and western blotting demonstrated that PLGA-PEG-B6/Cur could reduce hippocampal β-amyloid formation and deposit and tau hyperphosphorylation. Thus, we suggested that PLGA-PEG-B6/Cur nanoparticles would be of potential and promising use for the treatment of Alzheimer's disease.
128 citations
TL;DR: Nanodrug delivery systems are promising in targeting several therapeutic moieties by easing the penetration of drug molecules across the CNS and improving their bioavailability and future prospects on potential molecular targets for nano-drug Delivery systems are discussed.
Abstract: In recent years, the incidental rate of neurodegenerative disorders has increased proportionately with the aging population. Alzheimer's disease (AD) is one of the most commonly reported neurodegenerative disorders, and it is estimated to increase by roughly 30% among the aged population. In spite of screening numerous drug candidates against various molecular targets of AD, only a few candidates - such as acetylcholinesterase inhibitors are currently utilized as an effective clinical therapy. However, targeted drug delivery of these drugs to the central nervous system (CNS) exhibits several limitations including meager solubility, low bioavailability, and reduced efficiency due to the impediments of the blood-brain barrier (BBB). Current advances in nanotechnology present opportunities to overcome such limitations in delivering active drug candidates. Nanodrug delivery systems are promising in targeting several therapeutic moieties by easing the penetration of drug molecules across the CNS and improving their bioavailability. Recently, a wide range of nano-carriers, such as polymers, emulsions, lipo-carriers, solid lipid carriers, carbon nanotubes, metal based carriers etc., have been adapted to develop successful therapeutics with sustained release and improved efficacy. Here, we discuss few recently updated nano-drug delivery applications that have been adapted in the field of AD therapeutics, and future prospects on potential molecular targets for nano-drug delivery systems.
128 citations
TL;DR: The molecular mechanisms of overcoming cellular barriers, especially transcytosis, are focused on and difficulties of oral drug delivery via nanocarriers are highlighted, and paracellular transport routes lack selectivity of transported molecules once opened up.
Abstract: The oral application of pharmaceuticals is unarguably the most convenient method of application. Especially for protein- or peptide-based drugs, however, the effectiveness is significantly reduced due to enzymatic digestion in the stomach as well as a poor bioavailability in the small intestine. For these difficult formulations, the encapsulation into nanocarriers would protect the sensitive drug and thus could considerably improve the efficiency of oral drug delivery. In the last years, many candidate biodegradable nanomaterials for such carrier systems have been published. However, before the cargo can be released, the nanocarrier needs to cross multiple barriers of the human body, including a layer of intestinal mucus and epithelial as well as endothelial cells. For overcoming these cellular barriers, transcytosis is favored over a paracellular transport for most nanomaterials as paracellular transport routes lack selectivity of transported molecules once opened up. The exact mechanisms behind the transcellular translocations are up to now still not completely understood. For the vast majority of nanocarriers, the rate of transcellular transport is not sufficient to realize their application in oral drug delivery. Especially trafficking into the endolysosomal pathway often marks a key problem. In this review, we focus on the molecular mechanisms of overcoming cellular barriers, especially transcytosis, and highlight difficulties of oral drug delivery via nanocarriers.
122 citations
TL;DR: H19EMNVs had a strong ability to neutralize the regeneration-inhibiting effect of hyperglycemia, and could remarkably accelerate the healing processes of chronic wounds, suggesting that bioengineered EMNVs can serve as a powerful instrument to effectively deliver LncRNA and will be an extremely promising multifunctional drug delivery system in the immediate future.
Abstract: Diabetic wounds, one of the most enervating complications of diabetes mellitus, affect millions of people worldwide annually. Vascular insufficiency, caused by hyperglycemia, is one of the primary causes and categories of diabetic impaired wound healing. Recently, long noncoding RNA (LncRNA)-H19, which is significantly decreased in diabetes and may be crucial in triggering angiogenesis, has attracted increasing interest. The possible relationship between the decrease of LncRNA-H19 and the impairment of angiogenesis in diabetes could involve impairment of the insulin-phosphatidylinositol 3-kinase (PI3K)-Akt pathway via the interdiction of LncRNA-H19. Thus, a therapeutic strategy utilizing LncRNA-H19 delivery is feasible. In this study, we investigated the possibility of using high-yield extracellular vesicle-mimetic nanovesicles (EMNVs) as an effective nano-drug delivery system for LncRNA, and studied the function of EMNVs with a high content of LncRNA-H19 (H19EMNVs). The results, which were exciting, showed that H19EMNVs had a strong ability to neutralize the regeneration-inhibiting effect of hyperglycemia, and could remarkably accelerate the healing processes of chronic wounds. Our results suggest that bioengineered EMNVs can serve as a powerful instrument to effectively deliver LncRNA and will be an extremely promising multifunctional drug delivery system in the immediate future.
104 citations
TL;DR: Findings of the study suggest that the developed FLZ loaded SLNs topical gels have superior significant fast therapeutic index in treatment of PV over commercially available Candistan® cream.
Abstract: Solid lipid nanoparticles (SLNs) are very potential formulations for topical delivery of antifungal drugs. Hence, the purpose of this research was to formulate the well-known antifungal agent Fluconazole (FLZ)-loaded SLNs topical gel to improve its efficiency for treatment of Pityriasis Versicolor (PV). FLZ-SLNs were prepared by modified high shear homogenization and ultrasonication method using different concentration of solid lipid (Compritol 888 ATO, Precirol ATO5) and surfactant (Cremophor RH40, Poloxamer 407). The physicochemical properties and the in vitro release study for all FLZ-SLNs were investigated. Furthermore, the optimized FLZ-SLN formula was incorporated into gel using Carpobol 934. A randomized controlled clinical trial (RCT) of potential batches was carried out on 30 well diagnosed PV patients comparing to market product Candistan® 1% cream. Follow up was done for 4 weeks by clinical and KOH examinations. The results showed that FlZ-SLNs were almost spherical shape having colloid...
103 citations
TL;DR: In vitro cytotoxic tests demonstrated that Cur SD induced higher cytotoxicity against glioblastoma U-87 MG cells than free Cur, and an improvement of membranes permeability of Cur SD was confirmed by parallel artificial membrane permeability assay.
Abstract: An amorphous solid dispersion (SD) of curcumin (Cur) with disodium glycyrrhizin (Na2GA) was prepared by mechanical ball milling. Curcumin loaded micelles were self-formed by Na2GA when SD dissolved...
94 citations
TL;DR: This review discussed the possible mechanisms of nanomaterial’s action on the regulation of immunological functions and several major applications of this advanced drug delivery system for tumor peptide vaccine.
Abstract: In the past 40 years, the nanoparticle drug delivery system for tumor peptide vaccines has been widely studied which also reached a splendid result. Nanomaterial can enhance the targeting of vaccines, help vaccines enter the cells and trigger immune response by themselves. They also help in increasing cellular uptake, improving permeability and efficacy. Currently, several categories of nanopreparation, such as liposome, polymeric micelle, polymeric nanoparticle, gold nanoparticle and so on, are proved that they are appropriate for peptide vaccines. This review we discussed the possible mechanisms of nanomaterial’s action on the regulation of immunological functions and several major applications of this advanced drug delivery system for tumor peptide vaccine.
81 citations
TL;DR: It is suggested that encapsulating glucocorticoids such as PD in HA-coated SLNs may render them safe and effective for treating inflammatory disorders.
Abstract: Rheumatoid arthritis (RA) is a chronic, systemic inflammatory disease. Long-term, high-dose glucocorticoid therapy can be used to treat the disease, but the fact that the drug distributes systemically can give rise to severe adverse effects. Here we develop a targeted system for treating RA in which the glucocorticoid prednisolone (PD) is encapsulated within solid lipid nanoparticles (SLNs) coated with hyaluronic acid (HA), giving rise to HA-SLNs/PD. HA binds to hyaluronic receptor CD44, which is over-expressed on the surface of synovial lymphocytes, macrophages and fibroblasts in inflamed joints in RA. As predicted, HA-SLNs/PD particles accumulated in affected joint tissue after intravenous injection into mice with collagen-induced arthritis (CIA), and HA-SLNs/PD persisted longer in circulation and preserved bone and cartilage better than free drug or drug encapsulated in SLNs without HA. HA-SLNs/PD reduced joint swelling, bone erosion and levels of inflammatory cytokines in serum. These results suggest that encapsulating glucocorticoids such as PD in HA-coated SLNs may render them safe and effective for treating inflammatory disorders.
79 citations
TL;DR: A new strategy exploiting M1 macrophage as carrier for drug delivery is provided, which improved targeting efficiency and therapeutic efficacy of chemodrugs for glioma therapy.
Abstract: Glioma remains difficult to treat because of the infiltrative growth of tumor cells and their resistance to standard therapy. Despite rapid development of targeted drug delivery system, the current therapeutic efficacy is still challenging. Based on our previous studies, macrophages have been proved to be promising drug carrier for active glioma delivery. To make full use of macrophage carrier, primary M1 macrophages were proposed to replace regular macrophage to deliver nanodrugs into glioma, because M1 macrophages not only have the natural ability to home into tumor tissues, but they also have stronger phagocytic capability than other types of macrophage, which can enable them to uptake enough drug-loaded nanoparticles for therapy. In addition, M1 macrophages are not easily affected by harsh tumor microenvironment and inhibit tumor growth themselves. In this study, M1 macrophage-loaded nanoparticles (M1-NPs) were prepared by incubating poly(lactide-co-glycolide) (PLGA) nanoparticles with primary M1 macrophages. In vitro cell assays demonstrated M1 macrophage still maintained good tumor tropism capability after particle loading, and could efficiently carry particles across endothelial barrier into tumor tissues. In vivo imaging verified that M1-NPs exhibited higher brain tumor distribution than free nanoparticles. DOX@M1-NPs (doxorubicin-loaded M1-NPs) presented significantly enhanced anti-glioma effect with prolonged survival median and increased cell apoptosis. In conclusion, the results provided a new strategy exploiting M1 macrophage as carrier for drug delivery, which improved targeting efficiency and therapeutic efficacy of chemodrugs for glioma therapy.
TL;DR: This review introduces the technique detail of membrane perforation, with a brief discussion for future development, with special emphasis on nanoparticles mediated optoporation that have developed as an new alternative transfection technique in the last two decades.
Abstract: Gene delivery as a promising and valid tool has been used for treating many serious diseases that conventional drug therapies cannot cure. Due to the advancement of physical technology and nanotechnology, advanced physical gene delivery methods such as electroporation, magnetoporation, sonoporation and optoporation have been extensively developed and are receiving increasing attention, which have the advantages of briefness and nontoxicity. This review introduces the technique detail of membrane perforation, with a brief discussion for future development, with special emphasis on nanoparticles mediated optoporation that have developed as an new alternative transfection technique in the last two decades. In particular, the advanced physical approaches development and new technology are highlighted, which intends to stimulate rapid advancement of perforation techniques, develop new delivery strategies and accelerate application of these techniques in clinic.
TL;DR: DOX-loaded liposomes, surface-modified with, R8 and transferrin (Tf) (Dual DOX-L), are reported on to improve targeting of A2780 ovarian carcinoma cells via the over-expressed transferrin receptors with R8-mediated intracellular DOX delivery.
Abstract: Off-target effects of drugs severely limit cancer therapy. Targeted nanocarriers are promising to enhance the delivery of therapeutics to tumors. Among many approaches for active tumor-targeting, a...
TL;DR: The in vivo results displayed higher anti-leishmanial activity by efficiently healing lesion and successfully reducing parasite burden, and indicated that the targeted delivery of SSG could be accomplished by using topically applied NDLs for the effective treatment of CL.
Abstract: Topical drug delivery against cutaneous leishmaniasis (CL) signifies an effective alternate for improving the availability and reducing the toxicity associated with the parenteral administration of conventional sodium stibogluconate (SSG) injection. The basic aim of the study was to develop nano-deformable liposomes (NDLs) for the dermal delivery of SSG against CL. NDLs were formulated by a modified thin film hydration method and optimized via Box–Behnken statistical design. The physicochemical properties of SSG-NDLs were established in terms of vesicle size (195.1 nm), polydispersity index (0.158), zeta potential (−32.8 mV), and entrapment efficiency (35.26%). Moreover, deformability index, in vitro release, and macrophage uptake studies were also accomplished. SSG-NDLs were entrapped within Carbopol gel network for the ease of skin application. The ex vivo skin permeation study revealed that SSG-NDLs gel provided 10-fold higher skin retention towards the deeper skin layers, attained without use ...
TL;DR: For the first time, the four-layer structural model of the artery tissue and its porosity parameters are modeled in this study which enables the interaction of particles with the tissue walls in blood flow to provide insights into the decisive factors in arterial MDT.
Abstract: Magnetic drug targeting (MDT) and magnetic-based drug/cargo delivery are emerging treatment methods which attracting the attention of many researchers for curing different cancers and artery diseases such as atherosclerosis. Herein, computational studies are accomplished by utilizing magnetic approaches for cancer and artery atherosclerosis drug delivery, including nanomagnetic drug delivery and magnetic-based drug/cargo delivery. For the first time, the four-layer structural model of the artery tissue and its porosity parameters are modeled in this study which enables the interaction of particles with the tissue walls in blood flow. The effects of parameters, including magnetic field strength (MFS), magnet size, particle size, the initial position of particles, and the relative magnetic permeability of particles, on the efficacy of MDT through the artery walls are characterized. The magnetic particle penetration into artery layers and fibrous cap (the covering layer over the inflamed part of the artery) is further simulated. The MDT in healthy and diseased arteries demonstrates that some of the particles stuck in these tissues due to the collision of particles or blood flow deviation in the vicinity of the inflamed part of the artery. Therefore the geometry of artery and porosity of its layers should be considered to show the real interaction of particles with the artery walls. Also, the results show that increasing the particles/drug/cargo size and MFS leads to more particles/drug/cargo retention within the tissue. The present work provides insights into the decisive factors in arterial MDT with an obvious impact on locoregional cancer treatment, tissue engineering, and regenerative medicine.
TL;DR: Dl-TPL-lip significantly enhanced TPL anti-cancer efficacy without apparent systemic toxicity after pulmonary administration in orthotopic lung tumor-bearing mice, presenting a potential system for localized and targeted delivery of anti- cancer drugs to improve their efficacy.
Abstract: The abilities of a drug delivery system to target and penetrate tumor masses are key factors in determining the system's chemotherapeutic efficacy. Here, we explored the utility of an anti-carbonic anhydrase IX (anti-CA IX) antibody and CPP33 dual-ligand modified triptolide-loaded liposomes (dl-TPL-lip) to simultaneously enhance the tumor-specific targeting and increase tumor cell penetration of TPL. In vitro, the dl-TPL-lip increased the cytotoxicity of TPL in CA IX-positive lung cancer cells, which showed tunable size (137.6 ± 0.8 nm), high-encapsulation efficiency (86.3 ± 2.6%) and sustained release. Dl-TPL-lip significantly improved the ability of liposomes to penetrate 3 D tumor spheroids and exhibited a superior inhibiting effect. Furthermore, pharmacokinetic studies in rats that received TPL liposomal formulations by endotracheal administration showed a reduced concentration of TPL (17.3%-30.6% compared to free TPL) in systemic circulation. After pulmonary administration in orthotopic lung tumor-bearing mice, dl-TPL-lip significantly enhanced TPL anti-cancer efficacy without apparent systemic toxicity. This dual-ligand modified liposomal vehicle presents a potential system for localized and targeted delivery of anti-cancer drugs to improve their efficacy.
TL;DR: Results indicated that anti-EPHA3-modified NPs may potentially serve as a nose-to-brain drug carrier for the treatment of glioblastoma.
Abstract: Glioblastoma is the most common malignant brain tumor Efficient delivery of drugs targeting glioblastomas remains a challenge Ephrin type-A receptor 3 (EPHA3) tyrosine kinase antibody-modified po
TL;DR: In vivo xenografts tumors in nude-mouse model results showed that siFoxM1-Apt-CNBs combined with UMND led to significant inhibition of tumor growth and prolonged the survival of the mice, with low toxicity, an obvious reduction in FoxM1 expression, and a higher apoptosis index.
Abstract: The Forkhead box M1 (FoxM1) transcription factor is an important anti-tumor target. A novel targeted ultrasound (US)-sensitive nanobubble that is likely to make use of the physical energy of US exposure for the improvement of delivery efficacy to target tumors and specifically silence FoxM1 expression appears as among the most potential nanocarriers in respect of drug delivery. In this study, we synthesized a promising anti-tumor targeted FoxM1 siRNA-loaded cationic nanobubbles (CNBs) conjugated with an A10-3.2 aptamer (siFoxM1-Apt-CNBs), which demonstrate high specificity when binding to prostate-specific membrane antigen (PSMA) positive LNCaP cells. Uniform nanoscaled siFoxM1-Apt-CNBs were developed using a thin-film hydration sonication, carbodiimide chemistry approaches, and electrostatic adsorption methods. Fluorescence imaging as well as flow cytometry evidenced the fact that the siFoxM1-Apt-CNBs were productively developed and that they specifically bound to PSMA-positive LNCaP cells. siFoxM1-Apt-CNBs combined with ultrasound-mediated nanobubble destruction (UMND) significantly improved transfection efficiency, cell apoptosis, and cell cycle arrest in vitro while reducing FoxM1 expression. In vivo xenografts tumors in nude-mouse model results showed that siFoxM1-Apt-CNBs combined with UMND led to significant inhibition of tumor growth and prolonged the survival of the mice, with low toxicity, an obvious reduction in FoxM1 expression, and a higher apoptosis index. Our study suggests that siFoxM1-Apt-CNBs combined with UMND might be a promising targeted gene delivery strategy for therapy of prostate cancer.
TL;DR: Investigation of a strategy based on the development of nanostructured lipid carriers (NLC) as an innovative oral pediatric formulation of HCT with improved therapeutic efficacy found NLCs exhibited great entrapment efficiency values clearly higher than previous SLNs.
Abstract: The hydrochlorothiazide (HCT) low solubility and permeability give rise to limited and variable bioavailability; its low stability makes it difficult to develop stable aqueous liquid formulations; ...
TL;DR: Azone, oleic acid, and Tc were able to provide adequate TQ flux and may be the agents of choice for use in a novel transdermal formulation of TQ, and these penetration enhancers were also able to generate TQ reservoirs in the skin that may be useful to provide sustained release of T Q from the stratum corneum over longer periods of time.
Abstract: Thymoquinone (TQ) is a quinone-based phytochemical that was first identified in 1963 in Nigella sativa (black cumin seed) by El-Dakhakhany. Based on the ideal characteristics of transdermal delivery, TQ is potentially an attractive candidate for transdermal drug delivery. The aim of this study was to investigate the feasibility of transdermal delivery of TQ and to assess the effect of an ethanol and propylene glycol donor solvent system along with various compositions of receptor solvents. The effects of penetration enhancers on the in vitro skin permeation and TQ skin absorption were studied using human cadaver skin in Franz diffusion cells. The permeation of saturated solutions of TQ was investigated with 5% v/v of each of the following enhancers: Azone (laurocapram), Transcutol® P (Tc), oleic acid, ethanol, Polysorbate 80 (Tween 80), and N-methyl-pyrrolidone (NMP). The results indicated that Azone, oleic acid, and Tc were able to provide adequate TQ flux and may be the agents of choice for use in a novel transdermal formulation of TQ. These penetration enhancers were also able to generate TQ reservoirs in the skin that may be useful to provide sustained release of TQ from the stratum corneum over longer periods of time.
TL;DR: This work proposes a new magnetically assisted strategy to elevate drug penetration into peritoneal tumor nodules and improve IP chemotherapy and shows an order of magnitude increase in the final intratumoral concentration of drug-coated MNPs with respect to free cytotoxic agents.
Abstract: Intraperitoneal (IP) chemotherapy has revived hopes during the past few years for the management of peritoneal disseminations of digestive and gynecological cancers. Nevertheless, a poor drug penet...
TL;DR: A two-factor three-level central composite face-centered design was employed to optimize the formulation variables to obtain LCDP polymeric micelles of high entrapment efficiency and small and uniform particle size (PS), which showed saturation solubility approximately 450 times that of raw LCDP.
Abstract: This study aims at preparing and optimizing lacidipine (LCDP) polymeric micelles using thin film hydration technique in order to overcome LCDP solubility-limited oral bioavailability. A two-factor ...
TL;DR: Prepared DP-CLPs–PTX–siRNA nanocomplex selectively induced CD133+ glioma stem cell apoptosis in vitro and in vivo exhibits great potential for targeted imaging and therapy of brain gliomas stem cells.
Abstract: Development of safe, efficient nanocomplex for targeted imaging and therapy of cancer stem cells in brain glioma has become a great challenge. Herein, a low-density lipoprotein receptor-related protein and a RNA aptamer bound CD133 were used as dual-targeting ligands to prepare dual-modified cationic liposomes (DP-CLPs) loaded with survivin siRNA and paclitaxel (DP-CLPs-PTX-siRNA) for actively targeting imaging and treating CD133+ glioma stem cells after passing through the blood-brain barrier. After being administrated with DP-CLPs-PTX-siRNA nanocomplex, DP-CLPs showed a persistent target ability to bind glioma cells and brain microvascular endothelial cells (BCECs) and to deliver drugs (PTX/siRNA) to CD133+ glioma stem cells. Prepared DP-CLPs-PTX-siRNA nanocomplex showed very low cytotoxicity to BCECs, but induced selectively apoptosis of CD133+ glioma stem cells, and improved CD133+ glioma stem cells' differentiation into non-stem-cell lineages, also markedly inhibited tumorigenesis, induced CD133+ glioma cell apoptosis in intracranial glioma tumor-bearing nude mice and improved survival rates. In conclusion, prepared DP-CLPs-PTX-siRNA nanocomplex selectively induced CD133+ glioma stem cell apoptosis in vitro and in vivo exhibits great potential for targeted imaging and therapy of brain glioma stem cells.
TL;DR: This work highlights a liposome-based nanomedicine that could effectively deliver oxygen to tumor and alleviate tumor hypoxia state, inducing greatly improved efficacy compared to conventional cancer PDT and demonstrates the promise of modulating unfavorable tumor microenvironment with nanotechnology to overcome limitations of cancer therapies.
Abstract: Photosensitizer, proper laser irradiation, and oxygen are essential components for effective photodynamic therapy (PDT) in clinical cancer therapy. However, native hypoxic tumoral microenvironment is a major barrier hindering photodynamic reactions in vivo. Thus, we have prepared biocompatible liposomes by loading complexes of oxygen-carrier (hemoglobin, Hb) and photosensitizer (indocyanine green, ICG) for enhanced PDT against hypoxic tumor. Ideal oxygen donor Hb, which is an oxygen-carried protein in red blood cells, makes such liposome which provide stable oxygen supply. ICG, as a photosensitizer, could transfer energy from lasers to oxygen to generate cytotoxic reactive oxygen species (ROS) for treatment. The liposomes loading ICG and Hb (LIH) exhibited efficient tumor homing upon intravenous injection. As revealed by T2-weighted magnetic resonance imaging and immunohistochemical analysis, the intratumoral hypoxia was greatly alleviated, and the level of hypoxia inducible factor-1α (HIF-1α) and vascular endothelial growth factor (VEGF) in tumor was obviously down-regulated. A weak PDT efficiency was found in cells incubated in simulated hypoxia condition in vitro, while PDT effect was dramatically enhanced in LIH treated hypoxia cells under near-infrared (NIR) laser, which was mainly attributed to massive generation of ROS with sufficient oxygen supply. ROS trigger oxidative damage of tumors and induce complete suppression of tumor growth and 100% survival rate of mice, which were also in good health condition. Our work highlights a liposome-based nanomedicine that could effectively deliver oxygen to tumor and alleviate tumor hypoxia state, inducing greatly improved efficacy compared to conventional cancer PDT and demonstrates the promise of modulating unfavorable tumor microenvironment with nanotechnology to overcome limitations of cancer therapies.
TL;DR: The preparation, characterization, and ‘switch-on/off’ mechanism of typical pullulan self-assembled nanogels (self-nanogels) are described, and the development of hybrid hydrogels that are numerous resources applied for regenerative medicine are introduced.
Abstract: Polymer nano-sized hydrogels (nanogels) as drug delivery carriers have been investigated over the last few decades. Pullulan, a nontoxic and nonimmunogenic hydrophilic polysaccharide derived from fermentation of black yeast like Aureobasidium pullulans with great biocompatibility and biodegradability, is one of the most attractive carriers for drug delivery systems. In this review, we describe the preparation, characterization, and 'switch-on/off' mechanism of typical pullulan self-assembled nanogels (self-nanogels), and then introduce the development of hybrid hydrogels that are numerous resources applied for regenerative medicine. A major section is used for biomedical applications of different nanogel systems based on modified pullulan, which exert smart stimuli-responses at ambient conditions such as charge, pH, temperature, light, and redox. Pullulan self-nanogels have found increasingly extensive application in protein delivery, tissue engineering, vaccine development, cancer therapy, and biological imaging. Functional groups are incorporated into self-nanogels and contribute to expressing desirable results such as targeting and modified release. Various molecules, especially insoluble or unstable drugs and encapsulated proteins, present improved solubility and bioavailability as well as reduced side effects when incorporated into self-nanogels. Finally, the advantages and disadvantages of pullulan self-nanogels will be analyzed accordingly, and the development of pullulan nanogel systems will be reviewed.
TL;DR: The biodistribution study showed that the transdermal 99mTc-SF hydrogel exhibited a more sustained release pattern and longer circulation duration with pulsatile behavior in the blood and higher brain levels than the oral 99mRq-SF dispersion.
Abstract: Haloperidol (Hal) is one of the widely used antipsychotic drugs. When orally administered, it suffers from low bioavailability due to hepatic first pass metabolism. This study aimed at developing Hal-loaded penetration enhancer-containing spanlastics (PECSs) to increase transdermal permeation of Hal with sustained release. PECSs were successfully prepared using ethanol injection method showing reasonable values of percentage entrapment efficiency, particle size, polydispersity index and zeta potential. The statistical analysis of the ex vivo permeation parameters led to the choice of F1L – made of Span® 60 and Tween® 80 at the weight ratio of 4:1 along with 1% w/v Labrasol® – as the selected formula (SF). SF was formulated into a hydrogel by using 2.5% w/v of HPMC K4M. The hydrogel exhibited good in vitro characteristics. Also, it retained its physical and chemical stability for one month in the refrigerator. The radiolabeling of SF showed a maximum yield by mixing of 100 µl of diluted formula wit...
TL;DR: The in-vivo pharmacodynamic study showed that OF could result in higher reduction in IOP, significantly sustain that reduction inIOP and increase Dorz bioavailability compared to Trusopt® eye drops, which is very promising for being used in glaucoma treatment.
Abstract: Glaucoma is the second cause of blindness worldwide. Frequent administration of traditional topical dosage forms may lead to patient incompliance and failure of treatment. Our study aims to formula...
TL;DR: In vitro cytotoxicity tests have demonstrated that this drug-delivery system can deliver efficiently DOX and CPT for combination therapy and is versatile and easy to assemble, not requiring the chemical modification of the drugs.
Abstract: A dual doxorubicin/camptothecin (DOX/CPT) pH-triggered drug delivery mesoporous silica nanoparticle (MSN)-based nano-vehicle has been prepared. In this drug-delivery system (DDS), CPT is loaded inside the pores of the MSNs, while DOX is covalently attached to the surface of an aldehyde-functionalized MSN through a dihydrazide-polyethylene glycol chain. Thus, DOX and the linker act as pH-sensitive gatekeeper. The system is versatile and easy to assemble, not requiring the chemical modification of the drugs. While at physiological conditions the release of the drugs is negligible, at acidic pH a burst release of DOX and a gradual release of CPT take place. In vitro cytotoxicity tests have demonstrated that this DDS can deliver efficiently DOX and CPT for combination therapy.
TL;DR: The data suggest that Bev-MVLs are biologically feasible to increase the retention time of bevacizumab in vitreous humor and may serve as a promising sustained release drug delivery system for the treatment of CNV.
Abstract: Bevacizumab is an anti-vascular endothelial growth factor drug that can be used to treat choroidal neovascularization (CNV). Bevacizumab-loaded multivesicular liposomes (Bev-MVLs) have been designed and developed to increase the intravitreal retention time of bevacizumab and reduce the number of injection times. In this study, Bev-MVLs with high encapsulation efficiency were prepared by double emulsification technique, and antibody activity was determined. The results revealed that 10% of human serum albumin (HSA) could preserve the activity of bevacizumab. In vitro release of Bev-MVLs appeared to be in a more sustained manner, the underlying mechanisms of Bev-MVLs indicated that bevacizumab was released from MVLs through diffusion and erosion. Results of sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) demonstrated that bevacizumab could retain its structural integrity after being released from MVLs in vitro. In vivo imaging was used to evaluate the retention time of antibody ...
TL;DR: It is demonstrated that HA-CH-NP/siRNA is a highly selective delivery platform for siRNA, and has broad potential to be used in anti-angiogenesis tumor therapy.
Abstract: Angiogenesis plays an essential role in the growth and metastasis of tumor cells, and the modulation of angiogenesis can be an effective approach for cancer therapy. We focused on silencing the angiogenic gene PLXDC1 as an important factor for anti-angiogenesis tumor therapy. Herein, we developed PLXDC1 small interfering siRNA (siRNA)-incorporated chitosan nanoparticle (CH-NP/siRNA) coated with hyaluronic acid (HA) to target the CD44 receptor on tumor endothelial cells. This study aimed to improve targeted delivery and enhance therapeutic efficacy for tumor anti-angiogenesis. The HA-CH-NP/siRNA was 200 ± 10 nm in size with a zeta potential of 26.4 mV. The loading efficiency of siRNA to the HA-CH-NP/siRNA was up to 60%. The selective binding of HA-CH-NP/siRNA to CD44-positive tumor endothelial cells increased by 2.1-fold compared with that of the CD44 nontargeted CH-NP/siRNA. PLXDC1 silencing by the HA-CH-NP/siRNA significantly inhibited tumor growth in A2780 tumor-bearing mice compared with that in the control group (p < .01), and mRNA expression of PLXDC1 was significantly reduced in the HA-CH-NP/siRNA-treated group. Furthermore, treatment with HA-CH-NP/siRNA resulted in significant inhibition of cell proliferation (p < .001), reduced microvessel density (p < .001), and increased cell apoptosis (p < .001). This study demonstrates that HA-CH-NP/siRNA is a highly selective delivery platform for siRNA, and has broad potential to be used in anti-angiogenesis tumor therapy.