Release of small molecules from aggregates consisting of an amphiphilic oligonucleotide functionalized by a photochromic azobenzene unit

Stimuli-responsive nanocarriers offer favorable properties for the target-specific delivery of drugs. Herein, we employed photoirradiation as an external stimulus for the construction of a molecular system that encapsulated small molecules, which were released upon photoirradiation. These nanocarriers consisted of DNA amphiphiles (ODAz 1), in which an oligodeoxynucleotide and an alkyl chain were employed as the hydrophilic and hydrophobic parts, respectively, and these two parts were linked by a photochromic azobenzene unit. In aqueous solutions, ODAz 1 formed nanosized aggregates that encapsulated hydrophobic molecules in their hydrophobic core. Photoirradiation induced isomerization of the azobenzene unit led to changes in aggregate size and the immediate release of the molecules. The aggregate smoothly penetrated the cell membrane, and the photochemical release and delivery of small molecules into living cells were achieved. Thus, ODAz 1 aggregates represent promising photosensitive nanocarriers that may be applicable to drug delivery and targeting.     

Systemic Brain Delivery of Antisense Oligonucleotides across the Blood–Brain Barrier with a Glucose-Coated Polymeric Nanocarrier

Current antisense oligonucleotide (ASO) therapies for the treatment of central nervous system (CNS) disorders are performed through invasive administration, thereby placing a major burden on patients. To alleviate this burden, we herein report systemic ASO delivery to the brain by crossing the blood–brain barrier using glycemic control as an external trigger. Glucose-coated polymeric nanocarriers, which can be bound by glucose transporter-1 expressed on the brain capillary endothelial cells, are designed for stable encapsulation of ASOs, with a particle size of about 45 nm and an adequate glucose-ligand density. The optimized nanocarrier efficiently accumulates in the brain tissue 1 h after intravenous administration and exhibits significant knockdown of a target long non-coding RNA in various brain regions, including the cerebral cortex and hippocampus. These results demonstrate that the glucose-modified polymeric nanocarriers enable noninvasive ASO administration to the brain for the treatment of CNS disorders.     

Systemic Brain Delivery of Antisense Oligonucleotides across the Blood–Brain Barrier with a Glucose‐Coated Polymeric Nanocarrier

Current antisense oligonucleotide (ASO) therapies for the treatment of central nervous system (CNS) disorders are performed through invasive administration, thereby placing a major burden on patients. To alleviate this burden, we herein report systemic ASO delivery to the brain by crossing the blood–brain barrier using glycemic control as an external trigger. Glucose‐coated polymeric nanocarriers, which can be bound by glucose transporter‐1 expressed on the brain capillary endothelial cells, are designed for stable encapsulation of ASOs, with a particle size of about 45 nm and an adequate glucose‐ligand density. The optimized nanocarrier efficiently accumulates in the brain tissue 1 h after intravenous administration and exhibits significant knockdown of a target long non‐coding RNA in various brain regions, including the cerebral cortex and hippocampus. These results demonstrate that the glucose‐modified polymeric nanocarriers enable noninvasive ASO administration to the brain for the treatment of CNS disorders.     

Modeling of highly efficient drug delivery system induced by self-assembly of nanocarriers: A density functional study

Owing to the importance of drug delivery in cancer or other diseases’ therapy, the targeted drug delivery (TDD) system has been attracting enormous interest. Herein, we model the TDD system and design a novel rod-like nanocarrier by using the coarse grained model-based density functional theory, which combines a modified fundamental measure theory for the excluded-volume effects, Wertheim’s first-order thermodynamics perturbation theory for the chain connectivity and the mean field approximation for van der Waals attraction. For comparison, the monomer nanocarrier TDD system and the no nanocarrier one are also investigated. The results indicate that the drug delivery capacity of rod-like nanocarriers is about 62 times that of the no nanocarrier one, and about 6 times that of the monomer nanocarriers. The reason is that the rod-like nanocarriers would self-assemble into the smectic phase perpendicular to the membrane surface. It is the self-assembly of the rod-like nanocarriers that yields the driving force for the targeted delivery of drugs inside the cell membrane. By contrast, the conventional monomer nanocarrier drug delivery system lacks the driving force to deliver the drugs into the cell membrane. In short, the novel rod-like nanocarrier TDD system may improve the drug delivery efficiency. Although the model in this work is simple, it is expected that the system may provide a new perspective for cancer targeted therapy.     

Size-controlled long-circulating PICsome as a ruler to measure critical cut-off disposition size into normal and tumor tissues

Selective disposition of nanocarriers into target tissue is an essential issue in drug delivery. Critical size of nanocarriers (～150 nm) discriminating the permeability into normal and tumor tissues was determined by the use of size-tunable, polyion complex hollow vesicles (PICsome) as a ruler.     

Progress in drug delivery to the central nervous system by the prodrug approach

This review describes specific strategies for targeting to the central nervous system (CNS). Systemically administered drugs can reach the brain by crossing one of two physiological barriers resistant to free diffusion of most molecules from blood to CNS: the endothelial blood-brain barrier or the epithelial blood-cerebrospinal fluid barrier. These tissues constitute both transport and enzymatic barriers. The most common strategy for designing effective prodrugs relies on the increase of parent drug lipophilicity. However, increasing lipophilicity without a concomitant increase in rate and selectivity of prodrug bioconversion in the brain will result in failure. In these regards, consideration of the enzymes present in brain tissue and in the barriers is essential for a successful approach. Nasal administration of lipophilic prodrugs can be a promising alternative non-invasive route to improve brain targeting of the parent drugs due to fast absorption and rapid onset of drug action. The carrier-mediated absorption of drugs and prodrugs across epithelial and endothelial barriers is emerging as another novel trend in biotherapeutics. Several specific transporters have been identified in boundary tissues between blood and CNS compartments. Some of them are involved in the active supply of nutrients and have been used to explore prodrug approaches with improved brain delivery. The feasibility of CNS uptake of appropriately designed prodrugs via these transporters is described in detail.     

Stellate porous silica based surface-enhanced Raman scattering system for traceable gene delivery

Numerous nanocarriers have been currently developed for intracellular delivery. The potential cytotoxicity of these very small inorganic nanocarriers has raised great consideration. Thus, it becomes of utmost importance to conduct the intracellular trace of nanocarriers. Among many analytical techniques, surface enhanced Raman scattering(SERS) method is one of the current state-of-the-art techniques for cell visualization and trace. In this work, a novel stellate porous silica based gene delivery system has been designed for SERS trace purpose. A stellate porous silica nanoparticle modified with many small Au nanoparticles is designed to replace common metallic SERS tags. The results show that the designed system not only could deliver si RNA into cells for therapy, but also could realize SERS trace with high sensitivity and non-invasive features. The constructed delivery system has considerable potential to trace the dynamic gene delivery in living cells.     

Calcium Phosphate Nanocarriers Dual‐Loaded with Bovine Serum Albumin and Ibuprofen: Facile Synthesis,Sequential Drug Loading and Sustained Drug Release

A simple and green strategy is reported for the preparation, drug loading, and release properties of a drug delivery system consisting of calcium phosphate (CP) nanocarriers dual‐loaded with bovine serum albumin (BSA) and hydrophobic drug ibuprofen (IBU). The sequential loading of BSA and IBU in calcium phosphate nanocarriers and in vitro simultaneous release of BSA and IBU are realized and investigated. In this method, BSA, which is used as a model protein drug, is encapsulated in situ in calcium phosphate nanocarriers. Subsequently, the typical hydrophobic drug IBU is loaded in the BSA/CP drug delivery system, forming the IBU/BSA/CP dual drug delivery system. The experiments reveal that the preloaded BSA not only reduces the cytotoxicity of calcium phosphate nanocarriers but also significantly improves the IBU drug loading capacity in calcium phosphate nanocarriers and greatly extends the duration of drug release. Thus, the as‐prepared IBU/BSA/CP dual drug delivery system is promising for drug delivery applications.     

Nano Carrier Drug Delivery Systems for the Treatment of Neuropsychiatric Disorders: Advantages and Limitations

Neuropsychiatric diseases are one of the main causes of disability, affecting millions of people. Various drugs are used for its treatment, although no effective therapy has been found yet. The blood brain barrier (BBB) significantly complicates drugs delivery to the target cells in the brain tissues. One of the problem-solving methods is the usage of nanocontainer systems. In this review we summarized the data about nanoparticles drug delivery systems and their application for the treatment of neuropsychiatric disorders. Firstly, we described and characterized types of nanocarriers: inorganic nanoparticles, polymeric and lipid nanocarriers, their advantages and disadvantages. We discussed ways to interact with nerve tissue and methods of BBB penetration. We provided a summary of nanotechnology-based pharmacotherapy of schizophrenia, bipolar disorder, depression, anxiety disorder and Alzheimer’s disease, where development of nanocontainer drugs derives the most active. We described various experimental drugs for the treatment of Alzheimer’s disease that include vector nanocontainers targeted on β-amyloid or tau-protein. Integrally, nanoparticles can substantially improve the drug delivery as its implication can increase BBB permeability, the pharmacodynamics and bioavailability of applied drugs. Thus, nanotechnology is anticipated to overcome the limitations of existing pharmacotherapy of psychiatric disorders and to effectively combine various treatment modalities in that direction.     

Single‐Particle Tracking and Modulation of Cell Entry Pathways of a Tetrahedral DNA Nanostructure in Live Cells

DNA is typically impermeable to the plasma membrane due to its polyanionic nature. Interestingly, several different DNA nanostructures can be readily taken up by cells in the absence of transfection agents, which suggests new opportunities for constructing intelligent cargo delivery systems from these biocompatible, nonviral DNA nanocarriers. However, the underlying mechanism of entry of the DNA nanostructures into the cells remains unknown. Herein, we investigated the endocytotic internalization and subsequent transport of tetrahedral DNA nanostructures (TDNs) by mammalian cells through single‐particle tracking. We found that the TDNs were rapidly internalized by a caveolin‐dependent pathway. After endocytosis, the TDNs were transported to the lysosomes in a highly ordered, microtubule‐dependent manner. Although the TDNs retained their structural integrity within cells over long time periods, their localization in the lysosomes precludes their use as effective delivery agents. To modulate the cellular fate of the TDNs, we functionalized them with nuclear localization signals that directed their escape from the lysosomes and entry into the cellular nuclei. This study improves our understanding of the entry into cells and transport pathways of DNA nanostructures, and the results can be used as a basis for designing DNA‐nanostructure‐based drug delivery nanocarriers for targeted therapy.     

Controlling the Stealth Effect of Nanocarriers through Understanding the Protein Corona

The past decade has seen a significant increase in interest in the use of polymeric nanocarriers in medical applications. In particular, when used as drug vectors in targeted delivery, nanocarriers could overcome many obstacles for drug therapy. Nevertheless, their application is still impeded by the complex composition of the blood proteins covering the particle surface, termed the protein corona. The protein corona complicates any prediction of cell interactions, biodistribution, and toxicity. In particular, the unspecific uptake of nanocarriers is a major obstacle in clinical studies. This Minireview provides an overview of what we currently know about the characteristics of the protein corona of nanocarriers, with a focus on surface functionalization that reduces unspecific uptake (the stealth effect). The ongoing improvement of nanocarriers to allow them to meet all the requirements necessary for successful application, including targeted delivery and stealth, are further discussed.     

Structure‐Based Rational Design of Prodrugs To Enable Their Combination with Polymeric Nanoparticle Delivery Platforms for Enhanced Antitumor Efficacy

Drug‐loaded nanoparticles (NPs) are of particular interest for efficient cancer therapy due to their improved drug delivery and therapeutic index in various types of cancer. However, the encapsulation of many chemotherapeutics into delivery NPs is often hampered by their unfavorable physicochemical properties. Here, we employed a drug reform strategy to construct a small library of SN‐38 (7‐ethyl‐10‐hydroxycamptothecin)‐derived prodrugs, in which the phenolate group was modified with a variety of hydrophobic moieties. This esterification fine‐tuned the polarity of the SN‐38 molecule and enhanced the lipophilicity of the formed prodrugs, thereby inducing their self‐assembly into biodegradable poly(ethylene glycol)‐block‐poly(d,l ‐lactic acid) (PEG‐PLA) nanoparticulate structures. Our strategy combining the rational engineering of prodrugs with the pre‐eminent features of conventionally used polymeric materials should open new avenues for designing more potent drug delivery systems as a therapeutic modality.     

Recent development in near infrared light-responsive polymeric materials for smart drug-delivery systems

Stimuli-responsive drug delivery systems (DDS) may overcome the drawbacks of conventional chemotherapy for cancer treatment. In particular, light-responsive polymer-based DDS may ensure spatio and temporal control in drug delivery. In this regard, near infrared (NIR) light triggered drug nanocarriers present several advantages when compared to UV–visible light triggered nanocarriers. This review surveys the recent development on the design, synthesis, functions, and applications of NIR photo-sensitive compounds in the development of long-wavelength light-responsive nanocarriers. Diverse NIR light responsive groups such as coumarin (CM), ortho-nitrobenzyl (ONB), 2-diazo-1,2-naphthoquinone (DNQ) and spiropyran (SP) derivatives and their photo-cleavage reaction mechanisms are discussed, as well as the use of indocyanine green (ICG) and its photo-thermal application. The loading into polymeric nanocarriers of up converting nanoparticles (UCNPs) which can convert NIR light into UV or visible light is also discussed. The described DDS are classified on the basis on the photo responsive groups. In details, the behavior of different polymeric materials such as micelles, hydrogels bearing photo responsive groups linked to bioactive molecules which are released under NIR light irradiation is reviewed and discussed. A section relative to commonly used instrument setup for drug release studies by NIR light irradiation is also presented for better understanding how the light has been used to irradiate in various experimental situations.     

Recent Progress in Transdermal Nanocarriers and Their Surface Modifications

Transdermal drug delivery system (TDDS) is an attractive method for drug delivery with convenient application, less first-pass effect, and fewer systemic side effects. Among all generations of TDDS, transdermal nanocarriers show the greatest clinical potential because of their non-invasive properties and high drug delivery efficiency. However, it is still difficult to design optimal transdermal nanocarriers to overcome the skin barrier, control drug release, and achieve targeting. Hence, surface modification becomes a promising strategy to optimize and functionalize the transdermal nanocarriers with enhanced penetration efficiency, controlled drug release profile, and targeting drug delivery. Therefore, this review summarizes the developed transdermal nanocarriers with their transdermal mechanism, and focuses on the surface modification strategies via their different functions.     

New prodrugs derived from 6-aminodopamine and 4-aminophenol as candidates for melanocyte-directed enzyme prodrug therapy (MDEPT)

Two novel tyrosinase mediated drug delivery pathways have been investigated for the selective delivery of cytotoxic units to melanocytes from urea and thiourea prodrugs. The synthesis of these prodrugs is reported, as well as oximetry data that illustrate that the targets are substrates for tyrosinase. The stability of each of the prodrugs in (i) phosphate buffer and (ii) bovine serum is discussed, and the urea prodrugs are identified as lead candidates for further studies. Finally, HPLC studies and preliminary cytotoxicity studies in a melanotic and an amelanotic cell line, that illustrate the feasibility of the approach, are presented.     

Niosomes from 80s to present: The state of the art

Efficient and safe drug delivery has always been a challenge in medicine. The use of nanotechnology, such as the development of nanocarriers for drug delivery, has received great attention owing to the potential that nanocarriers can theoretically act as “magic bullets” and selectively target affected organs and cells while sparing normal tissues. During the last decades the formulation of surfactant vesicles, as a tool to improve drug delivery, brought an ever increasing interest among the scientists working in the area of drug delivery systems. Niosomes are self assembled vesicular nanocarriers obtained by hydration of synthetic surfactants and appropriate amounts of cholesterol or other amphiphilic molecules. Just like liposomes, niosomes can be unilamellar or multilamellar, are suitable as carriers of both hydrophilic and lipophilic drugs and are able to deliver drugs to the target site. Furthermore, niosomal vesicles, that are usually non-toxic, require less production costs and are stable over a longer period of time in different conditions, so overcoming some drawbacks of liposomes.     

Effects of the Molecular Weight of PLGA on Degradation and Drug Release In vitro from an mPEG-PLGA Nanocarrier

We successfully synthesized four kinds of copolymers with varying molecular weights of poly(lactide-co-glycolide)(PLGA) to yield methoxy-poly(ethylene glycol)-block-poly(lactide-co-glycolide)(mPEG-PLGA) nanocarriers:mPEG-PLGA(3k), mPEG-PLGA(9k), mPEG-PLGA(11k) and mPEG-PLGA(16k). An antitumor drug, 10-hydroxycamptothecin(HCPT), was encapsulated into the mPEG-PLGA nanocarrier cores by self-assembly in dialysis. The lower molecular weight nanocarriers degraded more quickly, resulting in mass loss, pH decline, and a rapid HCPT release rate in vitro. The degradation and drug release of the nanocarriers were dependent on the PLGA molecular weight. However, the larger molecular weight nanocarriers could not increase the loading content and encapsulation efficiency. Considering the antitumor effect of these nanocarriers, the mPEG-PLGA(9k) nanocarrier, which had the highest drug loading content[(7.72±0.57)%] and a relatively high encapsulation efficiency[(22.71±5.53)%], is an optimum agent for drug delivery.     

Efficient exosome extraction through the conjugation of superparamagnetic iron oxide nanoparticles for the targeted delivery in rat brain

Exosomes possess endogenous attributes and distinct biological functions, and thereby, their uses as drug nanocarriers have attracted increasing attention for biomedical practices. However, to achieve targeted therapeutic purposes, complicated extractions, as well as modifications of exosomes, are involved. Here, based on the use of superparamagnetic iron oxide nanoparticles conjugated exosome (Ex-SPIONs), a facile exosome extraction through magnetism was established. The produced Ex-SPIONs exhibited a uniform size distribution and desirable biocompatibility. Moreover, taking advantage of the magnetic properties of SPIONs, the targeted delivery of Ex-SPIONs was demonstrated in the rat brain. Therefore, the constructed SPIONs functionalized exosome shows promising therapeutic potentials, including the treatment of brain diseases.     

Rational design of nanocarriers for mitochondria-targeted drug delivery

Well-developed mitochondria-targeted nanocarriers for function regulation are highly desirable. Numerous studies have been conducted on the treatment of mitochondria-related diseases; however, further improvements are required to develop more effective drug delivery methods. Herein, we comprehensively introduce recent developments progress in rational design of mitochondria-targeted nanocarriers, and discuss the different strategies of available nanocarriers for targeting mitochondria. We also highlight the advantages and disadvantages of various carrier systems that are currently in use. Finally, perspective on new generation for mitochondria-targeted delivery systems in the emerging area of drug-based therapeutics is also discussed.     

DNA origami nanostructures for controlled therapeutic drug delivery

DNA nanostructures are emerging as a versatile platform for controlled drug delivery as a result of recent progress in production yield and strategies to obtain prolonged stability in biological environments. The construction of nanostructures from this unique biomaterial provides unparalleled control over structural and functional parameters. Recent applications of DNA origami-based nanocarriers for therapeutic drug delivery in preclinical phases highlight them as promising alternatives to conventional nanomaterials, as they benefit from the inherent favorable properties of DNA including biocompatibility and precise spatial addressability. By incorporating targeting aptamers and responsive properties into the nanocarrier design, more selective DNA origami-based nanocarriers are successfully prepared. On the other hand, current systems remain poorly understood in terms of biodistribution, final fate, and controlled drug release. As such, advances are needed to translate this material platform in its full potential for therapeutic applications.