Nanoscale Carriers Research Articles

Biodegradable Nanoparticles for Delivery of Therapeutics in CNS Infection.

Despite the significant advances in neurological medicine, it remains difficult to treat ailments directly involving the brain. The blood brain barrier (BBB) is a tightly regulated, selectively permeable barrier that restricts access from the blood into the brain extracellular fluid (BEF). Many conditions such as tumors or infections in the brain are difficult to treat due to the fact that drugs and other therapeutic agents are unable to easily pass through this relatively impermeable barrier. Human Immunodeficiency Virus (HIV) presents a particular problem as it is able to remain dormant in the brain for years protected from antiretroviral drugs by the BBB. The development of nanoscale carriers over the past few decades has made possible the delivery of therapies with the potential to overcome membrane barriers and provide specific, targeted delivery. This review seeks to provide a comprehensive overview of the various aspects of nanoparticle formulation and their applications in improving the delivery efficiency of drugs, specifically antiretroviral therapeutics to the brain to treat HIV.

The Impact of Variables on Particle Size of Solid Lipid Nanoparticles and Nanostructured Lipid Carriers; A Comparative Literature Review.

During the past decade, pharmaceutical science has seen rapid growth in interest for nanoscale materials. Solid lipid nanoparticles (SLNs) and nanostructured lipid carriers (NLCs) are popular research topics recently introduced as nano-scale drug carriers; they have shown numerous merits in drug delivery. Size is the most important index in a nanocarrier affecting its drug delivery efficiency. The influence of preparation conditions and type of lipidic components on the size of SLN and NLC in comparable states seems to be interesting for researchers who investigate these types of carriers. This review highlights the results of SLN and NLC particle size and size distribution comparisons.

Hydrogel nanoparticles and nanocomposites for nasal drug/vaccine delivery.

Over the past few years, nasal drug delivery has attracted more and more attentions, and been recognized as the most promising alternative route for the systemic medication of drugs limited to intravenous administration. Many experiments in animal models have shown that nanoscale carriers have the ability to enhance the nasal delivery of peptide/protein drugs and vaccines compared to the conventional drug solution formulations. However, the rapid mucociliary clearance of the drug-loaded nanoparticles can cause a reduction in bioavailability percentage after intranasal administration. Thus, research efforts have considerably been directed towards the development of hydrogel nanosystems which have mucoadhesive properties in order to maximize the residence time, and hence increase the period of contact with the nasal mucosa and enhance the drug absorption. It is most certain that the high viscosity of hydrogel-based nanosystems can efficiently offer this mucoadhesive property. This update review discusses the possible benefits of using hydrogel polymer-based nanoparticles and hydrogel nanocomposites for drug/vaccine delivery through the intranasal administration.

Nanoscale drug delivery for targeted chemotherapy

Despite significant improvements in diagnostic methods and innovations in therapies for specific cancers, effective treatments for neoplastic diseases still represent major challenges. Nanotechnology as an emerging technology has been widely used in many fields and also provides a new opportunity for the targeted delivery of cancer drugs. Nanoscale delivery of chemotherapy drugs to the tumor site is highly desirable. Recent studies have shown that nanoscale drug delivery systems not only have the ability to destroy cancer cells but may also be carriers for chemotherapy drugs. Some studies have demonstrated that delivery of chemotherapy via nanoscale carriers has greater therapeutic benefit than either treatment modality alone. In this review, novel approaches to nanoscale delivery of chemotherapy are described and recent progress in this field is discussed.

A New Era of Pulmonary Delivery of Nano-antimicrobial Therapeutics to Treat Chronic Pulmonary Infections.

Pulmonary infections may be fatal especially in immunocompromised patients and patients with underlying pulmonary dysfunction, such as those with cystic fibrosis, chronic obstructive pulmonary disorder, etc. According to the WHO, lower respiratory tract infections ranked first amongst the leading causes of death in 2012, and tuberculosis was included in the top 10 causes of death in low income countries, placing a considerable strain on their economies and healthcare systems. Eradication of lower respiratory infections is arduous, leading to high healthcare costs and requiring higher doses of antibiotics to reach optimal concentrations at the site of pulmonary infection for protracted periods. Hence direct inhalation to the respiratory epithelium has been investigated extensively in the past decade, and seems to be an attractive approach to eradicate and hence overcome this widespread problem. Moreover, engineering inhalation formulations wherein the antibiotics are encapsulated within nanoscale carriers could serve to overcome many of the limitations faced by conventional antibiotics, like difficulty in treating intracellular pathogens such as mycobacteria spp. and salmonella spp., biofilmassociated pathogens like Pseudomonas aeruginosa and Staphylococcus aureus, passage through the sputum associated with disorders like cystic fibrosis and chronic obstructive pulmonary disorder, systemic side effects following oral/parenteral delivery and inadequate concentrations of antibiotic at the site of infection leading to resistance. Encapsulation of antibiotics in nanocarriers may help in providing a protective environment to combat antibiotic degradation, confer controlled-release properties, hence reducing dosing frequency, and may increase uptake via specific and non-specific targeting modalities. Hence nanotechnology combined with direct administration to the airways using commercially available delivery devices, is a highly attractive formulation strategy to eradicate microorganisms from the lower respiratory tract, which might otherwise present opportunities for multi-drug resistance.

POTENTIAL APPLICATION OF DENDRIMERS IN DRUG DELIVERY: A CONCISE REVIEW AND UPDATE

This review gives concise information about the application of dendrimers in the field of drug delivery. Due to their unique architecture these have improved physical and chemical properties. Due to their terminal groups these show high solubility, miscibility and reactivity. Dendrimers have well defined size, shape, molecular weight and monodispersity. These properties make the dendrimers a suitable carrier in drug delivery application. Dendrimers are unimolecular miceller in nature and due to this enhances the solubility of poorly soluble drugs. Their compatibility with DNA, heparin and polyanions make them more versatile. Dendrimers, also referred as modern day polymers, they offer much more good properties than the conventional polymers. Due to their multivalent and mono disperse character dendrimers have stimulated wide interest in the field of chemistry biology, especially in applications like drug delivery, gene therapy and chemotherapy. Self assembly produces a faster means of generating nanoscopic functional and structural systems. But their actual utility in drug delivery can be assessed only after deep understanding of factors affecting their properties and their behavior in vivo . Key words: Dendrimers, Drug targeting, nanoscale carriers.

Multiple pH responsive zwitterionic micelles for stealth delivery of anticancer drugs

Subtle tumor micro-environmental pH gradient activates functionalization of the zwitterionic micelles for stealth delivery and intelligent release of anti-cancer drug doxorubicin.

Nanoscale "fluorescent stone": Luminescent Calcium Fluoride Nanoparticles as Theranostic Platforms.

Calcium Fluoride (CaF2) based luminescent nanoparticles exhibit unique, outstanding luminescent properties, and represent promising candidates as nanoplatforms for theranostic applications. There is an urgent need to facilitate their further development and applications in diagnostics and therapeutics as a novel class of nanotools. Here, in this critical review, we outlined the recent significant progresses made in CaF2-related nanoparticles: Firstly, their physical chemical properties, synthesis chemistry, and nanostructure fabrication are summarized. Secondly, their applications in deep tissue bio-detection, drug delivery, imaging, cell labeling, and therapy are reviewed. The exploration of CaF2-based luminescent nanoparticles as multifunctional nanoscale carriers for imaging-guided therapy is also presented. Finally, we discuss the challenges and opportunities in the development of such CaF2-based platform for future development in regard to its theranostic applications.

Enhancement in ionic liquid tolerance of cellulase immobilized on PEGylated graphene oxide nanosheets: Application in saccharification of lignocellulose

The objective of the present work was to improve ionic liquid (IL) tolerance of cellulase based on the exploration of functional nanoscale carriers for potential application in lignocellulosic biorefinery. PEGylated graphene oxide (GO) composite was successfully fabricated by chemical binding of 4-arm-PEG-NH2 and GO and applied to the immobilization of cellulase. The PEGylated GO-Cellulase retained 61% of the initial activity in 25% (w/v) 1-butyl-3-methylimidazolium chloride ([Bmim][Cl]) while free cellulase only retained 2%. The IL stability was enhanced more than 30 times. The relatively minor change in Km value (from 2.7 to 3.2mgmL−1) after the immobilization suggested that PEGylated GO-Cellulase was capable of closely mimicking the performance of free enzyme. After treating rice straw with [Bmim][Cl] and dilution to a final IL concentration of 15% (w/v), the slurry was directly hydrolyzed using PEGylated GO-Cellulase without IL removing and a high hydrolysis rate of 87% was achieved.

Modelling ion, water and ion-water cluster entering peptide nanotubes

Recently, organic nanostructures have attracted much attention, and amongst them peptide nanotubes are of interest in many fields of application including medicine and nanobiotechnology. Peptide nanotubes are formed by self-assembly of cyclic peptides with alternating L- and D-amino acids. Due to their biodegradability, flexible design and easy synthesis, many applications have been proposed such as artificial transmembrane ion channels, templates for nanoparticles, mimicking pore structures, nanoscale testing tubes, biosensors and carriers for targeted drug delivery. The mechanisms of an ion, a water molecule and an ion–water cluster entering into a peptide nanotube of structure cyclo[(-D-Ala-L-Ala-)4] are explored here. In particular, the Lennard-Jones potential and a continuum approach are employed to determine three entering mechanisms: (i) through the tube open end, (ii) through a region between each cyclic peptide ring and (iii) around the edge of the tube open end. The results show that while entering the nanotube by method (i) is possible, an ion or a molecule requires initial energy to overcome an energetic barrier to be able to enter the nanotube through positions (ii) and (iii). Due to its simple structure, the D-, L-Ala cyclopeptide nanotube is chosen in this model; however, it can be easily extended to include more complicated nanotubes. doi:10.1017/S1446181115000164

Artificial oxygen carriers rescue placental hypoxia and improve fetal development in the rat pre-eclampsia model.

Pre-eclampsia affects approximately 5% of all pregnant women and remains a major cause of maternal and fetal morbidity and mortality. The hypertension associated with pre-eclampsia develops during pregnancy and remits after delivery, suggesting that the placenta is the most likely origin of this disease. The pathophysiology involves insufficient trophoblast invasion, resulting in incomplete narrow placental spiral artery remodeling. Placental insufficiency, which limits the maternal-fetal exchange of gas and nutrients, leads to fetal intrauterine growth restriction. In this study, in our attempt to develop a new therapy for pre-eclampsia, we directly rescued placental and fetal hypoxia with nano-scale size artificial oxygen carriers (hemoglobin vesicles). The present study is the first to demonstrate that artificial oxygen carriers successfully treat placental hypoxia, decrease maternal plasma levels of anti-angiogenic proteins and ameliorate fetal growth restriction in the pre-eclampsia rat model.

Cuboplexes: Topologically Active siRNA Delivery.

RNAi technology is currently experiencing a revival due to remarkable improvements in efficacy and viability through oligonucleotide chemical manipulations and/or via their packaging into nanoscale carriers. At present, there is no FDA-approved system for siRNA technology in humans. The design of the next generation of siRNA carriers requires a deep understanding of how a nanoparticle's physicochemical properties truly impart biological stability and efficiency. For example, we now know that nanoparticles need to be sterically stabilized in order to meet adequate biodistribution profiles. At present, targeting, uptake, and, in particular, endosomal escape are among the most critical challenges impairing RNAi technologies. The disruption of endosomes encompasses membrane transformations (for example, pore formation) that cost significant elastic energy. Nanoparticle size and shape have been identified as relevant parameters impacting tissue accumulation and cellular uptake. In this paper, we demonstrate that the internal structure of lipid-based particles offers a different handle to promote endosomal membrane topological disruptions that enhance siRNA delivery. Specifically, we designed sterically stabilized lipid-based particles that differ from traditional liposomal systems by displaying highly ordered bicontinuous cubic internal structures that can be loaded with large amounts of siRNA. This system differs from traditional siRNA-containing liposomes (lipoplexes) as the particle-endosomal membrane interactions are controlled by elasticity energetics and not by electrostatics. The resulting "PEGylated cuboplex" has the ability to deliver siRNA and specifically knockdown genes with efficiencies that surpass those achieved by traditional lipoplex systems.

MODELLING ION, WATER AND ION–WATER CLUSTER ENTERING PEPTIDE NANOTUBES

Recently, organic nanostructures have attracted much attention, and amongst them peptide nanotubes are of interest in many fields of application including medicine and nanobiotechnology. Peptide nanotubes are formed by self-assembly of cyclic peptides with alternating L- and D-amino acids. Due to their biodegradability, flexible design and easy synthesis, many applications have been proposed such as artificial transmembrane ion channels, templates for nanoparticles, mimicking pore structures, nanoscale testing tubes, biosensors and carriers for targeted drug delivery. The mechanisms of an ion, a water molecule and an ion–water cluster entering into a peptide nanotube of structure cyclo[(-D-Ala-L-Ala-)$_{4}$] are explored here. In particular, the Lennard-Jones potential and a continuum approach are employed to determine three entering mechanisms: (i) through the tube open end, (ii) through a region between each cyclic peptide ring and (iii) around the edge of the tube open end. The results show that while entering the nanotube by method (i) is possible, an ion or a molecule requires initial energy to overcome an energetic barrier to be able to enter the nanotube through positions (ii) and (iii). Due to its simple structure, the D-, L-Ala cyclopeptide nanotube is chosen in this model; however, it can be easily extended to include more complicated nanotubes.

Dendritic macromolecules as nano-scale drug carriers: Phase solubility, in vitro drug release, hemolysis and cytotoxicity study

Potential of nanoscale triazine based dendritic macromolecules G1, G2 and G3 as solubility enhancers of drug was investigated. Effect of pH, concentration and generation of synthesized dendritic macromolecules on solubility of ketoprofen was studied. G3 dendrimer was further exploited as carrier for sustained release. Ketoprofen was encapsulated by inclusion complex method and also characterized by Flourier Transform Infrared spectroscopy. Sustained release study of ketoprofen from ketoprofen loaded dendrimer was carried out and compared with free ketoprofen. Hemolytic potential and Cytotoxicity assay using A-549 lung cancer cell lines revealed that synthesized triazine based dendritic macromolecules having more potential that commercially available PAMAM dendrimer.

Light-triggered capture and release of DNA and proteins by host-guest binding and electrostatic interaction.

The development of an effective and general delivery method that can be applied to a large variety of structurally diverse biomolecules remains a bottleneck in modern drug therapy. Herein, we present a supramolecular system for the dynamic trapping and light-stimulated release of both DNA and proteins. Self-assembled ternary complexes act as nanoscale carriers, comprising vesicles of amphiphilic cyclodextrin, the target biomolecules and linker molecules with an azobenzene unit and a charged functionality. The non-covalent linker binds to the cyclodextrin by host-guest complexation with the azobenzene. Proteins or DNA are then bound to the functionalized vesicles through multivalent electrostatic attraction. The photoresponse of the host-guest complex allows a light-induced switch from the multivalent state that can bind the biomolecules to the low-affinity state of the free linker, thereby providing external control over the cargo release. The major advantage of this delivery approach is the wide variety of targets that can be addressed by multivalent electrostatic interaction, which we demonstrate on four types of DNA and six different proteins.

Scope of nanotechnology in future agriculture-an overview

To address the challenges in agriculture such as stagnation in crop yields, low nutrient use efficiency, declining soil organic matter, multinutrient deficiencies, climate change, shrinking arable land and water availability and shortage of labour besides exodus of people from farming and to attain a sustainable growth in agriculture to meet the food security challenges, application of nanotechnology in agriculture has the potential to revolutionize the agricultural scenario to increase the farm productivity with reduced resource costs and higher input use efficiencies while ensuring environmental safety. The application of nanotechnology to agriculture and food industries is getting attention nowadays. Investments in agriculture and food, nanotechnologies carry increasing weight because their potential benefits range from improved food quality and safety to reduced agricultural inputs and improved processing and nutrition. Nanotechnology-based products and its applications in agriculture include nanofertilizers, nano herbicides, nano-pesticides, recalcitrant contaminants from water, nano-scale carriers, nanosensors, detection of nutrient deficiencies, preservation, photocatalysis, etc. While nanotechnologies offer many opportunities for innovation, the use ofnanomaterials in food and agriculture has also raised a number of safety, environmental, ethical, policy and regulatory issues. This review is focused on modem strategies used for the management of seed germination, fertilizers, herbicides, pesticides, water, carriers, sensors and potential of nanomaterials in sustainable agriculture management as modem approaches ofnanotechnology.

Theranostic Magnetic Nanostructures (MNS) for Cancer.

Despite the complexities of cancer, remarkable diagnostic and therapeutic advances have been made during the past decade, which include improved genetic, molecular, and nanoscale understanding of the disease. Physical science and engineering, and nanotechnology in particular, have contributed to these developments through out-of-the-box ideas and initiatives from perspectives that are far removed from classical biological and medicinal aspects of cancer. Nanostructures, in particular, are being effectively utilized in sensing/diagnostics of cancer while nanoscale carriers are able to deliver therapeutic cargo for timed and controlled release at localized tumor sites. Magnetic nanostructures (MNS) have especially attracted considerable attention of researchers to address cancer diagnostics and therapy. A significant part of the promise of MNS lies in their potential for "theranostic" applications, wherein diagnostics makes use of the enhanced localized contrast in magnetic resonance imaging (MRI) while therapy leverages the ability of MNS to heat under external radio frequency (RF) field for thermal therapy or use of thermal activation for release of therapy cargo. In this chapter, we report some of the key developments in recent years in regard to MNS as potential theranostic carriers. We describe that the r₂relaxivity of MNS can be maximized by allowing water (proton) diffusion in the vicinity of MNS by polyethylene glycol (PEG) anchoring, which also facilitates excellent fluidic stability in various media and extended in vivo circulation while maintaining high r₂values needed for T₂-weighted MRI contrast. Further, the specific absorption rate (SAR) required for thermal activation of MNS can be tailored by controlling composition and size of MNS. Together, emerging MNS show considerable promise to realize theranostic potential. We discuss that properly functionalized MNS can be designed to provide remarkable in vivo stability and accompanying pharmacokinetics exhibit organ localization that can be tailored for specific applications. In this context, even iron-based MNS show extended circulation as well as diverse organ accumulation beyond liver, which otherwise renders MNS potentially toxic to liver function. We believe that MNS, including those based on iron oxides, have entered a renaissance era where intelligent synthesis, functionalization, stabilization, and targeting provide ample evidence for applications in localized cancer theranostics.

Cellulose nanocrystals with tunable surface charge for nanomedicine

Crystalline nanoparticles of cellulose exhibit attractive properties as nanoscale carriers for bioactive molecules in nanobiotechnology and nanomedicine. For applications in imaging and drug delivery, surface charge is one of the most important factors affecting the performance of nanocarriers. However, current methods of preparation offer little flexibility for controlling the surface charge of cellulose nanocrystals, leading to compromised colloidal stability under physiological conditions. We report a synthesis method that results in nanocrystals with remarkably high carboxyl content (6.6 mmol g(-1)) and offers continuous control over surface charge without any adjustment to the reaction conditions. Six fractions of nanocrystals with various surface carboxyl contents were synthesized from a single sample of softwood pulp with carboxyl contents varying from 6.6 to 1.7 mmol g(-1) and were fully characterized. The proposed method resulted in highly stable colloidal nanocrystals that did not aggregate when exposed to high salt concentrations or serum-containing media. Interactions of these fractions with four different tissue cell lines were investigated over a wide range of concentrations (50-300 μg mL(-1)). Darkfield hyperspectral imaging and confocal microscopy confirmed the uptake of nanocrystals by selected cell lines without any evidence of membrane damage or change in cell density; however a charge-dependent decrease in mitochondrial activity was observed for charge contents higher than 3.9 mmol g(-1). A high surface carboxyl content allowed for facile conjugation of fluorophores to the nanocrystals without compromising colloidal stability. The cellular uptake of fluoresceinamine-conjugated nanocrystals exhibited a time-dose dependent relationship and increased significantly with doubling of the surface charge.

Protein corona change the drug release profile of nanocarriers: The “overlooked” factor at the nanobio interface

The emergence of nanocarrier systems in drug delivery applications has ushered in rapid development of new classes of therapeutic agents which can provide an essential breakthrough in the fight against refractory diseases. However, successful clinical application of nano-drug delivery devices has been limited mainly due to the lack of control on sustained release of therapeutics from the carriers. A wide range of sophisticated approaches employs the formation of crosslinkable, non-crosslinkable, stimuli-responsive polymer nanocarriers in order to enhance their delivery efficiency. Despite the extensive research conducted on the development of various nanocarriers, the effect of the biological milieu on the drug release profile of these constructs is not yet fully investigated. In particular, the formation of a protein corona on the surface of nanocarriers, when they interact with living organisms in vivo is largely decisive for their biological function. Using a number of synthetized (i.e., superparamagnetic iron oxide nanoparticles and polymeric nanocapsules) and commercialized nanocarriers (i.e., Abraxane®, albumin-bound paclitaxel drug), this study demonstrates that the protein corona can shield the nanocarriers and, consequently, alters the release profile of the drugs from the nanocarriers. More specifically, the protein corona could significantly reduce the burst effect of either protein conjugated nanocarriers or carriers with surface loaded drug (i.e., SPIONs). However, the corona shell only slightly changed the release profile of polymeric nanocapsules. Therefore, the intermediary, buffer effect of the protein shells on the surface of nanoscale carriers plays a crucial role in their successful high-yield applications in vivo.

Sugar-based amphiphilic polymers for biomedical applications: from nanocarriers to therapeutics.

Various therapeutics exhibit unfavorable physicochemical properties or stability issues that reduce their in vivo efficacy. Therefore, carriers able to overcome such challenges and deliver therapeutics to specific in vivo target sites are critically needed. For instance, anticancer drugs are hydrophobic and require carriers to solubilize them in aqueous environments, and gene-based therapies (e.g., siRNA or pDNA) require carriers to protect the anionic genes from enzymatic degradation during systemic circulation. Polymeric micelles, which are self-assemblies of amphiphilic polymers (APs), constitute one delivery vehicle class that has been investigated for many biomedical applications. Having a hydrophobic core and a hydrophilic shell, polymeric micelles have been used as drug carriers. While traditional APs are typically comprised of nondegradable block copolymers, sugar-based amphiphilic polymers (SBAPs) synthesized by us are comprised of branched, sugar-based hydrophobic segments and a hydrophilic poly(ethylene glycol) chain. Similar to many amphiphilic polymers, SBAPs self-assemble into polymeric micelles. These nanoscale micelles have extremely low critical micelle concentrations offering stability against dilution, which occurs with systemic administration. In this Account, we illustrate applications of SBAPs for anticancer drug delivery via physical encapsulation within SBAP micelles and chemical conjugation to form SBAP prodrugs capable of micellization. Additionally, we show that SBAPs are excellent at stabilizing liposomal delivery systems. These SBAP-lipid complexes were developed to deliver hydrophobic anticancer therapeutics, achieving preferential uptake in cancer cells over normal cells. Furthermore, these complexes can be designed to electrostatically complex with gene therapies capable of transfection. Aside from serving as a nanocarrier, SBAPs have also demonstrated unique bioactivity in managing atherosclerosis, a major cause of cardiovascular disease. The atherosclerotic cascade is usually triggered by the unregulated uptake of oxidized low-density lipoprotein, a cholesterol carrier, in macrophages of the blood vessel wall; SBAPs can significantly inhibit oxidized low-density lipoprotein uptake in macrophages and abrogate the atherosclerotic cascade. By modification of various functionalities (e.g., branching, stereochemistry, hydrophobicity, and charge) in the SBAP chemical structure, SBAP bioactivity was optimized, and influential structural components were identified. Despite the potential of SBAPs as atherosclerotic therapies, blood stability of the SBAP micelles was not ideal for in vivo applications, and means to stabilize them were pursued. Using kinetic entrapment via flash nanoprecipitation, SBAPs were formulated into nanoparticles with a hydrophobic solute core and SBAP shell. SBAP nanoparticles exhibited excellent physiological stability and enhanced bioactivity compared with SBAP micelles. Further, this method enables encapsulation of additional hydrophobic drugs (e.g., vitamin E) to yield a stable formulation that releases two bioactives. Both as nanoscale carriers and as polymer therapeutics, SBAPs are promising biomaterials for medical applications.