A polyelectrolyte nanocomplex was prepared via the ionic interaction between the anionic heparin-pheophorbide a (HPhA) conjugate, which served as a water-soluble polysaccharide photosensitizer (PS), and the cationic polyethylenimine (PEI)-beta-carotene (PCAR) conjugate, which served as a polymeric scavenger. This nanocomplex was designed to improve the water solubility and tumor specificity of PhA and to only release singlet oxygen at the tumor cell. A stable 150 nm-sized nanocomplex could be formed in the weight ratio range (PCAR/HPhA) of 0.3-0.5 in an aqueous environment. The PCAR scavenger significantly diminished the generation of active singlet oxygen from HPhA in a buffer solution. Singlet oxygen scavenging activity was lost only when HPhA and PCAR were separated from each other due to the dissociation of the complex nanostructures. It was confirmed that HPhA itself has neither colloidal properties nor a decrease in its ability to produce singlet oxygen. At the same time, the HPhA/PEI complex produced singlet oxygen in response to light. In a cell culture system, the cytotoxicity of the HPhA/PCAR nanocomplex toward cancer cells was greatly enhanced due to the efficient generation of singlet oxygen under light irradiation; this finding implies that the scavenging activity of PCAR can be restricted to intracellular environments. These results suggest that the HPhA/PCAR nanocomplex could provide a new activatable PS platform that facilitates more accurate and reliable photodynamic therapy (PDT) with site-specific and controllable production of singlet oxygen to be used for the treatment of cancer. (C) 2014 Elsevier Ltd. All rights reserved.

Although nanocarriers hold promise for cancer chemotherapy, their intracellular drug delivery pathways are not fully understood. In particular, the influence of nanocarrier stability on cellular uptake is still uncertain. By physically loading hydrophobic FRET probes, we revealed different intracellular drug delivery routes of self-assembled and disulfide bonded micelles. The self-assembled micelles were structurally dissociated by micelle-membrane interactions, and the hydrophobic probes were distributed on the plasma membrane. Alternatively, intact disulfide bonded micelles carrying hydrophobic probes were internalized into cancer cells via multiple endocytic pathways. Following internalization, disulfide bonded micelles were decomposed in early endosomes by glutathione-mediated disulfide bond reduction, exposing the probes to intracellular organelles.

Preventing plant loss and improving their health status are essential for agricultural industry. Correspondingly, the deprivation of plants severely impacts our ecological system. As such, global efforts have been intensely made to promote the development of advanced sensing and treatment platforms to forestall plant loss. Existing technologies mainly encounter a number of challenges in providing results in a non-invasive, rapid turnaround, and affordable fashions. Accordingly, notable progressions in innovative approaches—particularly biosensing and delivery platforms, are vastly required for agriculture realm. In this regard, microneedles have emerged as a pivotal technological tool that plays multifaceted roles in biosensing and delivery systems, with attention of growing towards agriculture. Simply put, microneedles offer several advantages over conventional methods for being less invasive, rapid, and highly precise. In this review, recent advancements in microneedle technologies including their implementations in agriculture are highlighted coherently. In particular, extracting DNA from plant leaves and expressing transient genes using microneedles are elaborated in details. Microneedle-based sensing platforms for detecting essential compounds and secondary metabolites are discussed as well. Recent advances focusing the delivery of agrochemicals and nanotherapeutics via microneedles are elaborated. By this means, this review aims to bridge the existing gaps between microneedles and agriculture precisely.

The success of drug eluting stents (DESs) has been challenged by the manifestation of late stent thrombosis after DES implantation. The incomplete regeneration of the endothelial layer poststenting triggers adverse signaling processes precipitating in thrombosis. Various approaches have been attempted to prevent thrombosis, including the delivery of biological agents, such as estradiol, that promote endothelialization, and the use of natural polymers as coating materials. The underlying challenge has been the inability to release the biological agent in synchronization with the temporal sequence of vascular wound healing in vivo. The natural healing process of the endothelium after an injury starts after a week and may take up to a month in humans. This article presents a novel DES formulation using a hemocompatible polyurethane (PU) matrix to sustain the release of probucol (PB), an endothelial agonist, by exploiting the greater difference in the solubility parameters of PB and PU. This results in the formation of crystalline PB aggregates retarding drug release from PU. The physicochemical properties of PB in PU were confirmed using differential scanning calorimetry and X-ray diffraction. Drug-polymer compatibility was examined using infrared spectral analysis. Also, in vitro studies using primary human aortic endothelial cells resulted in the selection of 5% w/w PB as the optimal dose, to be further tested in vitro and in vivo. This work develops and tests a promising new DES formulation to enable faster endothelial cell proliferation poststenting, potentially minimizing the incidence and severity of thrombotic events after DES implantation.

Due to their high intrinsic thermal conductivity, carbon nanotubes (CNTs) have previously been incorporated into a variety of thermal management applications to improve cooling performance. Implementation of controlled CNT growth techniques and functionalization methods are applied herein to enhance boiling heat transfer from the porous capillary wicking surfaces widely used in high heat flux thermal management devices. A microwave plasma-enhanced chemical vapor deposition (MPCVD) synthesis process resulted in growth of a permeable CNT coating, and physical vapor deposition of copper over these nanotubes yielded the requisite hydrophilic wicking surface. An array of test samples was fabricated and then evaluated using an experimental test facility to determine the reduction in surface temperature resulting from CNT coating and micropatterning of the porous surfaces under two-phase heat transfer conditions with water as the working fluid. Both CNT coating and micropatterning techniques were able to provide significant performance enhancements, reducing the surface superheat up to 72% compared to baseline tests and eliminating disadvantageous temperature overshoot corresponding to boiling incipience. Such performance gains are attributable to the formation of nanoporous cavities that increase nucleation site density and high permeability vents through which vapor can readily depart the surface under vigorous boiling conditions. The synthesis procedures developed that result in the observed enhancement can be readily incorporated into currently employed devices.

Although targeted delivery mediated by ligand modified or tumor microenvironment sensitive nanocarriers has been extensively pursued for cancer chemotherapy, the efficiency is still limited by premature drug release after systemic administration. Herein we report a highly blood-stable, tumor-adaptable drug carrier made of disulfide (DS) bonded mPEG-(Cys)4-PDLLA micelles. Intravenously injected disulfide bonded micelles stably retained doxorubicin in the bloodstream and efficiently delivered the drug to a tumor, with a 7-fold increase of the drug in the tumor and 1.9-fold decrease in the heart, as compared with self-assembled (SA), non-crosslinked mPEG-PDLLA micelles. In vivo administration of disulfide bonded micelles led to doxorubicin accumulation in cancer cell nuclei, which was not observed after administration of self-assembled micelles. With a doxorubicin dose as low as 2 mg/kg, disulfide bonded micelles almost completely suppressed tumor growth in mice.

Piezoelectric inkjet printing of polymers and proteins holds great promise for fabrication of miniaturized bioelectronic devices, such as biochips and biosensors. In this study, a bienzymatic glucose biosensor prototype based on poly(3,4-ethylenedioxythiophene)-poly(styrene sulfonic acid) (PEDOT-PSS), glucose oxidase (GOD), and horseradish peroxidase (HRP) was fabricated by a piezoelectric inkjet printer. An aqueous bioelectrical ink containing PEDOT-PSS, GOD, and HRP was prepared and printed on an indium-tin-oxide (ITO)-coated poly(ethylene terephthalate) (PET) film. The PEDOT-PSS/GOD/HRP sensor was covered with a cellulose acetate membrane. The use of bienzymatic sensing combined with conducting polymers via piezoelectric inkjet printing showed a synergistic effect resulting in significant amplification of the response signal. The glucose sensor reached steady-state current density within 3 s, indicating a fast response time, and exhibited a linear dose-dependent electrochemical response with high sensitivity. The overall result demonstrates that a glucose sensor with high sensitivity could be readily fabricated by a piezoelectric inkjet printing system.

In vitro-in vivo correlation (IVIVC) allows prediction of the in vivo performance of a drug based on the in vitro drug release profiles. To develop an effective IVIVC, the physicochemical and biopharmaceutical properties of the drug as well as the physiological environment in the body must be taken into consideration. Key factors include drug solubility, pK(a), drug permeability, octanol-water partition coefficient and pH of environment. In general, construction of an IVIVC involves three stages of mathematical manipulation: construct a functional relationship between input (in vitro dissolution) and output (in vivo dissolution); establish a structural relationship using data collected; parameterize the unknowns in the structural model. Some key mathematical relationships used in IVIVC development are presented. The establishment of an effective IVIVC has important implications in quality control and regulatory compliance.

Biocompatible polysaccharides, such as alginate and chitosan are widely used as drug carriers. Microspheres based on the electrostatic interaction between these two polymers have been attractive as a means to deliver protein drugs because the use of organic solvents can be avoided during their preparation. On the other hand, the mechanisms for drug release, such as disintegration of microspheres, are not completely understood. This paper examined the phenomena of disintegration of the core-shell type microspheres consisting of alginate and chitosan. The microspheres formed by either chitosan-coated alginate or alginate-coated chitosan were generated using a labmade instrument consisting of a syringe pump connected to a glass nozzle. Using fluorophore-labeled polysaccharides, the disintegration of each polymer layer from the microspheres was monitored as a function of time. The alginate- coated chitosan microspheres demonstrated enhanced stability with increasing concentration of the chitosan core. The presence of an alginate shell itself also increased the stability of the microsphere compared to the microspheres without an alginate coating. The chitosan concentration, however, did not have any effect on the stability of the chitosan-coated alginate microspheres. The microspheres synthesized with alginate in the core demonstrated concentration-dependent stability. In these microsphere experiments, the microsphere stability was found to be related directly to the protein release kinetics. In the alginate/chitosan-based microspheres, the disintegration property is the primary factor modulating the encapsulated drug release, which suggests the easiest simple method for time-dependent protein drug delivery.

Polymer micelles have been used widely for delivery of poorly water-soluble drugs. Such drug delivery, however, has been based primarily on hydrophobic interactions. For better drug loading and improved stability, hydrotropic polymer micelles were used. To develop a versatile polymer micelle for solubilizing various poorly soluble drugs, two different hydrotropic agents were examined. The solubilizing properties of two hydrotropic agents, N,N-diethylnicotinamide (DENA) and N,N-dimethylbenzamide (DMBA), in polymeric form were investigated for their ability to solubilize five drugs with low aqueous solubility covering a wide range of hydrophobicity and molecular structures. The hydrotropes were covalently linked to the hydrophobic block of a block copolymer that also had a hydrophilic poly(ethylene glycol) (PEG) block.The solubilizing capacity of the polymeric hydrotropes was compared with that of the non polymeric hydrotropes, as well as of two conventional (non hydrotropic) copolymer systems. The solubilizing capacity of polymeric hydrotropes reflects combined effects of the micellar solubilization by the hydrophobic micelle core and hydrotropic solubilization. Because of the highly localized configuration, hydrotropes in the polymeric form are more powerful solubilizers than in the monomeric (non-polymeric) solution. It is possible to produce 1~3 orders of magnitude increase in solubility with polymeric hydrotropes at the 1% (w/v) level. Of the two hydrotropic polymeric systems in this study, the DENA-based system is highly specific, whereas the DMBA-based system is a general solubilizer of hydrophobic drugs. An additional advantage of polymeric hydrotropes over the non-polymeric form is absence of high concentrations of free hydrotropes in the formulation. Solubilization vehicles based on polymeric hydrotropes are expected to provide a new and versatile means of preparing formulations for various poorly soluble drugs and drug candidates without using organic solvents. This advantage is accompanied with the inherent controlled release property of the hydrotropic polymer micelles, making them ideal for pharmaceutical formulations used in drug candidate screening and toxicology studies.

Recently, a variety of bioactive protein drugs have been available in large quantities as a result of advances in biotechnology. Such availability has prompted development of long-term protein delivery systems. Biodegradable microparticulate systems have been used widely for controlled release of protein drugs for days and months. The most widely used biodegradable polymer has been poly(d,l-lactic-co-glycolic acid) (PLGA). Protein-containing microparticles are usually prepared by the water/oil/water (W/O/W) double emulsion method, and variations of this method, such as solid/oil/water (S/O/W) and water/oil/oil (W/O/O), have also been used. Other methods of preparation include spray drying, ultrasonic atomization, and electrospray methods.

Importance of the field: Spontaneously constructed from block copolymers in aqueous media, the polymer micelle has been extensively studied as a potential carrier of poorly water-soluble drugs, but cellular uptake pathways and stability of micelles in blood have not yet been clearly understood. An in-depth insight into the physical and biological behaviors of polymer micelles is necessitated for designing next-generation micelles.Areas covered in this review: This review suggests possible solutions to improve micellar drug loading capacity, scrutinizes the parameters influencing the micelle stability in blood, and also discusses the fate of micelles in cellular and in vivo environment, respectively. Direct and indirect evidences from the literatures mostly published after 90's were collected, analyzed and summarized.What the reader will gain: A critical analysis of micelle's stability in vivo and micelle-cell interaction is provided to highlight the key issues to be addressed to affirm that micelle can properly work as a drug carrier in clinical settings.Take home message: With a clear understanding of its behaviors in biological environment, the polymer micelle is a promising nanocarrier for chemotherapy.

Polymer micelles have been used widely in the delivery of various therapeutic drugs, which are also known as active pharmaceutical ingredients (APIs). Recent advances in drug discovery technology, including an accumulated database on therapeutic targets, combinational chemistry, and high-throughput screening (HTS), have further increased the number of candidate compounds and constructed a huge pipeline for the discovery and development of new chemical entities (NCEs).1,2 A very large number of chemicals are hailed as new drug candidates, but almost one-third of them are poorly water soluble.3 Polymer micelles consisting of amphiphilic CONTENTS

The solubilizing ability of two aromatic hydrotropes, N,N-diethylnicotinamide (DENA) and N,N-dimethylbenzamide (DMBA), was investigated using a set of 13 poorly soluble, structurally diverse drugs. The number of aromatic rings in the solute molecule has a very strong effect on the solubility enhancement produced by either hydrotrope. However, although solubility enhancements in the order of 1000- to 10,000-fold were obtained with each of the hydrotropic agents, important differences were found between the two. DMBA is more hydrophobic and undergoes more extensive self-association than DENA, as determined by vapor osmometry. As a result, DMBA is generally a more powerful solubilizer of hydrophobic drugs. DENA, on the other hand, is more polar and its self-association is essentially limited to dimer formation. However, despite being less hydrophobic, DENA is an extremely powerful solubilizer of paclitaxel, a highly hydrophobic compound. Such a result is attributed to the higher hydrogen bonding ability of DENA over DMBA and the very high hydrogen bonding ability of paclitaxel. These observations in turn illustrate the strong interplay between specific and hydrophobic interactions on the observed solubilization by hydrotropic agents. © 2010 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 99:3953–3965, 2010

Engineered polymers have been utilized for developing advanced drug delivery systems. The development of such polymers has caused advances in polymer chemistry, which, in turn, has resulted in smart polymers that can respond to changes in environmental condition such as temperature, pH, and biomolecules. The responses vary widely from swelling/deswelling to degradation. Drug-polymer conjugates and drug-containing nano/micro-particles have been used for drug targeting. Engineered polymers and polymeric systems have also been used in new areas, such as molecular imaging as well as in nanotechnology. This review examines the engineered polymers that have been used as traditional drug delivery systems and as more recent applications in nanotechnology.

Spinal cord injury results in immediate disruption of neuronal membranes, followed by extensive secondary neurodegenerative processes. A key approach for repairing injured spinal cord is to seal the damaged membranes at an early stage. Here, we show that axonal membranes injured by compression can be effectively repaired using self-assembled monomethoxy poly(ethylene glycol)-poly(d,l-lactic acid) di-block copolymer micelles. Injured spinal tissue incubated with micelles (60 nm diameter) showed rapid restoration of compound action potential and reduced calcium influx into axons for micelle concentrations much lower than the concentrations of polyethylene glycol, a known sealing agent for early-stage spinal cord injury. Intravenously injected micelles effectively recovered locomotor function and reduced the volume and inflammatory response of the lesion in injured rats, without any adverse effects. Our results show that copolymer micelles can interrupt the spread of primary spinal cord injury damage with minimal toxicity.

Hydrotropic polymers (HPs) and their micelles have been recently developed as vehicles for delivery of poorly water-soluble drugs, such as paclitaxel (PTX), by oral administration. The release of PTX from HP micelles, however, was slow and it took more than a day for complete release of the loaded PTX. Since the gastrointestinal (GI) transit time is known to be only several hours, pH-sensitive HP micelles were prepared for fast release of the loaded PTX responding to pH changes along the GI tract. Acrylic acid (AA) was introduced, as a release modulator, into HPs by copolymerization with 4-(2-vinylbenzyloxy)-N,N-(diethylnicotinamide) (VBODENA). The AA content was varied from 0% to 50% (in the molar ratio to VBODENA). HPs spontaneously produced micelles in water, and their critical micelle concentrations (CMCs) ranged from 31 microg/mL to 86 microg/mL. Fluorescence probe study using pyrene showed that blank HP micelles possessed a good pH sensitivity, which was clearly observed at relatively high AA contents and pH>6. The pH sensitivity also affected the PTX loading property. Above pH 5, the PTX loading content and loading efficiency in HP micelles were significantly reduced. Although this may be primarily due to the AA moieties, other factors may include PTX degradation and polymer aggregation. The PTX release from HP micelles with more than 20% (mol) AA contents was completed within 12 h in a simulated intestinal fluid (SIF, pH=6.5). The HP micelles without any AA moiety showed very slow release profiles. In the simulated gastric fluid (SGF, pH=1.6), severe degradation of the released PTX was observed. The pH-dependent release of PTX from HP micelles can be used to increase the bioavailability of PTX upon oral delivery.