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Fluorescent Penetration Enhancers Reveal Complex Interactions among the Enhancer, Drug, Solvent, and Skin
摘要： Skin penetration/permeation enhancers facilitate drug delivery through the skin barrier. However, the specific mechanisms that govern the enhancer interactions with the skin, drug, and donor solvent are not fully understood. We designed and synthesized fluorescent-labeled enhancers by attaching 7-nitrobenzo[c][1,2,5]oxadiazol-4-yl (NBD) groups to 6-aminohexanoic acid esters. These NBD esters (applied at a 1% concentration) enhanced the permeation of the model drugs theophylline and hydrocortisone through human skin in vitro up to 6.6 and 3.9 times, respectively. The enhancement effects were strongly affected by the ester chain length (C8-C12) and the polarity of the donor solvent. Using HPLC with fluorescence detection, no NBD esters were detected in the acceptor buffer, but their hydrolysis product, NBD acid, was detected, whereas both acid and esters were found in the skin. The enhancer hydrolysis occurred in the lower stratum corneum and epidermis; the more hydrophilic NBD acid, which is an inactive enhancer, penetrated deeper. This illustrates the principle of biodegradable enhancers. The enhancer concentrations in the skin depended not only on the enhancer chain length and the donor solvent but also on the drug used. Thus, the drug, when co-applied with the enhancer, modulates the enhancer penetration into the skin and, consequently, its effect. Finally, active (NBD-C8 ester) and inactive (NBD acid) enhancers were visualized in human skin by confocal laser scanning microscopy. Both compounds were found mostly in the stratum corneum intercellular spaces, suggesting that although both are located within the skin barrier lipids, only the active ester is able to effectively interact with the lipids, which was proved by infrared spectroscopy of enhancer-treated stratum corneum. This proof-of-concept study illustrates the use of fluorescent enhancers to obtain insight into the skin penetration/permeation process; interactions among the enhancer, drug, solvent, and skin; and enhancer metabolism.
关键词： penetration enhancer,skin,fluorescent labeling,Transdermal drug delivery
更新于2025-09-23 15:22:29
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Nepafenac-Loaded Cyclodextrin/Polymer Nanoaggregates: A New Approach to Eye Drop Formulation
摘要： The topical administration route is commonly used for targeting therapeutics to the eye; however, improving the bioavailability of drugs applied directly to the eye remains a challenge. Different strategies have been studied to address this challenge. One of them is the use of aggregates that are formed easily by self-assembly of cyclodextrin (CD)/drug complexes in aqueous solution. The aim of this study was to design a new eye drop formulation based on aggregates formed between CD/drug complexes. For this purpose, the physicochemical properties of the aggregates associated with six CDs and selected water-soluble polymers were analysed. Complex formation was studied using differential scanning calorimetry (DSC), Fourier-transform infrared spectroscopy (FT-IR) and 1H nuclear magnetic resonance spectroscopy (1H-NMR). Results showed that HPβCD performed best in terms of solubilization, while γCD performed best in terms of enhancing nanoaggregate formation. Formation of inclusion complexes was con?rmed by DSC, FT-IR and 1H-NMR studies. A mixture of 15% (w/v) γCD and 8% (w/v) HPβCD was selected for formulation studies. It was concluded that formulations with aggregate sizes less than 1 μm and viscosity around 10–19 centipoises can be easily prepared using a mixture of CDs. Formulations containing polymeric drug/CD nanoaggregates represent an interesting strategy for enhanced topical delivery of nepafenac.
关键词： cyclodextrin,self-assemble,nepafenac,aggregate,polymer,complexation,ocular drug delivery
更新于2025-09-23 15:22:29
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Carbon Nanomaterials for Bioimaging, Bioanalysis, and Therapy || Functionalized Carbon Nanomaterials for Drug Delivery
摘要： Chemical functionalization of nanomaterials is important to control their physical properties. Since their applications frequently require the homogeneity in the physical properties of the components, many precise functionalization methods for nanomaterials have been developed in view of their applications from electronics and optics to biomedicine. Nanomedicine has been attracting growing interest in terms of therapy and diagnosis, or so called theranostics. In the field, nanomaterials play a key role and hence they are chemically functionalized frequently to meet the requirements for the purpose. In the nanomaterial‐based drug delivery system (DDS), for example, the following functions are required: the nanodrug has to disperse well in the blood to avoid embolism; circulate throughout the body to avoid leaking from the pores in the blood vessel and trapping in the reticuloendothelial system; accumulate in the targeting organ or tissue; and finally, release the loaded drug. Among the nanomaterials in the DDS, carbon nanomaterials have the following characteristic properties: (i) basically inert, but functionizable at the functional groups such as carboxylic and hydroxyl ones on the surface, edge, and defect through organic transformation; (ii) variety of options in terms of shapes including zero‐dimensional (0D, fullerenes), one‐dimensional (1D, carbon nanotubes, CNTs), two‐dimensional (2D, graphene, G), and three‐dimensional (3D, nanodiamond, ND); (iii) commercially available; and (iv) fluorescence emission from semiconducting SWNTs, relatively small size graphenes and color center in ND. The carbon nanomaterials discussed in this chapter are graphene (Section 10.2) and ND (Sections 10.3 and 10.4). Graphene has a flat and hydrophobic surface consisting of sp2 carbons. It exhibits high affinity to the flat molecules, including π‐electrons such as triphenylene, as we reported quite recently. Therefore, it has been utilized as carrier for anti‐cancer drugs with flat and hydrophobic properties. In addition, it can work as photosensitizer in photothermal therapy, making it more fascinating as a bifunctional material in cancer therapy. However, the graphene‐based carriers that have been used so far are graphene oxide (GO), because the carrier is required to have sufficient dispersibility in a physiological environment. The direct use of pristine graphene as a drug carrier, which will be described below, is the first example, as far as we know. On the other hand, ND has been reported to be low toxicity or even nontoxic nanomaterial. It is composed of the curved surface and core, not the flat surface and edge for graphene. As in the case of edge and defect in graphene, the ND surface is covered with various functional groups such as carboxylic and hydroxyl groups. Although ND is categorized as an inorganic nanomaterial due to its robustness and chemical stability, the surface functionalities impart the organic characteristics to ND, enabling the control of the physical property by controlling the surface functionality. Recently, surface chemical functionalization of ND has been actively investigated in view of its applications. In this chapter (Sections 10.3 and 10.4), chemical functionalization on ND for drug carrier will be described; the requisite functions of aqueous dispersibility, targeting specificity, and cytotoxicity are imparted to ND through stepwise surface chemical functionalization. This chapter covers synthesis, characterization, and evaluation of the following three nanodrugs: chlorin e6 (Ce6)‐loaded graphene for cancer phototherapy; Pt drug‐loaded nanodiamond for cancer chemotherapy; and DNA‐loaded nanodiamond for gene therapy.
关键词： nanodiamond,functionalization,drug delivery,graphene,phototherapy,chemotherapy,carbon nanomaterials,gene therapy
更新于2025-09-23 15:22:29
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Development of a photon induced drug-delivery implant coating
摘要： A thin surface coating intended for medical devices such as implants where local drug release is enabled using near infrared light (NIR) as an external stimulus has been developed. The delivery system consists of a thin Poly (N-isopropylacrylamide)-co-acrylamide (PNIPAAm-AAm) polymer layer with incorporated gold nanorods (GNRs). The aspect ratio of the GNRs were chosen to absorb NIR light, thus ?tting the biological window of low tissue absorption, to locally heat the polymeric layer to initiate a drug release. Hence, controlled drug delivery from a surface within tissue orchestrated from outside the body is achievable. Composition of the PNIPAAm-AAm co-polymer was systematically varied to ?nd a suitable phase transition temperature for in vivo applications. Di?erential scanning calorimetry (DSC) analysis showed that PNIPAAm-AAm containing 10% acrylamide had an appropriate phase transition temperature of 42 °C. As visualized by scanning electron microscopy (SEM), the surface coating consisted of 200 nm uniform polymer layer. Quartz crystal microbalance with dissipation monitoring (QCM-D) analysis coupled with in situ NIR irradiation demonstrated a dramatic shift in frequency that was attributed to mass being released from the surface upon irradiation. This mass release correlated well with the drug release pro?le as determined using UV/VIS spectroscopy with phenol as a model drug. In addition, proof-of-concept of the drug-delivery system was demonstrated by releasing the antibiotic vancomycin to eradicate Staphylococcus epidermidis bacteria in culture.
关键词： Thermo-sensitive,Drug delivery,Controlled release,Poly(N-isopropylacrylamide),Implant coating
更新于2025-09-23 15:22:29
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Toward a Precision Ophthalmology: Targeting the Retina
摘要： Efficacious drug delivery to the posterior chamber of the eye is a very challenging problem due to the many physiological barriers that protect the eye against the entry of exogenous substances. To avoid, or to limit, the action of these barriers several drug delivery routes are being investigated and used in clinical ophthalmology. To assist medical and pharmaceutical research, mathematical modeling of the release kinetics assumes a crucial role. In this paper three-dimensional computational models that simulate drug delivery from two different biodegradable polymeric platforms---intravitreal and transscleral---are presented. The models consist of coupled systems of partial differential equations linked by interface conditions, where the properties of the drug, of the implant, and of the eye tissues are taken into account. Peak concentrations and residence times are compared for the two delivery routes. Particular attention is devoted to the modeling of the blood retinal barrier (BRB). The influence of retinal diseases, represented by parameters that characterize the permeation through the BRB, is analyzed. Numerical simulations that illustrate the differences in the behavior of drug released from intravitreal and transscleral implants are included. The numerical results are compared with available experimental data.
关键词： partial differential equations,well-posedness,numerical simulation,drug delivery,retina
更新于2025-09-23 15:21:21
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Nanoparticulate Transscleral Ocular Drug Delivery
摘要： Ocular drug delivery is one of the most challenging areas of drug delivery due to the unique mostly avascular nature of the major eye structures and presence of two blood barriers. Effectiveness of a more conventional systemic delivery falls short due to low drug levels in the eye tissue. Periocular approaches require penetration of fibrous sclera and present their own limitations. Utilization of nanotechnology presents new avenue of drug system development with potential to penetrate protective barriers and sustain ample tissue saturation. More specifically, transscleral delivery permits a range of applications in targeted delivery, gene, stem cell, protein and peptides, oligonucleotide, and ribozyme therapies. The exciting range of current applications is expounded in this review.
关键词： Drug delivery systems,Drug delivery,Nanotechnology,Ocular delivery,Transscleral delivery,Macular degeneration,Nanoparticle,Retina
更新于2025-09-23 15:21:01
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Drug Delivery System Using Photothermal Effect of Gold Nanorods
摘要： Gold nanorods have absorption bands in the near-infrared region. The absorbed light energy is converted into heat by gold nanorods. Therefore, drug delivery systems that can be controlled by the heat produced by near-infrared light irradiation will be constructed. First, we modified gold nanorods with double-stranded DNA. That is, release of single stranded DNA is induced by the produced heat from the gold nanorods. We also constructed a controlled release system of PEG chain mediated by retro Diels-Alder reaction induced by the photothermal effect. Next, we designed transdermal protein delivery system enhanced by the photothermal effect. We first casted gold nanorods, acting as a heating device in response to near-infrared light irradiation, onto the skin surface. After applying an aqueous solution of ovalbumin to the skin, the skin was irradiated by near-infrared laser light. The irradiation increased the skin temperature resulting in an efficient translocation of ovalbumin into the skin. Thus, the controlled-release systems and enhanced transdermal protein delivery system triggered by near-infrared light irradiation will be further expanded to development of functional drug delivery system.
关键词： photothermal effect,gold nanorods,transdermal protein delivery,drug delivery system,near-infrared light
更新于2025-09-23 15:21:01
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Drug-releasing Biopolymeric Structures Manufactured via Stereolithography
摘要： Additive manufacturing (AM) techniques, such as stereolithography (SLA), enable the preparation of designed complex structures. AM has gained interest especially in the tissue engineering field due to the possibility to manufacture patient specific implants. However, AM could be useful also in controlled drug release applications, since the size and shape of the device, pore architecture and surface to volume ratio can be accurately designed. In this study, SLA was used to prepare polycaprolactone scaffold structures containing the model drug lidocaine. The release of lidocaine was studied and the influence of porosity and surface to volume ratio of structures to the drug release was analyzed. Porous samples released lidocaine faster compared to solid ones, whereas the degree of porosity and surface to volume ratio did not have a clear effect on the drug release profile.
关键词： drug delivery,stereolithography,additive manufacturing,drug release,lidocaine,scaffold,controlled release,polycaprolactone
更新于2025-09-23 15:21:01
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Controlled Peptide-Mediated Vesicle Fusion Assessed by Simultaneous Dual-Colour Time-Lapsed Fluorescence Microscopy
摘要： We have employed a model system, inspired by SnARe proteins, to facilitate membrane fusion between Giant Unilamellar Vesicles (GUVs) and Large Unilamellar Vesicles (LUVs) under physiological conditions. in this system, two synthetic lipopeptide constructs comprising the coiled-coil heterodimer-forming peptides K4, (KiAALKe)4, or e4, (eiAALeK)4, a peG spacer of variable length, and a cholesterol moiety to anchor the peptides into the liposome membrane replace the natural SnARe proteins. GUVs are functionalized with one of the lipopeptide constructs and the fusion process is triggered by adding LUVs bearing the complementary lipopeptide. Dual-colour time lapse fluorescence microscopy was used to visualize lipid- and content-mixing. Using conventional confocal microscopy, lipid mixing was observed on the lipid bilayer of individual GUVs. in addition to lipid-mixing, content-mixing assays showed a low efficiency due to clustering of K4-functionalized LUVs on the GUVs target membranes. We showed that, through the use of the non-ionic surfactant Tween 20, content-mixing between GUVs and LUVs could be improved, meaning this system has the potential to be employed for drug delivery in biological systems.
关键词： coiled-coil peptides,LUVs,drug delivery,GUVs,membrane fusion,Tween 20
更新于2025-09-23 15:21:01
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Photophysical Properties of Fluorescent Self-Assembled Peptide Nanostructures for Singlet Oxygen Generation
摘要： In this work, a drug delivery system for perillyl alcohol based on the peptide self-assembly containing 3-(2-benzothiazolyl)-7-(diethylamino)coumarin (C6) as a fluorescent additive is obtained, and its photophysical characteristics as well as its release dynamics were studied by steady-state and time-resolved fluorescence spectroscopy. Results proved the dynamics of drug release from the peptide nanostructures and showed that the system formed by the self-assembled peptide and C6, along with perillyl alcohol, presents unique photophysical properties that can be exploited to generate singlet oxygen (1O2) upon irradiation, which is not achieved by the sole components. Through epifluorescence microscopy combined with time-correlated single photon counting fluorescence spectroscopy, the release mechanism was proven to occur upon peptide structure interconversion, which is controlled by environmental changes.
关键词： photophysical properties,perillyl alcohol,drug delivery system,time-resolved fluorescence spectroscopy,fluorescent additive,peptide self-assembly,epifluorescence microscopy,singlet oxygen generation
更新于2025-09-23 15:21:01