Current Drug Delivery (v.14, #3)

Meet Our Editorial Board Member: by Francesco Peri (305-305).

Micro-Nanomaterials for Tumor Microwave Hyperthermia: Design, Preparation, and Application by Xue Chen, Longfei Tan, Tianlong Liu, Xianwei Meng (307-322).
Background: Cancer hyperthermia is attracting much attention in basic science and clinics. Among the hyperthermia techniques, microwave (MW) heating is most commonly used for cancer treatment. It offers highly competitive advantages: faster heat generation from microwave radiation, less susceptibility to heat up local tissues, maneuverability, and depth of penetration in tissues and capability of killing tumor cells. Although the encouraging clinical results are being collected, MW hyperthermia has its own challenges, such as inaccurate targeting and low selectivity, which lead to damage to the surrounding vital organs and tissues. To address these issues, this review aims to introduce micronanomaterials as promising agents for receiving the electromagnetic wave, which should be beneficial for improving the efficacy of MW hyperthermia.
Methods: We have searched many peer-reviewed papers in medical and chemical material databases about micro-nanomaterials for tumor microwave hyperthermia. Distinguishing features and important progresses are introduced in this review.
Results: One hundred and forty papers were chosen and included in this review. Four parts were described, including hyperthermia techniques and the application of micro-nanomaterials, microwave thermal therapy and treatment principle, microwave absorbing micro-nanomaterials, the preparation and application of micro-nanomaterials in microwave thermal therapy.
Conclusion: We review the most recent literatures on micro-nanomaterials-based MW heating strategies for cancer treatment, with the aim to give the reader an overview of the state-of-the-art of MW hyperthermia therapy. The future of MW responsive materials will also be discussed, including combination of imaging probes and targeting moieties.

Tumor Thermal Ablation Enhancement by Micromaterials by Fan Zhao, Hongying Su, Xiangjun Han, Han Bao, Ji Qi (323-333).
Thermal ablation is a minimally invasive therapeutic technique that has shown remarkable potential in treating unresectable tumors. However, clinical applications have stalled, due to safety ambiguities, slow heat induction, lengthy ablation times, and post-therapeutic monitoring issues. To further improve treatment efficacy, an assortment of micromaterials (e.g., nanoparticulates of gold, silica, or iron oxide and single-walled carbon nanotubes) are under study as thermal ablative adjuncts. In recent years, the micromaterial domain has become especially interesting. In vivo and in vitro animal studies have validated the use of microspheres as embolic agents in liver tumors, in advance of radiofrequency ablation. Microcapsules and microbubbles serving as ultrasound contrast and ablation sensibilizers are strong prospects for clinical applications. This review was conducted to explore benefits of the three aforementioned microscale technologies, in conjunction with tumor thermal ablation.

Chitosan Functionalized CuS Nanoparticles Boots Gene Transfection via Photothermal Effect by Li Lin, Xiaoda Li, Yongbo Yang, Lijia Jing, Xiuli Yue, Xuzhu Chen, Zhifei Dai (334-341).
Background: The lack of smart and controllable gene vectors with high safety and efficiency is still a main obstruction for clinical applications of gene therapy. Recently, the external physical stimuli, such as near infrared light induced temperature elevation, have been applied to enhance the gene transfection efficiency and specificity. The aim of this paper is to fabricate chitosan functionalized CuS nanoparticles (CuS@CS NPs) with small size and higher biocompatibility for enhanced gene delivery by photothermal effect.
Methods: CuS@CS NPs were successfully prepared by simple hydrothermal method. The biocompatibility was detected by MTT method and hymolytic analysis. pEGFP-C1was used as gene model, and its expression efficiency was detected by fluorescence microscopy and flow cytometry to investigate the effect of photothermal effect on the transfection efficiency.
Results: The CuS@CS NPs around 15 nm were successfully engineered. The modification of CuS nanoparticles with chitosan conduced to higher physiological stability and biocompatibility. The utilization of CuS@CS NPs in combination with external near infrared (NIR) laser irradiation could enhance gene transfection efficiency due to photothermal effect. The gene transfection efficiency of CuS@CS NPs found to increase from 5.05±0.54% (0 min) to 23.47±1.27% (10 min), significantly higher than the free polyethylenimine (18.15±1.03%).
Conclusion: CuS@CS NPs showed great capability to control gene delivery by an external NIR laser irradiation and enhance the gene transfection efficiency and specificity because of convenient preparation, stabilized optical properties, excellent photothermal effect and good biocompatibility. It encourages further exploration of the CuS@CS NPs as a photocontrollable nanovector for combined photothermal and gene therapy, as well as image guided therapy.

Fabrication of Eu-doped Gd(OH)3 Nanorods with Enhanced Magnetic- Resonance and Luminescence Imaging by Yuanwen Zou, Zhi Wu, Zhongbing Huang, Guangfu Yin, Lei Wang, Fabao Gao (342-348).
Background: Multimodal bio-imaging is a new technique with more than one imaging modality. Eu3+ doping can tailor the multi-functions of Gd-based nanorods (NRs) to obtain the resolution the imaging at the cellular level. Silk fibroin with His and Lys can induce to fabricate metal compounds particles. However, one-step preparation of SFP-linked Eu-Gd(OH)3 NRs with cyto-compatibility is very challenging.
Methods: Eu-doped Gd(OH)3 nanorods with silk fibroin peptides (SFP-NRs) are synthesized via a simple and feasible biomimetic method in the assistance of SFPs.
Results: The measurement results showed that these hexagonal crystal NRs possessed 300 nm of the length. Compared with pure NRs, SFP-NRs exhibited better in vitro T1 signal-enhancement of magnetic resonance (MR) imaging due to their higher ratio of Eu and Gd and SFP coating on their surface, and the longitudinal relaxivity r1 value is 2.57 (Gd mM·s)-1 under a 7.0 T MR imaging system. Furthermore, a series of in vivo T1-weighted MR images between pre- and post-injection in tumor regions for 9 h indicated that average intensity of post-injection of SF-NRs was enhanced to 68%, higher the increased value of pure NRs (19.6%), but also SFP-NRs showed the good luminescence labeling of viable cell in the fluorescence observation.
Conclusion: These results indicate that Eu-doped SFP-NRs have potential as T1 MR imaging contrast agents and optical imaging probe in tumor-detection field.

Biomimetic Mineralization of Tumor Targeted Ferromagnetic Iron Oxide Nanoparticles Used for Media of Magnetic Hyperthermia by Siyu Xie, Guangfu Yin, Ximing Pu, Yang Hu, Zhongbin Huang, Xiaoming Liao, Yadong Yao, Xianchun Chen (349-356).
Background: The magnetic hyperthermia has been recognized as a useful therapeutic modality for malignant tumors, and IONPs have received a great deal of attentions for potential biomedical applications. The aims of this paper are to design a biomimetic mineralization procedure to synthesize the ferromagnetic and tumor targeting Fe3O4 nanoparticles, to conjugate bioactive molecule on particles, to analyze properties of product.
Methods: IONPs were synthesized with the WSG-PF127 as the mineralization templates, which were mixed by conjugating the peptide WSG on the surface of PF127. And the influence of different conditions, such as templates, temperature, stirring speed on the particles was investigated.
Results: Above the critical micelle concentration (CMC), the catenulate PF127 molecules were assembled into the hollow sphere-like micelle, and the morphology and size of the IONPs mineralized inside the hollow cores of PF127 micelles could be controlled due to the space restricted effect. The saturation magnetization was increased due to the higher crystallinity degree of the WSG-PF127-IONPs, the cytocompatibility was improved by the WSG-PF127 wrapped around the IONPs, and the targetability was endowed via the mediation of the peptide-WSG conjugated on hydrophilic segments of PF127 molecular chains.
Conclusion: The iron oxide nanoparticles with homogenous morphology, uniform size, and excellent ferromagnetism have been successfully mineralized under the regulation of the PF127 micelles coupled with the peptide-WSG. The improved ferromagnetism, the negligible cytotoxicity to HUVECs, and the targetability to tumor cells of the biomimetically mineralized IONPs coupled with WSG-PF127 have greater potential to be applied as the active tumor targeted media for magnetic hyperthermia.

Background: The use of microneedles for transdermal drug delivery is a feasible alternative to injections and tablets. As different types of microneedles are being developed from a variety of materials, it is important to understand their insertion and fracture forces. In this review, it has been emphasized that for microneedles to be clinically useful, they must penetrate the skin without breaking. It means that the insertion force must be smaller than fracture force.
Methods: Transdermal experiments involving these forces have been described and theoretical models highlighted. The knowledge of these forces is important for microneedle design and experimental/ clinical use.
Results: From an experimental standpoint, different techniques are used to measure insertion and fracture forces. To measure insertion and failure forces, a texture analyzer can be used. In this review, the measurement of insertion and fracture forces has been discussed and their utility in transdermal experiments presented.
Conclusion: This review has focused on insertion and failure forces in transdermal drug delivery experiments. Although the question is complex since there is a wide variety of skin models and forces involved, studies carried out in the last few years have thrown more light to aid better understanding of these forces in transdermal drug delivery research.

Background: Resveratrol belonging to stilbene family has emerged as a leading candidate for enhancing the health span by potentially decreasing the aging process and reducing chronic diseases.
Objective: The aim of this review is to focus on various studies related to chemical composition l, pharmacological activities, bioavailability problems associated with resveratrol. In addition, it includes section discussing the challenges associated with drug and strategies to improve resveratrol solubility, stability and bioavailability.
Current Scenario: It is being revealed currently in various literature that resveratrol is a potential drug candidate with multi-spectrum pharmacological applications. The poor bioavailability of resveratrol in humans is a matter of great concern for transforming basic science findings into clinical application. Although couple of research projects have emerged from human clinical trials, however results are conflicting, that may partially belong to defined dosing protocols. A number of theoretical methods have been developed to improve the bioavailability of resveratrol, including micronization of particles which are combined with additional phytochemicals, novel delivery systems, and nanotechnology applied formulations.
Conclusion: If bioavailability is such a limitation in the clinical application of resveratrol, then methods need to be optimized for resveratrol formulations. Drug stability needs to be improved, so that the bioavailability enhances and side-effects of resveratrol reduces. The novel drug delivery systems have been designed to bring this potential molecule to the first line treatment of diseases. This review focuses on the current bioavailability literature, reveals data from humans, and provides suggested actions to be taken for future research.

Enhanced Bioavailability of Curcumin Nanoemulsions Stabilized with Phosphatidylcholine Modified with Medium Chain Fatty Acids by Angélica A. Ochoa-Flores, Josafat A. Hernández-Becerra, Adriana Cavazos-Garduño, Ida Soto-Rodríguez, Maria Guadalupe Sanchez-Otero, Eduardo J. Vernon-Carter, Hugo S. García (377-385).
Background: Curcumin is a natural, oil-soluble polyphenolic compound with potent anticancer, anti-inflammatory, and antioxidant activities. In its free form, it is very poorly absorbed in the gut due to its very low solubility. The use of nanoemulsions as carrier is a feasible way for improving curcumin bioavailability. To this end, the choice of emulsifying agent for stabilizing the nanoemulsions is of the upmost importance for achieving a desired functionality.
Methods: Phosphatidylcholine (PC) and phosphatidycholine enriched (PCE) with medium chain fatty acids (42.5 mol %) in combination with glycerol as co-surfactant, were used for preparing oil-in water nanoemulsions coded as NEPC and NEPCE, respectively.
Results: NEPCE displayed significantly smaller mean droplet size (30 nm), equal entrapment efficiency (100%), better droplet stability and suffered lower encapsulation efficiency loss (3%) during storage time (120 days, 4°C) than NEPC. Bioavailability, measured in terms of area under the curve of curcumin concentration versus time, and maximum curcumin plasma concentration, was in general terms significantly higher for NEPCE than for NEPC, and for curcumin coarse aqueous suspension (CCS). Also, NEPCE produced significantly higher curcumin concentrations in liver and lung than NEPC and CCS.
Conclusion: These data support the role of phosphatidylcholine enriched with medium chain fatty acids to increase the bioavailability of nanoemulsions for therapeutic applications.

Novel Drug Delivery System for Dermal Uptake of Etofenamate: Semisolid SLN Dispersion by Ulya Badilli, C. Tuba Sengel-Turk, Gulin Amasya, Nilufer Tarimci (386-393).
Background: Semisolid SLNs are novel strategy for dermal drug administration instead of incorporating the SLN dispersions into conventional semisolids. Etofenamate loaded semisolid SLNs were successfully prepared and in vitro characterization of formulations were performed in our previous study. The present study is an attempt to evaluate the dermal behavior of the semisolid SLNs selected on the basis of previous research and investigate the properties in terms of the convenience for topical applications.
Objective: The objective of this study is to evaluate the skin penetration characteristics of semisolid SLN formulations. The occlusive and mechanical properties of semisolid SLNs were also evaluated because of their impression on the dermal behavior of the formulations.
Method: The occlusive properties were investigated by in vitro occlusion test. Texture analysis was performed to define the hardness, compressibility, adhesiveness, cohesiveness and elasticity of the formulations. Rat skin was chosen to evaluate the ex vivo penetration of etofenamate loaded semisolid SLNs and commercial gel product. Coumarin-6 was used to visualize the dermal distribution of the semisolid SLN formulations. For monitorizing the penetration of coumarin-6 into the skin samples Confocal Laser Scanning Microscopy was employed.
Results: The occlusive and mechanical properties of C1 coded semisolid SLN formulation were found more favorable in comparison with P1. The cumulative etofenamate amount in skin samples was found to be 39.88 ± 1.50 ?g/cm2 for C1 and 30.56 ± 2.10 ?g/cm2 for P1 coded formulations. According to CLSM images, greater fluorescence intensities and deeper skin penetrations were obtained with both of the semisolid SLNs in comparison to plain Carbopol gel.
Conclusion: It can be concluded that the semisolid SLNs are promising alternative dermal drug delivery systems to the conventional dosage forms.

A New Application Route of Nitrofurantoin: Preparation and Characterization of Novel Transdermal Formulations by Mesut Arici, Salih Kavukcu, Sakine Tuncay Tanriverdi, Aylin Arici, Sedef Gidener, Ayse Gelal, Ozgen Ozer (394-405).
Objectives: Nitrofurantoin is widely used in the prophylaxis of urinary-tract infections. The aim of this study was to develop and characterize innovative transdermal formulations of nitrofurantoin, to increase the patient compliance and decrease the adverse effects such as nausea and vomiting which limit the drug use in long-term.
Methods: Nitrofurantoin loaded microemulsion, gel (hydrogel, lipogel and DMSO gel) and film formulations were prepared and characterized via several parameters. Ex-vivo drug permeation studies were performed to determine the amount of drug permeated through the rat skin. In in-vivo studies, in order to detect nitrofurantoin in urine, the selected formulations were applied to male Wistar rats transdermally. Also, skin irritation tests (transepidermal water loss and erythema) were performed.
Results: All nitrofurantoin loaded formulations were prepared successfully and were stable at +4°C for 3 months. 13%, 16%, 32.5%, 36.5% and 39% of drugs permeated through the rat skin in the 168th hour for hydrogel, lipogel, film, microemulsion and DMSO gel, respectively. Only with film and DMSO gel formulations, nitrofurantoin was detected in urine. Transepidermal water loss was increased compared to basal level in film type formulations (p<0.05). However, in erythema experiments there was no difference (p>0.05).
Conclusion: There is no approved transdermal formulation of nitrofurantion on the market. Therefore, the prepared film formulations could be an alternative due to their high penetration through the rat skin, the presence of nitrofurantoin in urine and because they cause no irritation on the skin.

Dextran based Polymeric Micelles as Carriers for Delivery of Hydrophobic Drugs by Georgeta Mocanu, Marieta Nichifor, Liviu Sacarescu (406-415).
Background: The improvement of drugs bioavailability, especially of the hydrophobic ones, by using various nanoparticles is a very exciting field of the modern research.
Objective: The applicability of nano-sized shell crosslinked micelles based on dextran as supports for controlled release of several hydrophobic drugs (nystatin, rifampicin, resveratrol, and curcumin) was investigated by in vitro drug loading/release experiments.
Methods: The synthesized crosslinked micelles were loaded with drugs of various hydrophobicities and their retention/release behavior was followed by dialysis procedure.
Results: Crosslinked micelles obtained from dextran with octadecyl end groups, with or without N-(2- hydroxypropyl)-N,N-dimethyl-N-benzylammonium chloride groups attached to the main dextran chains, could retain the drugs in amounts which increased with increasing drug hydrophobicity (water insolubility), as follows: 30-60 mg rifampicin/g, 70-100 mg nystatin/g, 120-144 mg resveratrol/g and 146-260 mg curcumin/g. The rate of drug release from the loaded micelles was also dependent on the drug hydrophobicity and was always slower than the free drug recovery. Antioxidant activity of curcumin and resveratrol released from the loaded micelles was preserved.
Conclusion: The results highlighted the potential of the new nano-sized micelles as carriers for prolonged and controlled delivery of various hydrophobic drugs.

A Multi-layered Particulate System for Desvenlafaxine Succinate Oral Customized Release by Nazik Elgindy, Ayman Elnoby, Hanan M. El-Gowelli, Wael Samy (416-425).
Background: With its reported side effects Desvenlafaxine succinate (DSV) is a good candidate to prepare prolonged release system. Such prolonged release could decrease the rapid DSV absorption after oral administration and reduce its exaggerated side effects.
Methods: A prolonged release Desvenlafaxine succinate (DSV) multilayered system was prepared by ionotropic gelation using sodium alginate (SA) and calcium chloride as a cross-linker. DSV was incorporated simultaneously during the gelation stage and the formed beads were evaluated for shape and particle size. Thirteen formulation variables including pH, DSV: polymer ratio, cross-linker concentration and curing time were optimized for optimal drug entrapment. The optimized formula was evaluated ex vivo using the everted sac technique to predict DSV absorption through intestinal mucosal cells, follow the permeation and calculate its apparent permeability coefficient.
Results: The optimum formulation variables were: pH (8-9), DSV: SA ratio (2:1), cross-linker concentration (5%w/v) and 30 min curing time. Multilayered beads coating using chitosan and SA was compared with uncoated beads or the innovator for DSV release. Coating of the beads greatly retarded DSV release with a release profile similar to that of the innovator. An optimized formula (T13) coated with 0.04% w/v of each of chitosan and SA was selected. The developed system gave rise to a prolonged release pattern with high similarity factor with the innovator.
Conclusion: The results of the current work can be applied to prepare controlled release systems of similar drugs that have intense side effects associated with their initial burst after oral administration.

Jojoba Oil Soft Colloidal Nanocarrier of a Synthetic Retinoid: Preparation, Characterization and Clinical Efficacy in Psoriatic Patients by Maha Nasr, Sameh Abdel-Hamid, Noha H. Moftah, Maha Fadel, Abdullah A. Alyoussef (426-432).
Background: Nanotechnology has provided substantial benefits in drug delivery, especially in the treatment of dermatological diseases. Psoriasis is a chronic inflammatory skin disease in which topical delivery of antipsoriatic agents is considered the first line treatment.
Objective: To investigate whether the encapsulation of the synthetic retinoid tazarotene in a nanocarrier based on jojoba oil would decrease its irritation potential and clinically improve its therapeutic outcome in psoriatic patients.
Method: A microemulsion system based on jojoba wax and labrasol/plurol isostearique was prepared and characterized.
Results: The selected formula displayed spherical morphology, particle size of 15.49±2.41 nm, polydispersity index of 0.20 ±0.08, negative charge and low viscosity. The microemulsion provided two folds increase in skin deposition of tazarotene, correlating with higher reduction in psoriatic patients PASI scores after treatment (68% reduction in PASI scores versus 8.96% reduction with the marketed gel). No irritation was encountered in patients using microemulsion, with redness and inflammation reported with the marketed gel-treated patients.
Conclusion: Jojoba oil microemulsion proved to be advantageous in reducing the irritancy of tazarotene, enhancing its skin deposition and achieving better therapeutic outcome in psoriatic patients.

Photothermal Ablation of Cancer Cells Using Folate-Coated Gold/ Graphene Oxide Composite by Nicol&#242; Mauro, Anna Li Volsi, Cinzia Scialabba, Mariano Licciardi, Gennara Cavallaro, Gaetano Giammona (433-443).
Objective: A new tumor targeted polymer-coated gold/graphene hybrid has been developed for achieving simultaneously thermoablation and chemoterapy of folate receptor-positive cancer cells.
Methods: The gold/graphene hybrid was prepared by depositing gold nanospheres onto graphene oxide and coating it with an inulin-folate conjugate. Paclitaxel was loaded by sonication. The hybrid was characterized by UV-Vis spectroscopy, DSC analysis and SEM microscopy. The cytotoxicity, thermoablation and anticancer activity were evaluated in vitro on MCF-7 and 16 HBE.
Results: In vitro tests showed that the paclitaxel-loaded hybrid improved the effectiveness of the drug especially after photothermal treatments.
Conclusion: On the whole, while gold/graphene composite provided an excellent time-dependent photothermal effect, the loading of paclitaxel allowed a suitable chemotherapy, thus killing cancer cells both via a selective laser beam thermoablation and hyperthermia-triggered chemotherapy.