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Background No willingness-to-pay (WTP) per quality-adjusted life-year (QALY) value exists for the Kingdom of Saudi Arabia (KSA). Objective The primary objective of this study was to determine the WTP for a QALY in the KSA. Methods Adult citizens of the KSA, patients with cancer, or members of the general public (MGP) were recruited to participate in a time trade-off survey to elicit health utilities. Cancer was chosen as the disease of interest for patients and the MGP, with a scenario describing stage 3 colorectal cancer, because it is a disease condition that impacts on both quality of life and survival time. In a second step, respondents were asked about their WTP to move from the estimated health state to a state of perfect health for 1 year (QALY). Finally, that amount was processed to generate the WTP for a full QALY. The second step was repeated with a 5-year horizon. Sensitivity analyses were performed without outliers. Results From 400 participants, data from 378 subjects were obtained and usable: 177 patients, 201 MGP; 278 male, 100 female subjects; 231 aged 26–65 years. Demographic distribution varied widely between the two subgroups for age, education level, and employment status, but with less variation in sex and income. Elicited health utilities were 0.413 (0.472 after adjustment) for the overall group, 0.316 (0.416) for patients, and 0.499 (0.508) for MGP. Overall WTP for a QALY was $US25,600 (adjusted $US32,000) for the 1-year horizon and $US19,200 (adjusted $US22,720) for the 5-year horizon. Conclusion This was the first empirical attempt to estimate the WTP per QALY for the KSA. Results are comparable to those in some other countries and to gross domestic product figures for the KSA. Further research in a country-wide sample is warranted. Electronic supplementary material The online version of this article (10.1007/s41669-020-00211-0) contains supplementary material, which is available to authorized users.

The aim of this study was to develop PEGylated phosphatidylcholine (PC)-rich nanovesicles (phosphatiosomes) carrying ciprofloxacin (CIPX) for lung targeting to eradicate extracellular and intracellular methicillin-resistant Staphylococcus aureus (MRSA). Soyaethyl morphonium ethosulfate (SME) was intercalated in the nanovesicle surface with the dual goals of achieving strengthened bactericidal activity of CIPX-loaded phosphatiosomes and delivery to the lungs. The isothermal titration calorimetry (ITC) results proved the strong association of SME phosphatiosomes with pulmonary surfactant. We demonstrated a superior anti-MRSA activity of SME phosphatiosomes compared to plain phosphatiosomes and to free CIPX. A synergistic effect of CIPX and SME nanocarriers was found in the biofilm eradication. SME phosphatiosomes were readily engulfed by the macrophages, restricting the intracellular MRSA count by 1-2 log units. SME phosphatiosomes efficiently accumulated in the lungs after intravenous injection. In a rat model of lung infection, the MRSA burden in the lungs could be decreased by 8-fold after SME nanosystem application.

Collecting evidence suggests that the intercellular infection of Chlamydia pneumoniae in lungs contributes to the etiology of lung cancer. Many proteins of Chlamydia pneumoniae outmanoeuvre the various system of the host. The infection may regulate various factors, which can influence the growth of lung cancer in affected persons. In this in-silico study, we predict potential targeting of Chlamydia pneumoniae proteins in mitochondrial and cytoplasmic comportments of host cell and their possible involvement in growth and development of lung cancer. Various cellular activities are controlled in mitochondria and cytoplasm, where the localization of Chlamydia pneumoniae proteins may alter the normal functioning of host cells. The rationale of this study is to find out and explain the connection between Chlamydia pneumoniae infection and lung cancer. A sum of 183 and 513 proteins were predicted to target in mitochondria and cytoplasm of host cell out of total 1112 proteins of Chlamydia pneumoniae. In particular, many targeted proteins may interfere with normal growth behaviour of host cells, thereby altering the decision of program cell death. Present article provides a potential connection of Chlamydia pneumoniae protein targeting and proposed that various targeted proteins may play crucial role in lung cancer etiology through diverse mechanisms. Keywords: Lung cancer, Chlamydia pneumoniae, Etiology, Systems biology, Protein targeting

Aim: Naphtho[1,2-b]furan-4,5-dione (N12D) and naphtho[2,3-b]furan-4,9-dione (N23D) are furanonaphthoquinone derivatives from natural resources. We examined the antimicrobial activity of N12D and N23D against drug-resistant Staphylococcus aureus. Materials & methods: Minimum inhibitory concentration, minimum bactericidal concentration, bacterial viability and agar diffusion assay were conducted against methicillin-resistant S. aureus (MRSA) and clinical isolates of vancomycin-resistant S. aureus. Results & conclusion: The minimum inhibitory concentration of N12D and N23D against MRSA was 4.9–9.8 and 39 μM, respectively. With regard to the agar diffusion test, the inhibition zone of the quinone compounds was threefold larger than that of oxacillin. N12D was found to inhibit MRSA biofilm thickness from 24 to 16 μm as observed by confocal microscopy. N12D showed a significant reduction of the intracellular MRSA burden without decreasing the macrophage viability. The antibacterial mechanisms of N12D may be bacterial wall/membrane damage and disturbance of gluconeogenesis and the tricarboxylic acid cycle.

A cationic amphiphile, soyaethyl morpholinium ethosulfate (SME), immobilized in liposomes or nanoemulsions, was prepared in an attempt to compare the antibacterial activity between SME intercalated in the phospholipid bilayer and oil–water interface. Before antibacterial assessment, the size of the liposomes and nanoemulsions was respectively recorded as 75 and 214 nm. The data of minimum inhibitory concentration (MIC)/minimum bactericidal concentration (MBC) and live/dead cell count demonstrated a superior antimicrobial activity of nanoemulsions compared to liposomes against Staphylococcus aureus , methicillin-resistant S. aureus (MRSA), and Staphylococcus epidermidis . Nanoemulsion incubation reduced biofilm thickness by 2.4-fold, whereas liposomes showed a 1.6-fold decrease in thickness. SME insertion in the oil–water phase was found to induce bacterial membrane disruption. SME nanosystems were nontoxic to keratinocytes. In vivo topical application of the cationic nanosystems reduced skin infection, MRSA load, and inflammation in mice. The deteriorated skin barrier function evoked by MRSA was recovered by nanoemulsion treatment.

Use of the ablative laser has been approved to enhance topical drug penetration. Investigation into the usefulness of the non-ablative laser for assisting drug delivery is very limited. In this study, we explored the safety and efficacy of the non-ablative fractional erbium:glass (Er:glass) laser as an enhancement approach to promote drug permeation. Both pig and nude mouse skins were employed as transport barriers. We histologically examined the skin structure after laser exposure. The permeants of 5-aminolevulinic acid (ALA), imiquimod, tretinoin, peptide, dextrans and quantum dots (QD) were used to evaluate in vitro and in vivo skin passage. The fractional laser selectively created an array of photothermal dots deep into the dermis with the preservation of the stratum corneum and epidermis. The barrier function of the skin could be recovered 8-60h post-irradiation depending on the laser spot densities. The application of the laser caused no local infection of Staphylococcus aureus and Pseudomonas aeruginosa. Compared to intact skin, ALA flux was enhanced up to 1200-fold after laser exposure. The penetration enhancement level by the laser was decreased following the increase of permeant lipophilicity. The skin accumulation of tretinoin, an extremely lipophilic drug, showed only a 2-fold elevation by laser irradiation. The laser promoted peptide penetration 10-fold compared to the control skin. Skin delivery of dextrans with a molecular weight (MW) of at least 40kDa could be achieved with the Er:glass laser. QD with a diameter of 20nm penetrated into the skin with the assistance of the non-ablative laser. The confocal microscopic images indicated the perpendicular and lateral diffusions of dextrans and nanoparticles via laser-created microscopic thermal zones. Controlled Er:glass laser irradiation offers a valid enhancement strategy to topically administer the permeants with a wide MW and lipophilicity range.

Tricyclic antidepressants (TCAs) are found to have an analgesic action for relieving cutaneous pain associated with neuropathies. The aim of this study was to assess cutaneous absorption and analgesia of topically applied TCAs. Percutaneous delivery was investigated using nude mouse and pig skin models at both infinite and saturated doses. We evaluated the cutaneous analgesia in nude mice using the pinprick scores. Among five antidepressants tested in the in vitro experiment, mesoridazine, promazine and doxepin showed a superior total absorption percentage. The drug with the lowest total absorption percentage was found to be fluphenazine (

Shigellosis is an acute invasive enteric infection by the Gram negative pathogen Shigella, which causes human diarrhea. Shigella, which are highly epidemic and pathogenic, have become a serious public health problem. The virulence plasmid is a large plasmid essential to the infected host cells. Many virulence factors are encoded in the ipa-mxi-spa region by the virulence plasmid. IpaB is a multifunctional and essential virulence factor in the infection process. In this review article, we introduce the recent studies of the effect of IpaB in Shigella-infected host cells. IpaB is involved in a type III secretion system (T3SS) structure. It also controls the secretion of virulence factors and Shigella adhesion to host cells. In addition, it forms the ion pore, destroys phagosomes, and induces the immune cell's apoptosis or necrosis. Moreover, IpaB can become a potential antigen for Shigella vaccine development.

Objective This study compares the current regulatory review process and good review practices at the Saudi Food and Drug Authority (SFDA) with those of regulatory agencies in Australia, Canada, and Singapore and identifies opportunities for developing the SFDA as a Regional Centre of Excellence. Methods A questionnaire completed by the SFDA included data regarding the organisation, key milestones, review timelines, and good review practices of the agency. Similar information was obtained within the same timeframe (2014/2015) through the same standard questionnaire regarding the processes and practices for Health Canada, Singapore’s Health Sciences Authority, and Australia’s Therapeutic Goods Administration. Results All four regulatory agencies have established target times for scientific assessment and regulatory review, examine dossier sections in parallel, and separate company response time from overall timing. Additionally, all four agencies have instituted good review practices including standard operating procedures, templates, dossier monitoring, and continuous improvement processes, and assign a high priority to transparency in their relationships with the public, healthcare professionals and industry. Of the four agencies, however, only the SFDA requires a Certificate of Pharmaceutical Product (CPP) at the time of the submission and pricing negotiations before final product approval. Conclusions To assist the SFDA in its efforts to become a Regional Centre of Excellence, it is suggested that the agency explore a risk stratification approach to select dossiers for verification, abridged, or full reviews; use forms of certification other than the CPP; make pricing negotiations independent to the review process; and introduce a feedback process for the quality of the dossier.

Photoaging is recognized as the factor damaging skin-barrier function. The aim of this study was to examine the impact of ultraviolet (UV) irradiation on the cutaneous penetration of soft nanoparticles, including nanostructured lipid carriers (NLCs) and poly(lactic-co-glycolic acid) polymer nanoparticles (PNs). In vitro cutaneous permeation of retinoic acid (RA) carried by nanoparticles was evaluated. In vivo nude mouse skin distribution of topically applied nanoparticles was observed by fluorescence and confocal microscopies. The association of nanoparticles with cultured keratinocytes was measured by flow cytometry and fluorescence microscopy. The average diameter and surface charge were 236 nm and −32 mV for NLCs, and 207 nm and −12 mV for PNs. The ultrastructural images of skin demonstrated that the application of UV produced a loss of Odland bodies and desmosomes, the organelles regulating skin-barrier function. UVA exposure increased skin deposition of RA regardless of nanoparticle formulation. UVB did not alter RA deposition from nanoparticles as compared to the non-treated group. Exposure to UVA promoted RA delivery into hair follicles from NLCs and PNs by 4.2- and 4.9-fold, respectively. The in vivo skin distribution also showed a large accumulation of Nile red-loaded nanoparticles in follicles after UVA treatment. The soft nanoparticles were observed deep in the dermis. PNs with higher lipophilicity showed a greater association with keratinocytes compared to NLCs. The cell association of PNs was increased by UVA application, whereas the association between NLCs and keratinocytes was reduced two times by UVA. It was concluded that both follicles and intercellular spaces were the main pathways for nanoparticle diffusion into photodamaged skin.

This study developed lipid nanocarriers, called squarticles, conjugated with anti-platelet-derived growth factor (PDGF)-receptor β antibody to determine whether targeted Minoxidil (MXD) delivery to the follicles and dermal papilla cells (DPCs) could be achieved. Squalene and hexadecyl palmitate (HP) were used as the matrix of the squarticles. The PDGF-squarticles showed a mean diameter and zeta potential of 195 nm and − 46 mV, respectively. Nanoparticle encapsulation enhanced MXD porcine skin deposition from 0.11 to 0.23 μg/mg. The antibody-conjugated nanoparticles ameliorated follicular uptake of MXD by 3-fold compared to that of the control solution in the in vivo mouse model. Both vertical and horizontal skin sections exhibited a wide distribution of nanoparticles in the follicles, epidermis, and deeper skin strata. The encapsulated MXD moderately elicited proliferation of DPCs and vascular endothelial growth factor (VEGF) expression. The active targeting of PDGF-squarticles may be advantageous to improving the limited success of alopecia therapy. From the Clinical Editor Topical use of minoxidil is only one of the very few treatment options for alopecia. Nonetheless, the current delivery method is far from ideal. In this article, the authors developed lipid nanocarriers with anti-platelet-derived growth factor receptor ? antibody to target dermal papilla cells, and showed enhanced uptake of minoxidil.

Cationic solid lipid nanoparticles (cSLNs) are extensively employed as the nanocarriers for drug/gene targeting to tumors and the brain. Investigation into the possible immune response of cSLNs is still lacking. The aim of this study was to evaluate the impact of cSLNs upon the activation of human polymorphonuclear neutrophil cells (PMNs). The cytotoxicity, pro-inflammatory mediators, Ca2+ mobilization, mitogen-activated protein kinases (MAPKs), and neutrophil extracellular traps (NETs) as the indicators of PMN stimulation were examined in this work. The cSLNs presented a diameter of 195 nm with a zeta potential of 44 mV. The cSLNs could interact with the cell membrane to produce a direct membrane lysis and the subsequent cytotoxicity according to lactate dehydrogenase (LDH) elevation. The interaction of cSLNs with the membrane also triggered a Ca2+ influx, followed by the induction of oxidative stress and degranulation. The cationic nanoparticles elevated the levels of superoxide anion and elastase by 24- and 9-fold, respectively. The PMN activation by cSLNs promoted the phosphorylation of p38 and Jun-N-terminal kinases (JNK) but not extracellular signal-regulated kinases (ERK). The imaging of scanning electron microscopy (SEM) and immunofluorescence demonstrated the production of NETs by cSLNs. This phenomenon was not significant for the neutral SLNs (nSLNs), although histones in NETs also increased after treatment of nSLNs. Our results suggest an important role of cSLNs in governing the activation of human neutrophils.

Topically applied natural antioxidants can be an effective treatment for inhibiting oxidative damage and photoaging of the skin. Due to the barrier function of the stratum corneum (SC), it is necessary to use an enhancement approach to promote the cutaneous absorption of natural antioxidants. Some factors that should be considered when developing delivery systems for natural antioxidants include increased solubility, enhanced storage stability, improved permeability and bioavailability, skin targeting, and minimal side effects. This review describes the skin delivery systems for natural antioxidant permeation that have been developed during the last decade. The antioxidants introduced include vitamins, polyphenols, and carotenoids. Various types of formulations are employed to improve the skin penetration of the antioxidants, such as hydrogels, cyclodextrin, microemulsions, nanoparticles, liposomes and niosomes. This review focuses on the introduction of natural antioxidants used in skin protection, the mechanisms of antioxidant activity on the skin, and formulation designs for enhancing absorption and efficacy.

Quantitative determination of gatifloxacin in tablets, solid lipid nanoparticles (SLNs) and eye-drops using a very simple and rapid chromatographic technique was validated and developed. Formulations were analyzed using a reverse phase SUPELCO® 516 C-18-DB, 50306-U, HPLC column (250 mm × 4.6 mm, 5 μm) and a mobile phase consisting of disodium hydrogen phosphate buffer:acetonitrile (75:25, v/v) and with orthophosphoric acid pH was adjusted to 3.3 The flow rate was 1.0 mL/min and analyte concentrations were measured using a UV-detector at 293 nm. The analyses were performed at room temperature (25 ± 2 °C). Gatifloxacin was separated in all the formulations within 2.767 min. There were linear calibration curves over a concentration range of 4.0-40 μg.mL(-1) and correlation coefficients of 0.9998 with an average recovery above 99.91%. Detection of analyte from different dosage forms at the same Rt indicates the specificity and stability of the developed method.

A set of honokiol derivatives was synthesized to evaluate skin permeation and bioactivity. The reaction for derivatization included acetylation and methylation. The anti-inflammatory activity against neutrophils and macrophages was examined. The experimental setup for the assessment of cutaneous absorption was the in vitro Franz diffusion assembly. Honokiol and its derivatives significantly downregulated superoxide anion and elastase production in neutrophils, with honokiol showing the greatest inhibition. All derivatives could be completely hydrolyzed to the parent compounds after passing into the skin. The skin deposition of honokiol at an infinite dose (3mM) was 0.33nmol/mg 4'-O-acetylhonokiol (AH), and 2,4'-diacetylhonokiol (DAH) exhibited comparable or less absorption than honokiol. The integrated acetylation and methylation (2-O-acetyl-4'-O-methylhonokiol, AMH) led to a 10.5-fold improvement of absorption compared to honokiol. AMH was advantageous for the targeted cutaneous treatment due to the high skin deposition and minimal penetration across the skin (8.40nmol/cm2 compared to 93.49nmol/cm2 for honokiol). The predicted therapeutic index for superoxide and interleukin (IL)-6 inhibition was much higher for topically applied AMH than for the other penetrants tested. The total polarity surface and hydrogen bond acceptor number calculated by molecular modeling were the parameters used to anticipate the cutaneous absorption. Our data suggest that AMH is a potent and safe candidate for cutaneous inflammation therapy.

In this study, we aimed to illustrate the utility of fractional radiofrequency (RF) that generated microchannels in the skin, allowing delivery of peptide and siRNA via the skin. The mechanisms involved in the correlation between macromolecule permeation and skin structure were also elucidated. The morphology of the skin was examined by transmission electron microscopy (TEM), higher harmonic generation microscopy (HGM), and physiological factors. In vivo skin distribution of macromolecules was assessed by fluorescence and confocal microscopies. RF thermolysis selectively created an array of micropores deep into the epidermis without significant removal of the stratum corneum (SC). With energy of 30 mJ, a pore depth of 35 μm was achieved. The bipolar RF resulted in a 3-fold increase of transepidermal water loss (TEWL) compared with intact skin. The respective skin accumulation and flux of the peptide with a molecular weight (MW) of 2335 Da was 3- and 23-fold greater for the RF-treated group than for the non-treatment group. RF enhanced skin accumulation of siRNAs with MW of 10 and 15 kDa by 6.2- and 2.6-fold, respectively. Cutaneous penetration of the macromolecules with an MW of at least 40 kDa could be accomplished by RF. Confocal microscopy imaging revealed that RF could effectively deliver the peptide up to at least a 74-μm depth. The penetration depth of siRNA by RF irradiation was about 50 μm. The novel RF device efficiently delivered macromolecules into the skin while reserving SC layers to support some barrier functions. In this work, for the first time the assistance of fractional RF on peptide and siRNA transport was demonstrated.

Alopecia usually cannot be cured because of the available drug therapy being unsatisfactory. To improve the efficiency of treatment, erbium–yttrium–aluminum–garnet (Er–YAG) laser treatment was conducted to facilitate skin permeation of antialopecia drugs such as minoxidil (MXD), diphencyprone (DPCP), and peptide. In vitro and in vivo percutaneous absorption experiments were carried out by using nude mouse skin and porcine skin as permeation barriers. Fluorescence and confocal microscopies were used to visualize distribution of permeants within the skin. Laser ablation at a depth of 6 and 10 μm enhanced MXD skin accumulation twofold to ninefold depending on the skin barriers selected. DPCP absorption showed less enhancement by laser irradiation as compared with MXD. An ablation depth of 10 μm could increase the peptide flux from zero to 4.99 and 0.33 μg cm −2 h −1 for nude mouse skin and porcine skin, respectively. The laser treatment also promoted drug uptake in the hair follicles, with DPCP demonstrating the greatest enhancement (sixfold compared with the control). The imaging of skin examined by microscopies provided evidence of follicular and intercellular delivery assisted by the Er–YAG laser. Besides the ablative effect of removing the stratum corneum , the laser may interact with sebum to break up the barrier function, increasing the skin delivery of antialopecia drugs. The minimally invasive, well‐controlled approach of laser‐mediated drug permeation offers a potential way to treat alopecia. This study's findings provide the basis for the first report on laser‐assisted delivery of antialopecia drugs.

Although the application of nanotechnology to drug therapy has been widely investigated, very few nanomedicine-based treatments for traumatic hemorrhage have been reported so far. The aim of this work was to develop nanostructured lipid carriers (NLCs) loaded with phosphodiesterase 4 (PDE4) inhibitors to treat acute inflammation in peripheral organs. The pharmacokinetics and biodistribution of DSM-RX78 and EFB-1, two novel PDE4 inhibitors, were examined using rats as an animal model. Entrapment by NLCs resulted in sustained drug release. The plasma concentrations of DSM-RX78 and EFB-1 in NLCs were lower, and their half-lives were much shorter in the NLC condition than in the control condition. PDE4 inhibitors delivered in NLCs accumulated with high abundance in many organs, especially the brain and lungs. Polyethylene glycol (PEG) coating on the particulate surface (P-NLCs) significantly reduced brain delivery of the drugs. P-NLCs enhanced drug distribution to the lungs by 5-fold compared to free control. In vivo real-time imaging confirmed rapid escape of nanoparticles from the blood circulation. Histological examination and aminotransferase measurement revealed that P-NLCs containing EFB-1 improved hemorrhagic shock-induced injuries in the lungs, intestines, and liver. P-NLCs even reversed acute lung inflammation to the level observed in an uninjured condition. Our results indicate that NLC-based delivery of PDE4 inhibitors is a candidate treatment for traumatic hemorrhage.

The successful ophthalmic delivery system is reliant on the diminution in the precorneal loss of drugs by increasing the corneal contact time and increasing the transcorneal permeability, which may enhance the bioavailability of drug to the eyes. The objective of this investigation was to develop and evaluate the potential of microemulsions of gatifloxacin with respect to the conventional eye drops of gatifloxacin. Oil-in-water microemulsions were prepared with different concentrations of oil, surfactant and co-surfactant using aqueous titration method. All formulations showed circular shape droplets, displayed an average droplet size ranged between 51 and 74 nm and absolute zeta potential values ranged from 15 to 24 mV, with optimum physicochemical characteristics suitable for eye. The optimized microemulsion possessed good stability, showed greater adherence to corneal surface and good permeation of gatifloxacin in the anterior chamber of the eye, resulting in a twofold increase in gatifloxacin concentration than the conventional dosage form. Hence, the optimized microemulsions showed increased intraocular penetration and enhance ocular bioavailability of gatifloxacin.

The present study was conducted to evaluate the impacts of fractional erbium (Er):YAG and CO 2 lasers on skin permeation of small interfering (si)RNA and plasmid (p)DNA vectors. In vitro skin delivery was determined with a Franz diffusion cell. In vivo absorption was investigated by observing fluorescence and confocal microscopic imaging. Fractional laser-mediated ablation of the skin resulted in significant enhancement of dextran and siRNA penetration. Respective fluxes of dextran (10 kDa) and siRNA, which had similar molecular size, with Er:YAG laser irradiation at 5 J/cm 2 were 56- and 11-fold superior to that of intact skin. The respective permeation extents of dextran and siRNA by the CO 2 laser at 4 mJ/400 spots were 42- and 12-fold greater than that of untreated skin. Fluorescence and confocal images showed increased fluorescence intensities and penetration depths of siRNA and pDNA delivery. According to an examination of the follicular permeant amount and fluorescence microscopy, hair follicles were important deposition areas for fractional laser-assisted delivery, with the Er:YAG modality revealing higher follicular siRNA selectivity than the CO 2 modality. This is the first report of siRNA and pDNA penetrating the skin with a sufficient amount and depth with the assistance of fractional lasers.

Physical ablation can be an effective drug-permeation-enhancement strategy forpromoting drug delivery into or across the skin. The control- led ablation of the stratum corneum (SC), the predominant barrier for drug absorption, is achieved by ablative techniques incorporating the use of lasers, microneedles, microdermabrasion, and radiofrequency. It has been demonstrated that ablative approaches used for enhancing drug transport provide some advantages, including increased bioavailability, fast treatment time, and quick recovery of SC integrity. In recent years the concept of using ablative techniques to treat skin has attracted increasing attention. This review describes recent developments using skin-ablative approaches for drug-permeation enhancement. This review systematically introduces the concepts and enhancement mechanisms of variousphysical ablative methods, highlighting the potential of these techniques for greatly increasing drug absorption via the skin. In this review, we principally focus on the small-molecule drugs approved by the US FDA for clinical use. The macromolecules and nanoparticles as the model permeants are not the focus of this review since they have not until recently been extensively applicable in clinical situations. Finally, future developments and trends are anticipated.

Hydroquinone and tranexamic acids (TXA) are skin-lightening agents with a hydrophilic nature and low skin absorption. A high dose is needed for clinical use, resulting in a high incidence of skin irritation. Co-drugs formed by conjugating hydroquinone and TXA were synthesized and their in vitro and in vivo skin absorption characteristics were evaluated. The two synthesized co-drugs were 4-hydroxyphenyl 4-(aminomethyl)cyclohexanecarboxylate (HAC) and 1,4- phenylene bis(aminomethyl)cyclohexanecarboxylate (BAC). The co-drugs were chemically stable in aqueous solution, but rapidly degraded to the respective parent drug in esterases and skin homogenates. Compared to hydroquinone application, 7.2- and 2.4-fold increments in the hydroquinone skin deposition were obtained with the in vitro application of HAC and BAC. HAC and BAC led to 3- and 2-fold enhancements of equivalent TXA deposition compared to TXA administration. The in vivo experiment showed a further enhancement of co-drugs compared to the in vitro setup. The transdermal penetration of co-drugs, especially BAC, was much lower than that of hydroquinone and TXA. This indicated high-level skin targeting by the co-drugs. HAC and BAC revealed strong affinities for the viable epidermis/dermis. Hair follicles are important reservoirs for co-drug delivery. Daily administration of co-drugs to the skin did not generate irritation for up to 7 days. Both co-drugs are superior candidates for treating skin hyperpigmentation.

The purpose of this study was to evaluate the skin permeation of tricyclic antidepressants (TCAs) with propamine moiety to select candidates for the development of topical analgesics to treat cutaneous pain. We sought to establish the structure-permeation relationship (SPR) of topical TCAs. The lipophilicity, melting point, and aqueous solubility were determined to develop the physicochemical characterization. The TCA permeation into pig and nude mouse skins was estimated using Franz diffusion cell. TCAs and lidocaine were comparatively examined for cutaneous analgesia by pinprick assay. Cutaneous tolerance to TCAs was assessed using nude mouse skin. The skin deposition increased following the increase of lipophilicity after excluding the effect of solubility, with clomipramine exhibiting the highest skin retention. A contrary result was observed for TCA penetration into the receptor. Of the permeants tested, clomipramine demonstrated the best skin-targeting ability. Nortriptyline and clomipramine demonstrated selective uptake into the hair follicles, exhibiting a 2.5-fold higher follicular accumulation than desipramine. Replacement of nitrogen with carbon in the seven-member ring increased skin absorption. The tertiary amine TCAs demonstrated higher absorption than the secondary amine TCAs. The position of the double bond also affected skin transport. Topical clomipramine had a longer duration of analgesic action than lidocaine (240min versus 60min). Exploring the SPR revealed that clomipramine could be an analgesic candidate drug for future development.

Different types of injectable nanoparticles, including metallic nanoparticles, polymeric nanocarriers, dendrimers, liposomes, niosomes, and lipid nanoparticles, have been employed to load drugs for lung delivery. Nanoparticles used for lung delivery offer some benefits over conventional formulations, including increased solubility, enhanced stability, improved epithelium permeability and bioavailability, prolonged half-life, tumor targeting, and minimal side effects. In recent years, the concept of using injectable nanocarriers as vehicles for drug delivery has attracted increasing attention. This review highlights recent developments using nanomedical approaches for drug targeting to the lungs. We systematically introduce the concepts and amelioration mechanisms of the nanomedical techniques for lung cancer therapy. Passive targeting by modulating the nanoparticulate structure and the physicochemical properties is an option for efficient drug delivery to the lungs. In addition, active targeting such as antibody or peptide conjugation to nanoparticles is another efficient way to deliver the drugs to the targeted site. This review describes various nanocarriers loaded with anticancer drugs for passive or active targeting of lung malignancy. In this review, we principally focus on the nanomedical application in animal studies. The article excludes investigations limited to cell-based experiments. The review ends by anticipating future developments and trends.

Food contamination by pathogenic microorganisms has been a serious public health problem and a cause of huge economic losses worldwide. Foodborne pathogenic Escherichia coli (E. coli) contamination, such as that with E. coli O157 and O104, is very common, even in developed countries. Bacterial contamination may occur during any of the steps in the farm-to-table continuum from environmental, animal, or human sources and cause foodborne illness. To understand the causes of the foodborne outbreaks by E. coli and food-contamination prevention measures, we collected and investigated the past 10 years’ worldwide reports of foodborne E. coli contamination cases. In the first half of this review article, we introduce the infection and symptoms of five major foodborne diarrheagenic E. coli pathotypes: enteropathogenic E. coli (EPEC), Shiga toxin-producing E. coli/enterohemorrhagic E. coli (STEC/EHEC), Shigella/enteroinvasive E. coli (EIEC), enteroaggregative E. coli (EAEC), and enterotoxigenic E. coli (ETEC). In the second half of this review article, we introduce the foodborne outbreak cases caused by E. coli in natural foods and food products. Finally, we discuss current developments that can be applied to control and prevent bacterial food contamination.

Background: Of the >140 anticancer drugs approved since 1940 and available for clinical application, >60% can be traced to a natural product. Of the small molecules among them, 67% are natural in origin. Nanocarriers can be effective anticancer drug delivery systems for preventing and treating cancers. It has been demonstrated that nanoparticles used for drug therapy provide some advantages over conventional formulations, including increased solubility, enhanced storage stability, improved permeability and bioavailability, prolonged half-life, tissue targeting, and minimal side effects. Methods: In recent years, the concept of using nanoparticles as the carriers of natural products or herbal drugs has attracted increasing attention. This review highlights recent developments using nanomedical approaches for natural product delivery. Results: We systematically introduce the concepts and amelioration mechanisms of the nanomedical techniques for natural product cancer therapy. These modalities are useful in the therapy incorporating a wide variety of natural products for treating brain, lung, breast, and colorectal cancers. The nanosystems for biomedicine can be categorized into three groups: polymeric, lipid, and metallic nanoparticles. All of these have been employed as anticancer carriers for natural products. This review describes various nanocarriers loaded with natural compounds for passive or active targeting of tumors. Conclusion: The nanomedicine research data for phytomedicine cancer remedies suggest a way forward for generating advances in chemotherapy.

Aim: Here we evaluated the antibacterial efficacy of soyaethyl morpholinium ethosulfate (SME) micelles as an inherent bactericide against Staphylococcus aureus and methicillin-resistant S. aureus (MRSA). Methodology: The antimicrobial activity was examined by in vitro culture model and murine model of skin infection. Cationic micelles formed by benzalkonium chloride or cetylpyridinium chloride were used for comparison. Results: The minimum inhibitory concentration and minimum bactericidal concentration against S. aureus and MRSA were 1.71–3.42 and 1.71–6.84 μg/ml, respectively. Topical administration of SME micelles significantly decreased the cutaneous infection and MRSA load in mice. The killing of bacteria was caused by direct cell wall/membrane rupture. SME micelles also penetrated into the bacteria to elicit a Fenton reaction and oxidative stress. Conclusion: SME micelles have potential as antimicrobial agents due to their lethal effect against S. aureus and MRSA with a low toxicity to mammalian cells.

This study describes corneal permeation of gatifloxacin from solid lipid nanoparticle (SLN) through the cornea and its effect on corneal hydration level. The aqueous humor levels of gatifloxacin after single topical instillation in Gate(®) Eyedrops and positively charged SLN-C were determined. A 3.37-fold increase in the relative bioavailability was observed with the SLN-C (AUC0→∞ 2.192 μg mL(-1) h) (AUC, area under the curve) as compared to Gate(®) Eyedrops (AUC0→∞ 0.651 μg mL(-1) h). The t1/2 of drug in SLN-C exhibited a 2.34-fold higher than Gate(®) Eyedrops seem to be significantly increased (p > 0.05), Cmax of gatifloxacin from SLN-C showed 1.09-fold higher concentration as compared to Gate(®) Eyedrops. The results suggested that SLNs could enhance ocular bioavailability of gatifloxacin and prolong its residence time in the eyes. Moreover, no signs of ocular irritation were seen with the SLN formulations, indicating their relative safety compared to the marketed drops.

The purpose of this study was to determine the pharmacokinetics (PK) of the 5-HT(2A) receptor antagonist ketanserin in healthy adult horses, and to develop a computational model that could be used to optimize dosing. Plasma concentrations of ketanserin were determined using liquid chromatography with mass spectrometry after single and multiple intravenous administration in the horse. A two-compartment linear pharmacokinetic model described the plasma concentration-time profile of ketanserin after single and multiple doses in healthy horses; the terminal half-life was 11.5 h; steady-state volume of distribution was 10.5 L/kg; AUC was 115 ng · h/mL; and clearance was 0.87 L/h/kg. Model simulations followed by the examination in three healthy horses suggest 0.3 mg/kg q.8 h exhibited linear PK and produced consistent systemic blood concentrations of ketanserin above 3 ng/mL.

The objective of this study was to determine the antitumor effects of alternate dosing schedules of topotecan in prostate cancer.A concentration-dependent increase in cytotoxicity was observed in PC-3 and LNCaP cells after topotecan treatment using conventional and metronomic protocols. A significant increase in potency (2.4-18 fold, after 72 hr) was observed following metronomic dosing compared to conventional dosing administration in both cell lines. Metronomic dosing also increased the percentage of PC-3 cells in the G2/M, compared to control, but did not alter LNCaP cell cycle distribution. Metronomic dosing increased p21 protein expression in LNCaP and PC-3 cells compared to conventional dosing. The observed in vitro activity was confirmed using an in vivo model of human prostate cancer. Metronomic dosing and continuous infusion decreased tumor volume significantly (p0.05) compared to control and conventional topotecan treatment, but had no effect on tumor vascular staining.The cytotoxicity of topotecan after conventional or metronomic dosing was determined by examining cellular morphology, mitochondrial enzymatic activity (MTT), total cellular protein (SRB), annexin V and propidium iodine (PI) staining, cell cycle and western blot analysis in human prostate cancer cell lines (PC-3 and LNCaP) and the effects metronomic or continuous infusion on tumor growth in an in vivo tumor xenograft model.These data support the hypothesis that low-dose continuous administration of topotecan increases potency compared to conventional dosing in prostate cancer. These data also suggest the novel finding that the enhanced antitumor activity of topotecan following low-dose exposure correlates to alterations in cell cycle and increased p21 expression.

The discrepancy in drug absorption between healthy and diseased skins is an issue that needs to be elucidated. The present study attempted to explore the percutaneous absorption of drugs via lesional skin by using atopic dermatitis (AD) as a model. Tape-stripping and ovalbumin (OVA) sensitization induced AD-like skin. The lesions were evaluated by physiological parameters, histology, cytokines, and differentiation proteins. The permeants of tacrolimus, 8-methoxypsoralen, methotrexate, and dextran were used to examine in vitro and in vivo cutaneous permeation. Transepidermal water loss (TEWL) increased from 5.2 to 27.4 g/m(2)/h by OVA treatment. AD-like lesions were characterized by hyperplasia, skin redness, desquamation, and infiltration of inflammatory cells. Repeated OVA challenge produced a T-helper 2 (Th2) hypersensitivity accompanied by downregulation of filaggrin, involucrin, and integrin β. Tacrolimus, the most lipophilic permeant, revealed an increase of cutaneous deposition by 2.7-fold in AD-like skin compared to intact skin. The transdermal flux of methotrexate and dextran, the hydrophilic permeants, across AD-like skin increased about 18 times compared to the control skin. Surprisingly, AD-like skin showed less skin deposition of 8-methoxypsoralen than intact skin. This may be because the deficient lipids in the atopic-affected stratum corneum (SC) diminished drug partitioning into the superficial skin layer. The fluorescence and confocal microscopic images demonstrated a broad and deep passage of small-molecular and macromolecular dyes into AD-like skin. The results obtained from this report were advantageous for showing how the lesional skin influenced percutaneous absorption.

In this study, we investigated whether tacrolimus extracted and purified from the commercial capsules (Prograf® 5 mg) have retained its original quality and activity beyond the capsules expiration date in order to be reused for research purposes after extraction. High-performance liquid chromatography (HPLC) assay method was developed and validated for the quantification of tacrolimus, using cyclosporine A as an internal standard (IS). Moreover, a combination of analytical methods, including nuclear magnetic resonance (NMR), gas chromatography–mass spectrometry (GC-MS), Fourier transform-infrared (FT-IR) spectroscopy, X-ray diffraction (XRD), and differential scanning calorimetry (DSC) were used to assess the quality of extracted/purified tacrolimus. Suppression of murine peripheral-blood mononuclear cells (PBMC) proliferation and the levels of interleukin-2 (IL-2) and interferon gamma (IFN-γ) were also assessed. The data obtained showed no detectable differences in the quality profile between the authentic sample and extracted drug. Also, the results showed that the extracted/purified tacrolimus was able to suppress T cell proliferation, induced by concanavalin A, indicating the retained pharmacological activity. We proved that tacrolimus extracted/purified from expired Prograf® capsuled retains its purity and immunosuppressive activity and can be reused for research and possibly in pharmaceutical manufacturing.

Ultraviolet (UV) exposure and menopause are known as the inducers of damage to the skin structure. The combination of these two factors accelerates the skin aging process. In this study, we aimed to evaluate the influence of UV and ovariectomy (OVX) on the permeation of drugs through the skin. The role of tight junctions (TJs) and adherens junctions (AJs) in the cutaneous absorption of extremely lipophilic permeants and macromolecules was explored. The OVX nude mouse underwent bilateral ovary removal. Both UVA and UVB were employed to irradiate the skin. The physiological and biochemical changes of the skin structure were examined with focus on transepidermal water loss (TEWL), skin color, immunohistochemistry, and mRNA levels of proteins. UVB and OVX increased TEWL, resulting in stratum corneum (SC) integrity disruption and dehydration. A hyperproliferative epidermis was produced by UVB. UVA caused a pale skin color tone due to keratinocyte apoptosis in the epidermis. E-cadherin and β-catenin showed a significant loss by both UVA and UVB. OVX downregulated the expression of filaggrin and involucrin. A further reduction was observed when UV and OVX were combined. The in vitro cutaneous absorption demonstrated that UV increased the skin permeation of tretinoin by about twofold. However, skin accumulation and flux of estradiol were not modified by photoaging. OVX basically revealed a negligible effect on altering the permeation of small permeants. OVX increased tretinoin uptake by the appendages from 1.36 to 3.52 μg/cm(2). A synergistic effect on tretinoin follicular uptake enhancement was observed for combined UV and OVX. However, the intervention of OVX to photoaged skin resulted in less macromolecule (dextran, molecular weight = 4 kDa) accumulation in the skin reservoir because of retarded partitioning into dry skin. The in vivo percutaneous absorption of lipophilic dye examined by confocal microscopy had indicated that the SC was still important to controlling topical delivery, although the role of epidermal junctions could not be simply ignored.

Tsong-Long Hwang,1,2 Ibrahim A Aljuffali,3 Chwan-Fwu Lin,4,5 Yuan-Ting Chang,6 Jia-You Fang6–8 1Cell Pharmacology Laboratory, Graduate Institute of Natural Products, 2Chinese Herbal Medicine Research Team, Healthy Aging Research Center, Chang Gung University, Kweishan, Taoyuan, Taiwan; 3Department of Pharmaceutics, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia; 4Department of Cosmetic Science, 5Chronic Diseases and Health Promotion Research Center, Chang Gung University of Science and Technology, Kweishan, Taoyuan, Taiwan; 6Pharmaceutics Laboratory, Graduate Institute of Natural Products, Chang Gung University, Kweishan, Taoyuan, Taiwan; 7Research Center for Industry of Human Ecology, Chang Gung University of Science and Technology, Kweishan, Taoyuan, Taiwan; 8Chang Gung Memorial Hospital, Kweishan, Taoyuan, Taiwan Abstract: This report compares the effect of lipid and polymeric nanoparticles upon human neutrophils in the presence of cationic surfactants. Nanostructured lipid carriers and poly(lactic-co-glycolic) acid nanoparticles were manufactured as lipid and polymeric systems, respectively. Some cytotoxic and proinflammatory mediators such as lactate dehydrogenase (LDH), elastase, O2•-, and intracellular Ca2+ were examined. The nanoparticles showed a size of 170–225 nm. Incorporation of cetyltrimethylammonium bromide or soyaethyl morpholinium ethosulfate, the cationic surfactant, converted zeta potential from a negative to a positive charge. Nanoparticles without cationic surfactants revealed a negligible change on immune and inflammatory responses. Cationic surfactants in both nanoparticulate and free forms induced cell death and the release of mediators. Lipid nanoparticles generally demonstrated a greater response compared to polymeric nanoparticles. The neutrophil morphology observed by electron microscopy confirmed this trend. Cetyltrimethylammonium bromide as the coating material showed more significant activation of neutrophils than soyaethyl morpholinium ethosulfate. Confocal microscope imaging displayed a limited internalization of nanoparticles into neutrophils. It is proposed that cationic nanoparticles interact with the cell membrane, triggering membrane disruption and the following Ca2+ influx. The elevation of intracellular Ca2+ induces degranulation and oxidative stress. The consequence of these effects is cytotoxicity and cell death. Caution should be taken when selecting feasible nanoparticulate formulations and cationic additives for consideration of applicability and toxicity. Keywords: cationic surfactant, neutrophil, inflammation, nanoparticle

A novel nanovesicle carrier, phosphatiosomes, was developed to enhance the targeting efficiency of phosphodiesterase 4 (PDE4) inhibitor to the lungs for treating acute lung injury (ALI) by intravenous administration. Phosphatiosomes were the basis of a niosomal system containing phosphatidylcholine (PC) and distearoylphosphatidylethanolamine polyethylene glycol (DSPE-PEG). Rolipram was used as the model drug loaded in the phosphatiosomes. Bioimaging, biodistribution, activated neutrophil inhibition, and ALI treatment were performed to evaluate the feasibility of phosphatiosomes as the lung-targeting carriers. An encapsulation percentage of >90% was achieved for rolipram-loaded nanovesicles. The vesicle size and zeta potential of the phosphatiosomes were 154 nm and -34 mV, respectively. Real-time imaging in rats showed a delayed and lower uptake of phosphatiosomes by the liver and spleen. Ex vivo bioimaging demonstrated a high accumulation of phosphatiosomes in the lungs. In vivo biodistribution exhibited increased lung accumulation and reduced brain penetration of rolipram in phosphatiosomes relative to the control solution. Phosphatiosomes improved the lungs/brain ratio of the drug by more than 7-fold. Interaction with pulmonary lipoprotein surfactants and the subsequent aggregation may be the mechanisms for facilitating lung targeting by phosphatiosomes. Rolipram could continue to inhibit active neutrophils after inclusion in the nanovesicles by suppressing O2(-) generation and elevating cAMP. Phosphatiosomes significantly alleviated ALI in mice as revealed by examining their pulmonary appearance, edema, myeloperoxidase (MPO) activity, and histopathology. This study highlights the potential of nanovesicles to deliver the drug for targeting the lungs and attenuating nervous system side effects.

It has been demonstrated that nanoparticles used for follicular delivery provide some advantages over conventional pathways, including improved skin bioavailability, enhanced penetration depth, prolonged residence duration, fast transport into the skin and tissue targeting. This review describes recent developments using nanotechnology approaches for drug delivery into the follicles. Different types of nanosystems may be employed for management of follicular permeation, such as polymeric nanoparticles, metallic nanocrystals, liposomes, and lipid nanoparticles. This review systematically introduces the mechanisms of follicles for nanoparticulate penetration, highlighting the therapeutic potential of drug-loaded nanoparticles for treating skin diseases. Special attention is paid to the use of nanoparticles in treating appendage-related disorders, in particular, nanomedical strategies for treating alopecia, acne, and transcutaneous immunization.

Background Ambient particulate matters (PMs) are known as inducers that adversely affect a variety of human organs. Objectives In this study, we aimed to evaluate the influence of PMs on the permeation of drugs and sunscreens via the skin. The role of skin-barrier properties such as the stratum corneum (SC) and tight junctions (TJs) during the delivery process was explored. Methods This work was conducted using both in vitro and in vivo experiments in pigs to check the responses of the skin to PMs. PMs primarily containing heavy metals (1648a) and polycyclic aromatic hydrocarbons (PAHs, 1649b) were employed to treat the skin. Results According to the transepidermal water loss (TEWL), 1649b but not 1648a significantly disrupted the SC integrity by 2-fold compared to the PBS control. The immunohistochemistry (IHC) of cytokeratin, filaggrin, and E-cadherin exhibited that 1649b mildly damaged TJs. The cytotoxicity of keratinocytes and skin fibroblasts caused by 1649b was stronger than that caused by 1648a. The 1649b elicited apoptosis via caspase-3 activation. The proteomic profiles showed that PMs upregulated Annexin A2 by >5-fold, which can be a biomarker of PM-induced barrier disruption. We found that the skin uptake of ascorbic acid, an extremely hydrophilic drug, was increased from 74 to 112 μg/g by 1649b treatment. The extremely lipophilic drug tretinoin also showed a 2.6-fold increase of skin accumulation. Oxybenzone and dextran absorption was not affected by PMs. The in vivo dye distribution visualized by fluorescence microscopy had indicated that 1649b intervention promoted permeant partitioning into SC. Conclusions Caution should be taken in exposing the skin to airborne dust due to its ability to reduce barrier function and increase the risk of drug overabsorption, although this effect was not very marked.

Cardiotoxicity associated with the use of doxorubicin (DOX), and other chemotherapeutics, limits their clinical potential. This study determined the pharmacokinetics and antitumor and cardioprotective activity of free and liposome encapsulated phenyl-2-aminoethyl-selenide (PAESe).The pharmacokinetics of free PAESe and PAESe encapsulated in liposomes (SSL-PAESe) were determined in rats using liquid chromatography tandem mass-spectrometry. The antitumor and cardioprotective effects were determined in a mouse xenograft model of human prostate (PC-3) cancer and cardiomyocytes (H9C2).The encapsulation of PAESe in liposomes increased the circulation half-life and area under the drug concentration time profile, and decreased total systemic clearance significantly compared to free PAESe. Free- and SSL-PAESe improved survival, decreased weight-loss and prevented cardiac hypertrophy significantly in tumor bearing and healthy mice following treatment with DOX at 5 and 12.5 mg/kg. In vitro studies revealed PAESe treatment altered formation of reactive oxygen species (ROS), cardiac hypertrophy and gene expression, i.e., atrial natriuretic peptide and myosin heavy chain complex beta, in H9C2 cells.Treatment with free and SSL-PAESe exhibited antitumor activity in a prostate xenograft model and mitigated DOX-mediated cardiotoxicity.

Background Hydroquinone (HQ) and salicylic acid (SA) are drugs for treating melasma through the mechanisms of tyrosinase inhibition and chemical peeling, respectively. Their high frequency of causing skin irritation has led to limited use of both drugs. Objectives We designed the new conjugates obtained by joining HQ and SA by the co-drug concept for evaluating cutaneous absorption capability. Methods Monoester (4-hydroxyphenyl 2-hydroxybenzoate, HPH) and diester (1,4-phenylene bis(2-hydroxybenzoate), PBH) forms of the conjugates were synthesized and physicochemically characterized. The enzymatic hydrolysis to the parent drugs was examined. Both an equimolar dose and a saturated solubility were utilized as the applied dose for testing cutaneous absorption via pig and nude mouse skins. Results The conjugates had higher lipophilicity, less aqueous solubility, and a lower melting point/crystallinity than the parent drugs. Both conjugates showed a quick conversion into the parent drugs in esterases and skin homogenates, with PBH showing the greater hydrolysis. The hydrolysis level in skin after topical application was less as compared to that in esterases and homogenates. The tyrosinase inhibition (%) and molecular docking demonstrated that the conjugates possessed skin-lightening capability (3% for HPH and 7% for PBH) although this activity was lower than that of HQ (23%). The conjugates showed an increased skin deposition compared to the respective parent drugs. Total absorption of HPH and PBH led to a 13- and 19-fold enhancement in cutaneous retention compared to HQ alone. A similar increment of skin deposition was shown for the conjugates when compared to SA. Contrary to skin reservoir retention, transdermal transport across the skin was decreased by the conjugates, especially for PBH. This indicates the maximization of cutaneous targeting by the conjugates. Conclusions Topically applied HPH and PBH can be the new candidates for treating melasma due to efficient skin absorption and acceptable skin tolerance.

Using lasers can be an effective drug permeation-enhancement approach for facilitating drug delivery into or across the skin. The controlled disruption and ablation of the stratum corneum (SC), the predominant barrier for drug delivery, is achieved by the use of lasers. The possible mechanisms of laser-assisted drug permeation are the direct ablation of the skin barrier, optical breakdown by a photomechanical wave and a photothermal effect. It has been demonstrated that ablative approaches for enhancing drug transport provide some advantages, including increased bioavailability, fast treatment time, quick recovery of SC integrity and the fact that skin surface contact is not needed. In recent years, the concept of using laser techniques to treat the skin has attracted increasing attention.This review describes recent developments in using nonablative and ablative lasers for drug absorption enhancement. This review systematically introduces the concepts and enhancement mechanisms of lasers, highlighting the potential of this technique for greatly increasing drug absorption via the skin. Lasers with different wavelengths and types are employed to increase drug permeation. These include the ruby laser, the erbium:yttrium-gallium-garnet laser, the neodymium-doped yttrium-aluminum-garnet laser and the CO2 laser. Fractional modality is a novel concept for promoting topical/transdermal drug delivery. The laser is useful in enhancing the permeation of a wide variety of permeants, such as small-molecule drugs, macromolecules and nanoparticles.This potential use of the laser affords a new treatment for topical/transdermal application with significant efficacy. Further studies using a large group of humans or patients are needed to confirm and clarify the findings in animal studies. Although the laser fluence or output energy used for enhancing drug absorption is much lower than for treatment of skin disorders and rejuvenation, the safety of using lasers is still an issue. Caution should be used in optimizing the feasible conditions of the lasers in balancing the effectiveness of permeation enhancement and skin damage.

Delivery of diphencyprone (DPCP) and minoxidil to hair follicles and related cells is important in the treatment of alopecia. Here we report the development of “squarticles,” nanoparticles formed from sebum-derived lipids such as squalene and fatty esters, for use in achieving targeted drug delivery to the follicles. Two different nanosystems, nanostructured lipid carriers (NLC) and nanoemulsions (NE), were prepared. The physicochemical properties of squarticles, including size, zeta potential, drug encapsulation efficiency, and drug release, were examined. Squarticles were compared to a free control solution with respect to skin absorption, follicular accumulation, and dermal papilla cell targeting. The particle size of the NLC type was 177 nm; that of the NE type was 194 nm. Approximately 80% of DPCP and 60% of minoxidil were entrapped into squarticles. An improved drug deposition in the skin was observed in the in vitro absorption test. Compared to the free control, the squarticles reduced minoxidil penetration through the skin. This may indicate a minimized absorption into systemic circulation. Follicular uptake by squarticles was 2- and 7-fold higher for DPCP and minoxidil respectively compared to the free control. Fluorescence and confocal images of the skin confirmed a great accumulation of squarticles in the follicles and the deeper skin strata. Vascular endothelial growth factor expression in dermal papilla cells was significantly upregulated after the loading of minoxidil into the squarticles. In vitro papilla cell viability and in vivo skin irritancy tests in nude mice suggested a good tolerability of squarticles to skin. Squarticles provide a promising nanocarrier for topical delivery of DPCP and minoxidil.

Multifunctional liposomes loaded with quantum dots (QDs) and anticancer drugs were prepared for simultaneous bioimaging and drug delivery. Different formulations, including cationic, PEGylated and deformable liposomes, were compared for their theranostic efficiency. We had evaluated the physicochemical characteristics of these liposomes. The developed liposomes were examined using experimental platforms of cytotoxicity, cell migration, cellular uptake, in vivo melanoma imaging and drug accumulation in tumors. The average size of various nanocomposite liposomes was found to be 92–134 nm. Transmission electron microscopy confirmed the presence of QDs within liposomal bilayers. The incorporation of polyethylene glycol (PEG) and Span 20 into the liposomes greatly increased the fluidity of the bilayers. The liposomes provided sustained release of camptothecin and irinotecan. The cytotoxicity and cell migration assay demonstrated superior activity of cationic liposomes compared with other carriers. Cationic liposomes also showed a significant fluorescence signal in melanoma cells after internalization. The liposomes were intratumorally administered to a melanoma-bearing mouse. Cationic liposomes showed the brightest fluorescence in tumors, followed by classical liposomes. This signal could last for up to 24 h for cationic nanosystems. Intratumoral accumulation of camptothecin from free control was 35 nmol g(−1); it could be increased to 50 nmol g(−1) after loading with cationic liposomes. However, encapsulation of irinotecan into liposomes did not further increase intratumoral drug accumulation. Cationic liposomes were preferable to other liposomes as nanocarriers in both bioimaging and therapeutic approaches.