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ABSTRACTIntroductionRNA interference (RNAi) has demonstrated great potential in treating skin-related diseases, as small interfering RNA (siRNA) can efficiently silence specific genes. The design of skin delivery systems for siRNA is important to protect the nucleic acid while facilitating both skin targeting and cellular ingestion. Entrapment of siRNA into nanocarriers can accomplish these aims, contributing to improved targeting, controlled release, and increased transfection.Areas coveredThe siRNA-based nanotherapeutics for treating skin disorders are summarized. First, the mechanisms of RNAi are presented, followed by the introduction of challenges for skin therapy. Then, the different nanoparticle types used for siRNA skin delivery are described. Subsequently, we introduce the mechanisms of how nanoparticles enhance siRNA skin penetration. Finally, the current investigations associated with nanoparticulate siRNA application in skin disease management are reviewed.Expert opinionThe potential application of nanotherapeutic RNAi allows for a novel skin application strategy. Further clinical studies are required to confirm the findings in the cell-based or animal experiments. The capability of large-scale production and reproducibility of nanoparticle products are also critical for translation to commercialization. siRNA delivery by nanocarriers should be optimized to attain cutaneous targeting without the risk of toxicity.

Psoriasis is a refractory and difficult-to-treat skin disorder. The neutrophil-targeting approach represents a promising option for psoriasis therapy. This study developed and examined NIMP-R14-conjugated immunonanoparticles for specific targeting to neutrophils associated with psoriasiform dermatitis. In the process, roflumilast (RFL), as a phosphodiesterase (PDE) 4 inhibitor, was encapsulated in the nanocarriers to assess the anti-inflammatory capability against primary neutrophil activation and murine psoriasiform lesion. The average size and surface charge of the immunonanocarriers were 305 ± 36 nm and −18 ± 6 mV, respectively. The monovalent antibody-conjugated nanoparticles offered precise uptake by both human and mouse neutrophils but failed to exhibit this effect in monocytes and lymphocytes. The intracellular RFL concentration of the immunonanocarriers was five-fold superior to that of the passive counterparts. The immunonanocarriers specifically recognized the neutrophils through the Ly6 antigen with no apparent cytotoxicity. The antibody-conjugated nanoparticles mitigated superoxide anion production and migration of the activated human neutrophils. The in vivobiodistribution in the psoriasiform mice, found using an in vivoimaging system (IVIS) and liquid chromatography (LC)-mass-mass analysis, showed that the antibody conjugation increased the nanoparticle residence in systemic circulation after intravenous administration. On the other hand, most of the nanoparticles were accumulated in the lesional skin after subcutaneous injection. The actively-targeted nanocarriers were better than the free RFL and unfunctionalized nanoparticles in suppressing psoriasiform inflammation. The immunonanocarriers reduced neutrophil recruitment and epidermal hyperplasia in the plaque. Intravenous and subcutaneous treatments with the immunonanocarriers significantly reduced the overexpressed cytokines and chemokines in the inflamed skin, demonstrating that the nanosystems could both systematically and locally alleviate inflammation. The results indicated that the NIMP-R14-conjugated RFL-loaded nanoparticles have potential as an anti-autoimmune disease delivery system for neutrophil targeting.

Dual photothermal and photodynamic therapy (PTT and PDT) is an attractive approach that generates a synergistic effect for inhibiting keratinocyte hyperproliferation in the treatment of psoriasis. Here, we developed phototheranostic nanocarriers capable of producing hyperthermia and reactive oxygen species (ROS) in response to near-infrared (NIR) illumination. To this end, IR820 with photothermal and photodynamic features was embedded in nano-sized polydopamine (PDA) acting as a PTT agent. A comprehensive characterization of the PDA/IR820 nanosystem was performed according to its morphology, size, zeta potential, UV absorbance, and heat generation. Its therapeutic efficacy was assessed by a keratinocyte-based study and using an imiquimod (IMQ)-stimulated psoriasiform murine model. PDA/IR820 nanoparticles were facilely internalized into keratinocytes and mainly resided in lysosomes. Upon irradiation with NIR light, ROS were generated inside the keratinocytes to cause a photodynamic effect. The live/dead cell assay and cytotoxicity assay demonstrated that PDA and IR820 acted as effective photoabsorbers to induce keratinocyte death. The highest cytotoxic effect was detected in the group of NIR-irradiated PDA/IR820 nanoparticles, which killed 52% of keratinocytes. The nanosystem acted through the caspase and poly ADP-ribose polymerase (PARP) pathways to induce keratinocyte apoptosis. In vitroand in vivoskin permeation indicated the selective accumulation of the topically applied PDA/IR820 nanoparticles within psoriasiform skin, suggesting their skin-targeting capability. The combination of PDA/IR820 nanoparticles and NIR irradiation increased the skin temperature by 11.7 °C. PTT/PDT eliminated psoriasiform plaques in mice by decreasing hyperplasia, inhibiting cytokine overexpression, and recovering the barrier function. The epidermal thickness of the IMQ-treated skin was reduced from 134 to 34 μm by the nanocarriers plus NIR. The IR820 nanoparticles were largely deposited on the inflamed areas of psoriasiform lesions for monitoring the severity of inflammation. The image-guided phototheranostic nanoparticles showed their potential for applications in psoriasis management vianoninvasive topical administration.

ABSTRACTIntroduction: The use of herbal compounds in cancer therapy has great potential to promote the efficacy of current cancer therapeutic strategies. Herbal compounds were successfully reported to enhance tumor cells sensitization to the action of chemo-, hormonal- and gene-therapeutic agents viadifferent mechanisms. Herbal ingredients can affect different signaling pathways, reduce the toxic side effects or inhibit the efflux of anticancer drugs.Areas covered: This review will discuss the delivery of herbal compounds with other cancer treatments such as hormonal, small molecule inhibitors and inorganic hybrids to tumor cells. An overview of physicochemical properties of herbal components that require intelligent design of combo-nanomedicines for efficient co-delivery of those herbal-derived and other anticancer agents was discussed. Nanocarriers provide various benefits to overcome the shortcomings of the encapsulated herbal compounds including improved solubility, increased stability and enhanced tumor targeting. Different nanocarrier systems were the focus of this review.Expert opinion: Multifunctional nanocarrier systems encapsulating herbal and different anticancer drugs showed to be a wonderful approach in the treatment of cancer enabling the co-delivery of anticancer drugs with versatile modes of action in an accurate manner in an attempt to enhance the efficacy, benefit from the synergism between the drugs as well as to minimize the development of multi-drug resistance. The main challenge point is the early detection and management of any developed adverse effect.

Localized drug delivery to lung cancer can overcome the limitations of systemic nanocarriers including low drug amounts reaching lung tissues and severe off-target toxicity. The current work presented novel inhalable nanocomposites as noninvasive platforms for lung cancer therapy. Nanoparticulate liquid crystals (LCNPs) based on monoolein were developed for synergistic co-encapsulation of the cytotoxic chemotherapeutic drug, pemetrexed, and the phytoherbal drug, resveratrol (PEM-RES-LCNPs). For active tumor targeting, lactoferrin (LF) and chondroitin sulfate (CS), natural polymers with intrinsic tumor-targeting capabilities, were exploited to functionalize the surface of LCNPs using a layer-by-layer (LbL) self-assembly approach. To maximize their deep lung deposition, LF/CS-coated PEM-RES-LCNPs were then microencapsulated within various carriers to obtain inhalable nanocomposites via spray-drying techniques. The inhalable dry powder nanocomposites prepared using a mannitol–inulin–leucine (1:1:1 wt) mixture displayed superior in vitro aerosolization performance (2.72 μm of MMAD and 61.6% FPF), which ensured deep lung deposition. In lung cancer-bearing mice using urethane as a chemical carcinogen, the inhalable LF/CS-coated PEM-RES-LCNP nanocomposites showed superior antitumor activity as revealed by a considerable decrease of the average lung weight, reduced number and diameter of cancerous lung foci, decreased expression of VEGF-1, and increased expression of active caspase-3 as well as reduced Ki-67 expression compared to the spray-dried free PEM/RES powder mixture and positive control. Moreover, the in vivo fluorescence imaging confirmed successful lung deposition of the inhalable nanocomposites. Conclusively, the inhalable liquid crystalline nanocomposites elaborated in the current work could open new avenues for noninvasive lung cancer treatment.

Localized pulmonary delivery of anticancer agents to lungs has proven to be pioneering approach for lung cancer therapy. Hybrid lipid nanocore-protein shell nanoparticles (HLPNPs) coloaded with all-trans retinoic acid (ATRA) and genistein (GNS) were prepared via sequential solvent evaporation followed by nanoprecipitation of zein shell onto the lipid core. The outer protein shell of HLPNPs provided additional drug reservoir for encapsulation of ATRA/stearyl amine ion pair and enabled dual tumor-targeting with biotin and ATRA. Enhanced uptake and cytotoxic activity of HLPNPs against A549 lung cancer cells was confirmed. To improve their deep lung deposition, dual-targeted drug-loaded HLPNP nanocomposites were fabricated. The nanocomposites prepared using mannitol/HPβCD/leucine demonstrated favorable aerosolization (MMAD = 2.47 μm and FPF = 70.81%). In vivo, the inhalable nanocomposites were superior to aerosolized or i.v. nanoparticle suspension against lung carcinoma bearing mice. Overall, inhalable dual-targeted HLPNPs nanocomposites provided localized codelivery of GNS and ATRA for lung cancer therapy.

ABSTRACTIntroduction: The ablative laser can be used as an effective approach for enhancing drug permeation via the skin. The enhancement mechanisms of laser-assisted drug permeation are the direct ablation of the superficial skin, optical breakdown by a photomechanical wave, and a photothermal effect.Areas covered: This review describes the development of laser-assisted drug delivery in the recent 5 years. This review systematically introduces the concepts and enhancement mechanisms of the technique, highlighting the potential of the laser approach for increasing drug absorption via the skin. A recent advance of this approach is the use of fractional laser offering limited skin damage and short recovery time. Another sign of progress regarding laser-assisted drug delivery in the recent 5 years is the clinical trials for treating various dermatological disorders.Expert opinion: The potential use of the laser-assisted approach affords a novel treatment for topical drug application with significant efficacy. Although many clinical studies have been performed, further studies using a large group for patients are needed to confirm and clarify the findings in the in vitro or animal experiments. The laser-assisted delivery should be optimized to achieve skin targeting without the risk of diffusion into circulation.

Herein, both strategies of synergistic drug combination together with dual active tumor targeting were combined for effective therapy of hepatocellular carcinoma (HCC). Therefore, based on the tumor sensitizing action, the herbal quercetin (QRC) was co-delivered with the targeted therapeutic drug sorafenib (SFB), preformulated as phospholipid complex, via protein shell-oily core nanocapsules (NCs). Inspired by the targeting action of lactoferrin (LF) via binding to LF receptors overexpressed by HCC cells, LF shell was electrostatically deposited onto the drug-loaded oily core to elaborate LF shell-oily core NCs. For dual tumor targeting, lactobionic acid (LA) or glycyrrhetinic acid (GA) was individually coupled to LF shell for binding to asialoglycoprotein and GA receptors on liver cancer cells, respectively. Compared to LF and GA/LF NCs, the dual-targeted LA/LF-NCs showed higher internalization into HepG2 cells with 2-fold reduction in half-maximal inhibitory concentration compared to free combination therapy after 48 h. Moreover, dual-targeted LF-NCs showed powerful in vivo antitumor efficacy. It was revealed as significant downregulation of the mRNA expression levels of nuclear factor-kappa B and tumor necrosis factor α as well as suppression of Ki-67 protein expression level in diethylnitrosamine (DEN)-induced HCC mice (P< 0.05). Furthermore, dual-targeted LF-NCs attenuated the liver toxicity induced by DEN in animal models. Overall, this study proposes dual-targeted LF-NCs for combined delivery of SFB and QRC as a potential therapeutic HCC strategy.

ABSTRACTIntroduction: Psoriasis is an autoimmune skin disease characterized by red plaques with silver or white multilayered scales with a thickened acanthotic epidermis. Using mouse models of cutaneous inflammation, IL-23/Th17 was identified to have a potential key role in psoriasis. New treatments to slow this inflammatory skin disorder are urgently needed. To aid their discovery, a psoriasis animal model mimicking human psoriasis is urgently needed for their early preclinical evaluation.Areas covered: The authors review animal models of psoriasis and analyze the features and molecular mechanisms involved in these mouse models. The application of various mouse models of psoriasis for drug discovery and development has also been reviewed and the possible molecular targets in psoriasis for future anti-psoriatic drug design is discussed.Expert opinion: So far, it has been difficult to create an animal model that exactly simulates a human disease or condition. The xenotransplantation model is regarded as the closest to incorporating the complete genetic, phenotypic, and immunopathogenic processes of psoriasis. However, the imiquimod (IMQ)-induced model is the most prevalent among psoriatic mouse models due to its ease of use, convenience, and low cost. Further efforts to develop psoriasis-like skin models in mice are needed for the study and treatment of this complex disease.

Background: Atopic dermatitis (AD) is a chronic inflammatory skin disorder involving defects in epidermal barrier function and abnormal immune response to environmental stimuli. Standard treatment of AD involves topical application of emollients and anti-inflammatory drugs such as corticosteroids. Objective: Because of the barrier function defects in AD skin, the topical drug delivery can lead to systemic drug absorption, thereby eliciting systemic complications. Nanoparticles as the carriers used for cutaneous drug delivery provide some benefits over conventional formulations, including enhanced stability, improved epithelium permeability and bioavailability, controlled drug release, skin targeting, and minimal side effects. In recent years, the concept of using nanocarriers as vehicles for drug delivery to manage AD has attracted increasing attention. Polymeric nanoparticles, lipid nanoparticles, and liposomes are the most extensively studied nanocarriers for the treatment of AD. In this review, we highlight the recent progress on the development of nanosystems for AD treatment. Method: We systematically introduce the concepts and amelioration mechanisms of the nanomedical techniques for AD treatment. Different AD animal models for evaluating the efficacy of the therapeutic nanoparticles are described herein. Results: The discrepancy of the nanoparticle skin absorption between healthy skin and AD skin is also discussed. Conclusion: This review aimed to summarize the evidence for the therapeutic advantages of nanoparticles over the conventional AD therapy.

Melanoma shows a high possibility of mortality after it metastasizes because of its aggressive nature. Although there are several options for anti-melanoma therapy, this skin malignancy is resistant to some therapies. Chemotherapy, biochemotherapy, immunotherapy, and adoptive cell therapy have failed to exhibit a significant amelioration in overall survival. Nanomedicine provides an opportunity to improve the efficiency of the antimelanoma regimen. Nanoparticles for treating melanoma provide the advantages over conventional therapies such as drug solubility increment, drug stability enhancement, epithelium permeability and bioavailability amelioration, half-life prolonging, tumor targeting, and side effect minimization. Polymeric nanocarriers are the most extensively studied platforms for the treatment of a variety of cancers. The polymers' sophisticated material engineering tailors the controllable physicochemical properties of the nanoparticles for melanoma penetration via passive and active delivery. The present study highlights the recent progress on the development of polymeric nanoparticles for melanoma treatment. We describe the concepts and improvement mechanisms of the nanomedical techniques for melanoma treatment. Passive targeting by modifying the structure and physicochemical characters of polymeric nanocarriers is a strategy for efficient drug delivery to the melanoma and its metastasis. On the other hand, active targeting such as peptide or antibody conjugation is another approach delivering the drugs or genes to the nidus site by the nanocarriers. This review offers an overview of the benefits of polymeric nanosystems for treating melanoma.

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.

Chemical and enzymatic barriers in the gastrointestinal (GI) tract hamper the oral delivery of many labile drugs. The GI epithelium also contributes to poor permeability for numerous drugs. Drugs with poor aqueous solubility have difficulty dissolving in the GI tract, resulting in low bioavailability. Nanomedicine provides an opportunity to improve the delivery efficiency of orally administered drugs. Solid lipid nanoparticles (SLNs) are categorized as a new generation of lipid nanoparticles consisting of a complete solid lipid matrix. SLNs used for oral administration offer several benefits over conventional formulations, including increased solubility, enhanced stability, improved epithelium permeability and bioavailability, prolonged half-life, tissue targeting, and minimal side effects. The nontoxic excipients and sophisticated material engineering of SLNs tailor the controllable physicochemical properties of the nanoparticles for GI penetration via mucosal or lymphatic transport. In this review, we highlight the recent progress in the development of SLNs for disease treatment. Recent application of oral SLNs includes therapies for cancers, central nervous system-related disorders, cardiovascular-related diseases, infection, diabetes, and osteoporosis. In addition to drugs that may be active cargos in SLNs, some natural compounds with pharmacological activity are also suitable for SLN encapsulation to enhance oral bioavailability. In this article, we systematically introduce the concepts and amelioration mechanisms of the nanomedical techniques for drug- and natural compound-loaded SLNs.

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.

ABSTRACTIntroduction: Codrug or mutual prodrug is a drug design approach to chemically bind two or more drugs to improve therapeutic efficiency or decrease adverse effects. The codrug can be cleaved in the body to generate parent actives. The codrug itself can be inactive, less active, or more active than the parent agents. It has been demonstrated that codrugs possess some benefits over conventional drugs, including enhanced solubility, increased permeation for passing across biomembranes, prolonged half-life for extending the therapeutic period, and reduced toxicity.Areas covered: This review article describes the history, design strategy, and potential applications of codrugs. Codrugs are predominantly used to treat some conditions such as neurodegenerative, cardiovascular, cancerous, infectious, and inflammatory disorders. Many codrugs are developed to increase lipophilicity for better transport into/across biomembranes, especially the skin and cornea. A targeted delivery of codrugs to specific tissues or organs thus can be achieved to promote bioavailability. The chemical and enzymatic hydrolysis, bioactivity, and pharmacokinetics of codrugs are systematically introduced in this review.Expert opinion: Additional profiles pertaining to clinical trials will support further applicability of codrug therapy. Caution should be used in optimizing the benefits of codrugs to ensure a balance between damage or toxicity and the effectiveness of delivery enhancement.

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.

Phosphodiesterase 4 (PDE4) inhibitors can be effective drugs for treating inflammation in different tissues/organs caused by conditions such as asthma, chronic obstructive pulmonary disease (COPD), psoriasis, and Alzheimer’s disease. It has been demonstrated that PDE4 inhibitors used for drug therapy provide some advantages over conventional formulations, including sensitivity to selective inhibitors, unique tissue distribution, and ease of oral administration. To date, the U.S. Food and Drug Administration (USFDA) had approved two PDE4 inhibitors, roflumilast (Daxas®, Daliresp®) and apremilast (Otezla®), for treating respective COPD and plaque psoriasis. Several pharmaceutical companies and academic laboratories continuously develop novel PDE4 inhibitors for clinical application. A concern pertaining to the development of PDE4 inhibitors is the high occurrence rate of side effects such as emesis, nausea, and headache. This review describes recent developments using PDE4 inhibitors for inflammation management. Special attention is paid to the use of PDE4 inhibitors in treating pulmonary and cutaneous inflammation. This review article focuses on issues related to animal and human studies. The action mode of the inhibitors is also addressed.

Background: Inflammation is an immune response that indicates several pathophysiological conditions, including pathogen infection, tissue injury, and tumor growth, in human diseases. During the processes of infection, tumor growth and autoimmune responses, tissue-associated macrophages distributed in the body play a central role in the onset of inflammation and are actively involved in maintaining homeostasis. Objective: Because the role of macrophages in diseases such as infectious diseases, chronic inflammatory diseases, and cancer are now well understood, strategies to target macrophages in uncontrollable diseases are of growing importance. The application of nanotechnology and nanoscience-based approaches for the treatment, diagnosis, monitoring, and control of biological systems has recently been referred to as “nanomedicine”. Nanoparticles not only are efficient for the delivery of therapeutic drugs and for imaging but also potentially facilitate cell activation and ablation. Certain unique types of nanoparticles naturally target cells of the mononuclear phagocyte system (MPS), and particularly macrophages. Results: This natural targeting capacity can be used for application in drug delivery and diagnosis. Controlling nanoparticles’ physicochemical properties, including size, charge, and composition, has emerged as a favored approach to target macrophages to achieve high endocytic activity. Ligand-receptor strategies for nanoparticle targeting to macrophages have been explored, including peptide, antibody, and lectin coating to specifically target drug-loaded nanoparticles to specific receptor types expressed on macrophages. Conclusion: This mini-review highlights rational approaches to the design and surface engineering of nanoparticles. Approaches to site-specific drug delivery and medical imaging for the treatment and diagnosis of macrophage-related human diseases are also discussed. Finally, recent nanotechnology-based approaches to devising macrophage-specific targeted therapy are highlighted.

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.

Nanoparticles can be effective drug delivery systems for treating bacterial and fungal infections in the skin. The nanoparticles used for drug therapy give many advantages over conventional formulations, such as increased solubility and storage stability, improved permeability and bioavailability, prolonged half-life, tissue targeting, and minimal side effects. In recent years, the concept of using nanoparticles to treat skin-microbiomerelated diseases has attracted increasing attention. This review article aimed to introduce recent progress using nanomedical strategies for drug delivery. Various modalities of nanocarriers can be used for antimicrobial therapy of disease, including liposomes, microemulsions, solid lipid nanoparticles (SLNs), nanostructured lipid carriers (NLCs), and polymeric nanoparticles. This review systematically describes the structures and physicochemical properties of different nanocarriers, emphasizing antibacterial activity of nanoparticles for inhibiting infection. Nanoparticles for treating appendageal bacteria have gained attention in recent years, in particular, nanomedical approaches for managing acne. Issues related to the treatment of non-appendageal bacteria and fungi are also discussed. Finally, current obstacles to using nanocarriers for delivering medicines aimed at inhibiting infection and future developments are addressed.

Introduction: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.Areas covered: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 CO2laser. 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.Expert opinion: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.

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.

In this study, we attempted to develop functional liposomes loaded with camptothecin and attached to α-melanocyte-stimulating hormone (α-MSH) to target melanoma cells. The liposomes were mainly composed of phosphatidylcholine, cholesterol, and stearylamine, and were characterized by the vesicle size, zeta potential, camptothecin encapsulation efficiency, and release behavior. Results revealed that α-MSH liposomes possessed an average size of approximately 250nm with a surface charge of 60mV. Camptothecin was successfully entrapped by the targeted liposomes with an encapsulation percentage of nearly 95%. The liposomes provided sustained and controlled camptothecin release. Non-targeted liposomes with the drug exerted superior cytotoxicity against melanomas compared to the free control. Cell viability was reduced from 48% to 32% compared to conventional liposomes. Peptide ligand conjugation further promoted cytotoxicity to 18% viability, which was a 2.7-fold decrease versus the free control. According to the images of fluorescence microscopy, α-MSH liposomes exhibited greater cell endocytosis than did non-targeted liposomes and the free control. α-MSH liposomes were predominantly internalized in the cytoplasm. These findings demonstrate that α-MSH liposomes could enhance the anti-melanoma activity of camptothecin owing to their targeting ability and controlled drug delivery.

Nanostructured lipid carriers (NLCs) are drug-delivery systems composed of both solid and liquid lipids as a core matrix. It was shown that NLCs reveal some advantages for drug therapy over conventional carriers, including increased solubility, the ability to enhance storage stability, improved permeability and bioavailability, reduced adverse effect, prolonged half-life, and tissue-targeted delivery. NLCs have attracted increasing attention in recent years. This review describes recent developments in drug delivery using NLCs strategies. The structures, preparation techniques, and physicochemical characterization of NLCs are systematically elucidated in this review. The potential of NLCs to be used for different administration routes is highlighted. Special attention is paid to parenteral injection and topical delivery since these are the most common routes for investigating NLCs. Relevant issues for the introduction of NLCs to market, including pharmaceutical and cosmetic applications, are discussed. The related patents of NLCs for drug delivery are also reviewed. Finally, the future development and current obstacles needing to be resolved are elucidated.

Introduction:Prodrugs are inactive compounds which are metabolized in the body to produce parent active agents. It has been shown that prodrugs hold some advantages over conventional drugs, such as increased solubility, improved permeability and bioavailability, reduced adverse effects and prolonged half-lives. Optimization of the vehicles used is very important in order to employ the advantages of prodrugs. Nanocarriers are currently being widely used as prodrug vehicles because of their ability to enhance storage stability, modulate prodrug release and tumor-targeted delivery and protect against enzymatic attack. This combined approach of prodrugs and nanoparticles has a particular attraction for developing anticancer therapies.Areas covered:This paper discusses liposomes, polymeric nanoparticles and lipid nanoparticles, which are all carriers commonly used for prodrug encapsulation. Macromolecular prodrugs can spontaneously form self-assembled nanoparticles with no intervention of other additives. This review also describes recent developments in prodrug delivery using nanoparticulate strategies. Pharmacokinetic, pharmacodynamic and cytotoxicity evaluations of anticancer prodrugs are systematically elucidated in this review.Expert opinion:More profiles involved in animal and clinical studies will encourage the future applicability of prodrug nanocarrier therapy. The possible toxicity associated with nanoparticles is a concern for development of prodrug delivery.

The aim of the present work was to evaluate the effects of lipid colloid systems on skin permeation of two antipsoriatic drugs, calcipotriol and methotrexate. Colloidal systems made of Precirol (solid lipid nanoparticles, SLN), Precirolsqualene (nanostructured lipid carriers, NLC), and squalene (lipid emulsions, LE) as the lipid core material were prepared. Calcipotriol was encapsulated in the inner phase of these carriers due to its high lipophilicity. The hydrophilic methotrexate resided in the aqueous phase of the systems. Particle sizes of SLN, NLC, and LE were 303, 192, and 212 nm, respectively. LE showed a lower negative zeta potential (-20 mV) compared to SLN and NLC (-30 mV). In vitro skin permeation was measured with a Franz assembly. The results showed that lipid colloids increased calcipotriol permeation via nude mouse skin by 2.6∼3.2-fold over the aqueous control. Application of lipid colloids enhanced methotrexate penetration by 4.5∼10.8-fold. Drug permeation was affected by the composition of the inner phases. The permeation of both drugs generally showed a trend of NLC > LE > SLN. The mechanisms of the permeation enhancement by nanoparticles were elucidated using various barriers against drug permeation, including delipidized skin, hairy mouse skin, and cellulose membranes. We determined that the release rate, partitioning ability to the skin, and enhancer effect were major factors enhancing drug permeation. Occlusiveness and follicular pathways were less important for calcipotriol and methotrexate delivery. The in vivo confocal laser scanning microscopic profiles confirmed the importance of the partitioning process for lipophilic drugs. The in vivo examination of transepidermal water loss demonstrated the maintenance of skin integrity after a 24-h application of lipid colloid systems.

The clinical application of apomorphine, a dopamine receptor agonist for treating Parkinsons disease, is limited by its instability and the need for frequent injections. In the present work, apomorphine was encapsulated within liposomes to protect it from degradation and enhance the permeability across the blood-brain barrier (BBB). Stearylamine was used to produce a positive surface charge for the liposomes. The liposomal systems with different compositions were characterized by the mean size, zeta potential, drug encapsulation percentage, stability, and in vitro release characteristics. PEGylated liposomes and liposomes incorporating Brij 78 showed a size of 130~160 nm. When Tween 80 was added to the liposomes, the vesicle size increased to > 260 nm. Apomorphine was successfully entrapped by liposomes with an encapsulation percentage of > 70, with the systems containing Brij 78 showing the highest level of 99. The loading of apomorphine into liposomes resulted in slower release behavior compared to the drug in an aqueous solution. In comparison to free drug, apomorphine in PEGylated liposomes exhibited greater stability in plasma. The in vivo brain uptake of PEGylated liposomes after an intravenous bolus injection into rats was monitored by in vivo real-time bioluminescence imaging for 1 h. The results showed that the uptake of PEGylated liposomes into the brain was rapid and prolonged. PEGylated liposomes may offer a promising strategy for targeting apomorphine to the brain. This opens up new opportunities for treating Parkinsons disease.

Prodrugs are inactive compounds which are metabolized either chemically or enzymatically in a controlled or predictable manner to the parent active drug inside the body. Prodrugs can enhance the therapeutic efficacy and/or reduce adverse effects via different mechanisms, including increased solubility, improved permeability and bioavailability, prolonged half-life, and tissue-targeted delivery. Besides the prodrug itself, optimization of vehicles and other enhancement techniques is important as well. Strategies to improve the oral bioavailability and achieve tumor-specific targeting have been the most important developments in prodrug design during the last 5 years. This review describes recent developments in orally administered and tumor-targeted prodrugs. Pharmacokinetic and pharmacodynamic evaluations of these prodrugs are systematically introduced in this review.

The standard treatment for patients with bladder cancer is surgical transurethral resection (TUR). Intravesical chemotherapy and immunotherapy are widely used after TUR to prevent recurrence and progression of superficial disease. There are many drug therapies for bladder cancer via intravesical instillation. This review describes the drugs which are approved or currently tested for treating bladder cancers. Some new chemotherapies and immunotherapies under investigation are also introduced. Vehicles to carry or encapsulate intravesical drugs are introduced in this review. Enhancement approaches to promote drug absorption or prolong residence times such as nano-sized particles, thermo-chemotherapy, and electromotive drug administration are also discussed. This review summarizes the information regarding intravesical therapy and its enhancement techniques. Recent developments of these drugs and their carriers for in vivo or clinical use are presented.

When used at a high dose, many anticancer drugs produce undesirable side effects including hepatotoxicity. Transdermal delivery bypasses first-pass metabolism, allowing the use of a lower dose of drug while decreasing systemic toxicity. In this review, we summarize various advanced technologies for improving anticancer drug delivery via the skin. This technology is discussed in the context of three anticancer drugs, 5-fluorouracil (5-FU), methotrexate (MTX) and 5-aminolevulinic acid (5-ALA). The use of a erbium:YAG (Er:YAG) laser for transdermal delivery of anticancer drugs is specifically highlighted in this review.

Background: Psoriasis is one of the most common human skin diseases. It is characterised by excessive growth and aberrant differentiation of corneocytes, but is fully reversible with appropriate therapy. Objective: There are many drug therapies for psoriasis via the topical delivery route. This review describes the topically applied drugs used to treat psoriasis. Methods: Formulations to carry or encapsulate these drugs are introduced in this review. Enhancing approaches such as liposome inclusion, iontophoresis and laser are also discussed. Conclusion: This review summarises developments in the design of formulations in the area of topical drug delivery for treating psoriasis.

Skin as a route for drug delivery has been extensively investigated. However, because of the predominant barrier function of stratum corneum in skin, the clinical application is limited. One strategy to solve this problem of drug permeation via skin is the use of prodrugs. Prodrugs are inactive compounds which are metabolized either chemically or enzymatically in a controlled or predictable manner to its parent active drug. Prodrugs can enhance dermal/transdermal drug delivery via different mechanisms, including increased skin partitioning, increased aqueous solubility, and reduced crystallization, etc. Besides the prodrug itself, the optimization of vehicle is important as well. The prodrug partitioning between skin and vehicle as well as prodrug-vehicle interaction may influence the enhancing efficacy on skin permeation. This review explores the synthesis and enhancing mechanisms of prodrugs for topical drug delivery. The prodrugs categorized by the therapeutic use of the parent drugs, including anticancer drugs, analgesics, anti-inflammatory drugs and vitamins, are systemically introduced in this review.

The delivery of drugs via skin routes has been extensively investigated. Nevertheless, clinical applications are limited by the stratum corneum (SC), the predominant barrier of the skin. One of the possibilities for increasing skin absorption or permeation of drugs is the use of nano/submicron vesicular systems. Classic liposomes are of little value as carriers for drug delivery via the skin because they do not deeply penetrate it. Only specially designed liposomes have been shown to be capable of achieving enhanced delivery. Liposomes are tiny spheres ranging in diameter from 50 nm to several microns. This review article explores the types and mechanisms involved with liposomes with nanostructures for enhancing topical or transdermal drug delivery. The incorporation of some additives such as anionic surfactants and ethanol can fluidize the phospholipid bilayers, thus increasing the depths to which liposomes can penetrate into the intercellular pathways of the skin. Hair follicles are also important for the enhancement of transdermal liposomes. Niosomes, non-ionic surfactant vesicles, are alternatives to liposomes, which are also discussed in this review. Physical methods such as iontophoresis, ultrasound, and tape-stripping can further assist the delivery of drugs encapsulated in liposomes. Recent breakthroughs with liposomes are beneficial to topically applied permeants, especially for dermatological medications, cosmetic ingredients, and protein/peptide macromolecules.

To improve the skin permeation of theophylline and cianidanol ((+)-catechin), the essential oil of Magnolia fargesiiwas evaluated using in-vitro and in-vivo permeation techniques. Oxygenated monoterpenes and sesquiterpenes are the major components of M. fargesiiessential oil. The in-vitro permeation of theophylline and cianidanol was significantly enhanced after treatment with M. fargesiiessential oil. The essential oil increased the in-vivo skin deposition of cianidanol but not theophylline. On the other hand, in-vivo microdialysis showed a higher subcutaneous theophylline amount after essential oil treatment. In-vitro cell viability and prostaglandin E2release by skin keratinocytes indicated that there was low or negligible cytotoxicity by M. fargesiiessential oil. The in-vivo skin tolerance study determined by transepidermal water loss and colorimetry confirmed that no irritation of the skin was detected when using M. fargesiiessential oil.

To improve the skin permeation of theophylline and cianidanol ((+)‐catechin), the essential oil of Magnolia fargesiiwas evaluated using in‐vitro and in‐vivo permeation techniques. Oxygenated monoterpenes and sesquiterpenes are the major components of M. fargesiiessential oil. The in‐vitro permeation of theophylline and cianidanol was significantly enhanced after treatment with M. fargesiiessential oil. The essential oil increased the in‐vivo skin deposition of cianidanol but not theophylline. On the other hand, in‐vivo microdialysis showed a higher subcutaneous theophylline amount after essential oil treatment. In‐vitro cell viability and prostaglandin E2release by skin keratinocytes indicated that there was low or negligible cytotoxicity by M. fargesiiessential oil. The in‐vivo skin tolerance study determined by transepidermal water loss and colorimetry confirmed that no irritation of the skin was detected when using M. fargesiiessential oil.

Curcumin is a predominant compound derived from the rhizomes of Curcuma longaL., and shows antibacterial, anti‐inflammatory and antineoplastic activity. The in‐vitro and in‐vivo skin absorption of curcumin was investigated after application of enhancers using Wistar rat as an animal model. The enhancers selected in this study included terpenes, flavonoids and cholestanol. The irritant profiles of these enhancers were also established by transepidermal water loss (TEWL) and histological observations. Cyclic monoterpenes generally showed stronger enhancement of curcumin permeation than the other enhancers. Modulation of concentration and pretreatment duration of enhancers possibly indicated that the enhancers have varied ability and mechanisms to enhance curcumin permeation. Terpineol produced the highest TEWL values among the enhancers tested, whereas ketocholestanol produced no, or only a negligible, increase in TEWL as compared with control. The results showed that skin disruption and inflammation did not necessarily correspond to the enhancing efficiency of the enhancers.

Curcumin is a predominant compound derived from the rhizomes of Curcuma longaL., and shows antibacterial, anti-inflammatory and antineoplastic activity. The in-vitro and in-vivo skin absorption of curcumin was investigated after application of enhancers using Wistar rat as an animal model. The enhancers selected in this study included terpenes, flavonoids and cholestanol. The irritant profiles of these enhancers were also established by transepidermal water loss (TEWL) and histological observations. Cyclic monoterpenes generally showed stronger enhancement of curcumin permeation than the other enhancers. Modulation of concentration and pretreatment duration of enhancers possibly indicated that the enhancers have varied ability and mechanisms to enhance curcumin permeation. Terpineol produced the highest TEWL values among the enhancers tested, whereas ketocholestanol produced no, or only a negligible, increase in TEWL as compared with control. The results showed that skin disruption and inflammation did not necessarily correspond to the enhancing efficiency of the enhancers.

The in‐vitro permeation of buprenorphine across skin was investigated to assess the effects of iontophoresis and electroporation on drug permeation from solutions as well as from hydrogels. Iontophoresis (0.3 mA cm−2) increased the buprenorphine permeation from solution by a factor of 14.27 as compared with passive diffusion; the application of electroporation increased the buprenorphine permeation from solutions by a factor of 8.45. The permeation experiments using cellulose membrane and stratum corneum (SC)‐stripped skin as permeation barriers suggested that the enhancement with iontophoresis was primarily due to strong electrophoretic drift of buprenorphine molecules, whereas the enhancement seen with electroporation was mainly attributed to the creation of transient aqueous pores in the SC layer. Application of high‐voltage pulses followed by iontophoresis resulted in a shorter permeation onset time from both solutions and hydrogels as compared with iontophoresis or electroporation alone. The charge repulsion between buprenorphine and chitosan vehicles as well as the competition effects of counter‐ions for carboxymethylcellulose (CMC)‐based polymers may account for the different permeation rates under electrical field. This study demonstrates the feasibility of using hydrogels for delivery of buprenorphine under the application of iontophoresis or electroporation, separately or together.