Intratumoral delivery of a highly active form of XCL1 enhances antitumor CTL responses through recruitment of CXCL9-expressing conventional type-1 dendritic cells.

Conventional type 1 dendritic cells (cDC1s) play a crucial role in antitumor immunity through the induction and activation of tumor-specific CD8 cytotoxic T cells (CTLs). The chemokine XCL1 is a major chemotactic factor for cDC1s and its receptor XCR1 is selectively expressed on cDC1s. Here, we investigated the effect of intratumoral delivery of a highly active form of murine XCL1 (mXCL1-V21C/A59C) on cDC1-mediated antitumor immunity using a hydrophilic gel patch.

Transcutaneous Administration of Imiquimod Promotes T and B Cell Differentiation into Effector Cells or Plasma Cells.

We are interested in promoting the development of transcutaneous immunization using microneedle technology and attempting to apply an adjuvant with transcutaneous immunization to improve the efficacy and reduce the amount of antigen and number of administrations needed. In this study, we collected basic information to help elucidate the mechanism responsible for the transcutaneous adjuvant activity of imiquimod (IMQ), which is a ligand of toll-like receptor (TLR) 7. In mouse groups administered ovalbumin (OVA), the OVA-specific IgG antibody titer of the IMQ-adjuvanted group was higher than that of the group administered OVA alone.

Characteristics of immune induction by transcutaneous vaccination using dissolving microneedle patches in mice.

Transcutaneous immunization (TCI) is an appealing vaccination method. Compared with conventional injectable immunization, TCI is easier and less painful. We previously developed a dissolving microneedle (MN) patch and demonstrated that TCI using MN patches demonstrates high vaccination efficacy without adverse events in humans.

CCR4 Involvement in the Expansion of T Helper Type 17 Cells in a Mouse Model of Psoriasis.

Psoriasis is a chronic skin disease associated with T helper (Th)17-mediated inflammation. Because CCR4 is a major chemokine receptor expressed on Th17 cells, we investigated the role of CCR4 in a modified imiquimod-induced psoriasis model that showed enhanced skin infiltration of Th17 cells. CCR4-deficient mice had less severe skin disease than wild-type mice.

Transcutaneous immunization with a highly active form of XCL1 as a vaccine adjuvant using a hydrophilic gel patch elicits long-term CD8 T cell responses.

Memory CD8 cytotoxic T-lymphocytes (CTLs) play a key role in protective immunity against infection and cancer. However, the induction of memory CTLs with currently available vaccines remains difficult. The chemokine receptor XCR1 is predominantly expressed on CD103 cross-presenting dendritic cells (DCs).

Characteristic of K3 (CpG-ODN) as a Transcutaneous Vaccine Formulation Adjuvant.

Transcutaneous immunization (TCI) is easy to use, minimally invasive, and has excellent efficacy in vaccines against infections. We focused on toll-like receptor (TLR) ligands as applicable adjuvants for transcutaneous formulations and characterized immune responses. TCI was performed using poke-and-patch methods, in which puncture holes are formed with a polyglycolic acid microneedle on the back skin of mice.

Immunogenicity of Milk Protein-Containing Hydrophilic Gel Patch for Epicutaneous Immunotherapy for Milk Allergy.

Purpose: Epicutaneous immunotherapy (EPIT) involving the skin's immune system is easy to use, painless and has a low risk of systemic side effects; it can be applied to food allergies that have a high morbidity rate in children. In this study, we evaluated the safety and efficacy of hydrophilic gel patch (HG) for EPIT.

Methods: Milk protein concentrate (MPC)-containing HG was applied to the skin that maintained a barrier function or formed puncture holes with microneedle, and MPC-specific antibodies were measured.

A CCR4 antagonist ameliorates atopic dermatitis-like skin lesions induced by dibutyl phthalate and a hydrogel patch containing ovalbumin.

CCR4 is a chemokine receptor highly expressed by Th2 cells, and regarded as a potential therapeutic target for atopic dermatitis (AD). CCL17 and CCL22 are the CCR4 ligands, and thymic stromal lymphopoietin (TSLP) is shown to promote the expression of CCL17 and CCL22 by dendritic cells. Here, by using dibutyl phthalate (DBP), a TSLP inducer, and a hydrogel patch as a transcutaneous delivery device for ovalbumin, we developed a novel murine AD model and investigated the effect of Compound 22, a CCR4 antagonist.

Self-Dissolving Microneedle Arrays for Transdermal Absorption Enhancement of Human Parathyroid Hormone (1-34).

Human parathyroid hormone (1-34) (PTH) has been widely used as the subcutaneous injection formulation for the treatment of osteoporosis. In the present study, we developed an efficient transdermal delivery system of PTH by using dissolving microneedle arrays (MNs) composed of hyaluronic acid (HA) for the treatment of osteoporosis. PTH-loaded MNs, with needle length 800 µm, were fabricated via a micro-molding method.

CCR4 Is Critically Involved in Skin Allergic Inflammation of BALB/c Mice.

Atopic dermatitis is a chronic inflammatory skin disease involving T-helper (Th) 2 cells, eosinophils, and mast cells. Although CCR4 is a major chemokine receptor expressed on Th2 cells and regarded as a potential therapeutic target for allergic diseases, its role in atopic dermatitis remains unclear. Here, by using a hydrogel patch as a transcutaneous delivery device for ovalbumin (an antigen) and Staphylococcus aureus δ-toxin (a mast cell activator), we efficiently induced acute atopic dermatitis-like skin lesions in BALB/c mice, a strain prone to Th2 responses, which were characterized by increased numbers of eosinophils, mast cells, and CCR4-expressing Th2 cells in the skin lesions; elevated levels of total and ovalbumin-specific IgE in the sera; and increased expression of IL-4, IL-17A, IL-22, CCL17, CCL22, and CCR4 in the skin lesions.

Development of novel double-decker microneedle patches for transcutaneous vaccine delivery.

Microneedle (MN) patches have great potential as transcutaneous vaccine delivery devices because MNs can effectively deliver vaccine antigen into the skin through the micropores formed in the stratum corneum by low-invasive and painless skin puncturing. This study aims to develop novel double-decker MN patches which have not only high safety and efficacy but also broad applicability to various vaccine antigens. We developed two types of MN patches (PGA-MN and Nylon-MN) that are made from polyglycolic acid and Nylon-6.

Efficient Transdermal Delivery of Alendronate, a Nitrogen-Containing Bisphosphonate, Using Tip-Loaded Self-Dissolving Microneedle Arrays for the Treatment of Osteoporosis.

To improve the transdermal bioavailability and safety of alendronate (ALN), a nitrogen-containing bisphosphonate, we developed self-dissolving microneedle arrays (MNs), in which ALN is loaded only at the tip portion of micron-scale needles by a dip-coating method (ALN(TIP)-MN). We observed micron-scale pores in rat skin just after application of ALN(TIP)-MN, indicating that transdermal pathways for ALN were created by MN. ALN was rapidly released from the tip of MNs as observed in an in vitro release study.

Development of Novel Faster-Dissolving Microneedle Patches for Transcutaneous Vaccine Delivery.

Microneedle (MN) patches are promising for transcutaneous vaccination because they enable vaccine antigens to physically penetrate the stratum corneum via low-invasive skin puncturing, and to be effectively delivered to antigen-presenting cells in the skin. In second-generation MN patches, the dissolving MNs release the loaded vaccine antigen into the skin. To shorten skin application time for clinical practice, this study aims to develop novel faster-dissolving MNs.

Permeation of sumatriptan succinate across human skin using multiple types of self-dissolving microneedle arrays fabricated from sodium hyaluronate.

Available formulations of sumatriptan succinate (SS) have low bioavailability or are associated with site reactions. We developed various types of self-dissolving microneedle arrays (MNs) fabricated from sodium hyaluronate as a new delivery system for SS and evaluated their skin permeation and irritation in terms of clinical application. In vitro permeation studies with human skin, physicochemical properties (needle length, thickness and density), and penetration enhancers (glycerin, sodium dodecyl sulfate and lauric acid diethanolamide) were investigated.

Clinical study of a retinoic acid-loaded microneedle patch for seborrheic keratosis or senile lentigo.

Aims: Pigmented lesions such as of seborrheic keratosis and senile lentigo, which are commonly seen on skin of people>50years of age, are considered unattractive and disfiguring because of their negative psychological impact. Drug therapy using all-trans retinoic acid (ATRA) is an attractive option for self-treatment at home. We have developed an ATRA-loaded microneedle patch (ATRA-MN) and confirmed the pharmacological effects of ATRA-MN application in mice.

Development of a drug-coated microneedle array and its application for transdermal delivery of interferon alpha.

Interferon alpha (IFNα) is one of the most famous drugs for the treatment of chronic hepatitis C and various types of human malignancy. Protein drugs, including IFNα, are generally administered by subcutaneous or intramuscular injection due to their poor permeability and low stability in the bloodstream or gastrointestinal tract. Therefore, in the present study, novel IFNα-coated polyvinyl alcohol-based microneedle arrays (IFNα-MNs) were fabricated for the transdermal delivery of IFNα without the painful injection.

Improvement of Transdermal Delivery of Exendin-4 Using Novel Tip-Loaded Microneedle Arrays Fabricated from Hyaluronic Acid.

The purpose of this study was to evaluate the characteristics of exendin-4 tip-loaded microneedle arrays and to compare their acute efficacy with subcutaneous injections in type 2 diabetic GK/Slc rats. Fluorescein isothiocyanate labeled dextran with an average molecular weight of 4,000 (FD4) was selected as a model drug, and FD4 tip-loaded microneedle arrays were prepared in this study. In addition, intraperitoneal glucose tolerance tests after application of exendin-4 tip-loaded microneedle arrays were also compared with those after subcutaneous injection in type 2 diabetic GK/Slc rats.

Clinical study and stability assessment of a novel transcutaneous influenza vaccination using a dissolving microneedle patch.

Transcutaneous immunization (TCI) is an attractive vaccination method compared with conventional injectable vaccines because it is easier to administer without pain. We developed a dissolving microneedle patch (MicroHyala, MH) made of hyaluronic acid and showed that transcutaneous vaccination using MH induced a strong immune response against various antigens in mice. In the present study, we investigated the clinical safety and efficacy of a novel transcutaneous influenza vaccine using MH (flu-MH), which contains trivalent influenza hemagglutinins (15 μg each).

Improvement of transdermal delivery of sumatriptan succinate using a novel self-dissolving microneedle array fabricated from sodium hyaluronate in rats.

The purpose of the present study was to develop an alternative transdermal formulation containing sumatriptan succinate (SS) for the treatment of migraine. Novel self-dissolving SS-loaded microneedle arrays (MNs) were fabricated from sodium hyaluronate and their efficacy for transdermal delivery of SS was characterized. The resulting MNs maintained their skin piercing abilities for at least 30 min after being placed at a high relative humidity of 75%.

[Development of a novel transdermal delivery system of peptide and protein drugs using microneedle arrays].

Transdermal delivery of peptide and protein drugs may be limited by the stratum corneum, which is a protective barrier against the entry of microorganisms and water. Many approaches have been utilized to promote peptide and protein drugs delivery across the stratum corneum, including chemical enhancer modification and physical disruption of barrier function. However, it has been difficult to achieve therapeutic levels of peptide and protein drugs via this route without any skin irritation.

Vaccine efficacy of transcutaneous immunization with amyloid β using a dissolving microneedle array in a mouse model of Alzheimer's disease.

Vaccine therapy for Alzheimer's disease (AD) based on the amyloid cascade hypothesis has recently attracted attention for treating AD. Injectable immunization using amyloid β peptide (Aβ) comprising 1-42 amino-acid residues (Aβ1-42) as antigens showed therapeutic efficacy in mice; however, the clinical trial of this injected Aβ1-42 vaccine was stopped due to the incidence of meningoencephalitis caused by excess activation of Th1 cells infiltrating the brain as a serious adverse reaction. Because recent studies have suggested that transcutaneous immunization (TCI) is likely to elicit Th2-dominant immune responses, TCI is expected to be effective in treating AD without inducing adverse reactions.

Transdermal delivery of relatively high molecular weight drugs using novel self-dissolving microneedle arrays fabricated from hyaluronic acid and their characteristics and safety after application to the skin.

The purpose of this study was to develop novel dissolving microneedle arrays fabricated from hyaluronic acid (HA) as a material and to improve the transdermal permeability of relatively high molecular weight drugs. In this study, fluorescein isothiocyanate-labeled dextran with an average molecular weight of 4kDa (FD4) was used as a model drug with a relatively high molecular weight. The microneedle arrays significantly increased transepidermal water loss (TEWL) and reduced transcutaneous electrical resistance (TER), indicating that they could puncture the skin and create drug permeation pathways successfully.

Development of a novel therapeutic approach using a retinoic acid-loaded microneedle patch for seborrheic keratosis treatment and safety study in humans.

Seborrheic keratosis is one of the most common skin benign tumors in humans with a high occurrence rate of 80%-100% in people > 50 years of age; however, its pathogenesis is still unclear. The standard treatment includes cryotherapy and laser surgery for physically removing lesions. Drug therapy for this condition has not been well established.

Development and clinical study of a self-dissolving microneedle patch for transcutaneous immunization device.

Purpose: We previously reported the safety and efficacy in animal experiments of transcutaneous immunization (TCI) using a self-dissolving microneedle patch (MicroHyala; MH) made of hyaluronic acid and collagen. However, this MH was an unsuitable TCI device for the human skin, as collagen is suspected to induce inflammation. In this study, we developed an improved collagen-free MH (new-MH) and conducted clinical study to evaluate the fundamental properties and safety in human.