17^th Annual Congress on Pharmaceutics & Drug Delivery Systems September 20-22, 2018 Prague, Czech Republic | Panorama Hotel Prague | Milevská 7, 140 63 Praha

Youhoon Chong has completed his PhD from University of Georgia, and Post-doctoral studies from The Scripps Research Institute. He is the Chairman of the Department of Integrative Bioscience and Biotechnology, Konkuk University. He has published more than 140 papers in reputed journals.

(-)-Epigallocatechin-3-gallate (EGCG) is known as a mitochondria-targeted molecule that can prevent mitochondrial deterioration and induce mitochondrial biogenesis by modulating key regulators of mitochondrial metabolism. In this study, we tackled whether derivatization of EGCG could result in enhancement of its effects on mitochondrial biogenesis. EGCG, EGCG peracetate (AcEGCG), and its 4″-O-alkyl substituted congeners prepared by previously reported procedures were biologically evaluated. Interestingly, EGCG and AcEGCG were only marginally effective in inducing mitochondrial biogenesis, while AcEGCG congeners with an alkyl group at the 4″-O position showed significantly increased biological activity compared to their parent compound. Among these series, compound 3f with a methyl-branched carbonate chain at the 4″-O position of the AcEGCG scaffold showed the most enhancements in inducing mitochondrial biogenesis. Hepa1-6 cells treated with 3f exhibited increases in both mitochondrial mass (1.5 times) and relative mtDNA content to nDNA (1.5 times). As a mitochondrial biogenesis enhancer, 3f also increased expression levels of regulators for mitochondrial function, including PGC-1α (4.0 fold), p-AMPK (2.5 fold), SIRT1 (4.2 fold), ERRα (1.8 fold), NRF-1 (1.6 fold), NRF-2 (1.7 fold), and mtTFA (2.0 folds). Investigation of oxidative phosphorylation by mitochondria in the presence of 3f revealed that 3f increased NAD+/NADH ratio, the amount of cytochrome C, ATP synthesis, and oxygen consumption in Hepa1-6 cells by 2.2, 1.4, 1.5, and 2.1 folds, respectively. Taken together, these results warrant extensive structure-activity relationship study for EGCG derivatives to develop novel mitochondrial biogenesis enhancers.

Laura Sánchez García is a PhD student at the Universitat Autònoma de Barcelona, Spain. She is doing her research in the Nanobiotechnology Group, which is working in the development of targeted protein-only nanoparticles against cancer stem cells. She has studied her degree in Microbiology and Master’s in Applied Microbiology. She has published 13 papers in reputed journals and has received an EMBO Fellowship to perform a three-month internship in Slovenia.

Nowadays, conventional cancer treatments present high systemic toxicity, leading to side effects on healthy tissues. For that reason, it is of great relevance to develop targeted drugs that can increase the local drug concentration, minimize toxic effects on off-target tissues and reduce the dose administered. Moreover, loading capacity and drug leakage from vehicles during circulation in blood is a major concern when developing nanoparticle-based cell-targeted cytotoxics. To circumvent this potential issue, it would be convenient the engineering of drugs as self-delivered nanoscale entities, devoid of any heterologous carriers. In this context, we have engineered potent protein toxins, using the active fragments of the diphtheria toxin and the Pseudomonas aeruginosa exotoxin, as self-assembling, self-delivered therapeutic materials targeted to CXCR4+ cancer stem cells. CXCR4 receptor is overexpressed in a variety of human cancers and plays a critical role in metastatic process. For this reason, we have fused T22 to the toxic domains (T22-TOXIN-H6), as it is a CXCR4 ligand able to bind specifically and internalize into the target cells. The systemic administration of both nanostructured drugs in a colorectal cancer xenograft mouse model promotes efficient and specific local destruction of target tumor tissues and a significant reduction of the tumor volume. This observation strongly supports the concept of intrinsically functional protein nanoparticles, which having a dual role as drug and carrier, are designed to be administered without the assistance of heterologous vehicles. The promising results obtained have allowed the development of a new patent (EP17169722) that has been licensed to Nanoligent SL.

Hidekazu Fukamizu is the Director of Department of Plastic and Reconstructive Surgery, Hamamatsu University School of Medicine. He published few articles on drug delivery in the following journals: “Development of three-microneedle device for hypodermic drug delivery and clinical application” in Plastic and Reconstructive Surgery, 2012; “Application of a three-microneedle device for the delivery of local anesthetics” in Patient Preference and Adherence, 2015.

Background & Objective: We have developed a new device with multiple fine needles fabricated with a bevel angle to release a drug broadly and homogeneously into the skin in a horizontal fashion and reported in the article. It led us to develop another type of multiple needles to release a drug in the epidermis or upper dermis. The intradermal (ID) route for vaccination represents an effective alternative to subcutaneous (SC)/intramuscular administration to induce protective immunity. However, a critical issue associated with ID vaccination is the precise delivery of solution in the upper dermis, which ensures enhanced immunity. Methods: We fabricated a hollow microneedle unit made of poly-glycolic acid by injection molding and bonding and developed a dedicated prototype injector. To ensure ID delivery of solution, the injected site was macroscopically and microscopically examined. Serum immunoglobulin G antibody production was measured by enzyme immunoassay and compared in groups of rats following either ID delivery with microneedles or SC administration with a 27-G stainless needle of graded vaccine doses. Results: The unit used a tandem array of six microneedles, each with a side delivery hole, and a conduit inside for solution. Microneedles installed in the injector punctured at the skin with the aid of a spring. Injection of solution formed a wheal due to ID distribution. Histologically, a wedge-shaped skin defect in the upper skin corresponded to each puncture site. Antibody titers following vaccinations on days one and eight were significantly higher with ID injection than with SC delivery on day 15 and every seven days, thereafter until day 36 with mumps vaccination, and until day 36 with varicella vaccination. Conclusions: The microneedle unit presented here delivered solution intradermally without any difficulty and evoked antibody responses against viruses even with the reduced vaccine volume. Our findings confirm promising results of ID delivery as an immunogenic option to enhance vaccination efficacy.

Leonardo Marchitto is a Vice President of the School of Pharmacy, Biotechnology in university of bologna, Italy. He completed his Master Degree in Industrial Pharmacy (University of Pavia), and Degree: Pharmacy (University of Camerino)

Mucoadhesion describes the attractive forces between a material and mucous membranes. Mucoadhesive formulations are designed to form specific interactions with mucosal membranes, providing localized drug release, prolonging residence time, reducing dosing frequency and increasing patient compliance. The aim of this project was to select the better performing polymer to develop a new mucoadhesive spray formulation, containing an anti-inflammatory drug, using a rheological approach. Hassan and Gallo rheological synergism method was chosen. This method is based on the idea that when a mucoadhesive polymer is mixed with mucin, there is a synergistic increase in viscosity. Commercial oral sprays (medical devices), claiming a mucoadhesive effect on the leaflet, were used to assess the method validity and to identify formulation viscosity values compatible with a spray device. Prototype spray formulations, containing different known mucoadhesive polymers, were prepared. The influence of polymer type and concentration on formulation bioadhesive properties was tested. Formulation prototypes were subjected to pre-stability studies at 4°C, 25°C and 40°C for 1 month (in absence of preservatives). A spraying test was used to investigate the polymer influence on the ability of the device to spray, even in the case of a discontinuous use over time. All formulations resulted to be physically stable at all temperatures. The mucoadhesive properties changed significantly depending on the polymer type and concentration. Prototypes containing sodium alginate as mucoadhesive agent showed the highest mucoadhesion properties, due to its ability to gel in the presence of Ca2+ ions of salivary fluid, which results in a rise in viscosity.