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Duong, Huu Thuy Trang,Kim, Nak Won,Thambi, Thavasyappan,Giang Phan, V.H.,Lee, Min Sang,Yin, Yue,Jeong, Ji Hoon,Lee, Doo Sung Elsevier 2018 Journal of controlled release Vol.269 No.-
<P><B>Abstract</B></P> <P>Successful delivery of a DNA vaccine to antigen-presenting cells and their subsequent stimulation of CD4<SUP>+</SUP> and CD8<SUP>+</SUP> T cell immunity remains an inefficient process. In general, the delivery of prophylactic vaccines is mainly mired by low transfection efficacy, poor immunogenicity, and safety issues from the materials employed. Currently, several strategies have been exploited to improve immunogenicity, but an effective strategy for safe and pain-free delivery of DNA vaccines is complicated. Herein, we report the rapid delivery of polyplex-based DNA vaccines using microneedle arrays coated with a polyelectrolyte multilayer assembly of charge reversal pH-responsive copolymer and heparin. The charge reversal pH-responsive copolymer, composed of oligo(sulfamethazine)-<I>b</I>-poly(ethylene glycol)-<I>b</I>-poly(amino urethane) (OSM-<I>b</I>-PEG-<I>b</I>-PAEU), was used as a triggering layer in the polyelectrolyte multilayer assembly on microneedles. Charge reversal characteristics of this copolymer, that is, the OSM-<I>b</I>-PEG-<I>b</I>-PAEU copolymer exhibit, positive charge at low pH (pH4.03) and becoming negative charge when exposed to physiological pH conditions (pH7.4), allowing the facile assembly and disassembly of polyelectrolyte multilayers. The electrostatic repulsion between heparin and OSM-<I>b</I>-PEG-<I>b</I>-PAEU charge reversal copolymer triggered the release of DNA vaccines. DNA vaccines laden on microneedles are effectively transfected into RAW 264.7 macrophage cells <I>in vitro</I>. Vaccination of BALB/c mice by DNA vaccine-loaded microneedle arrays coated with a polyelectrolyte multilayer generated antigen-specific robust immune responses. These findings provide potential strategy of charge reversal pH-responsive copolymers coated microneedles for DNA vaccine delivery.</P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>
Duong, Huu Thuy Trang,Yin, Yue,Thambi, Thavasyappan,Nguyen, Thanh Loc,Giang Phan, V.H.,Lee, Min Sang,Lee, Jung Eun,Kim, Jaeyun,Jeong, Ji Hoon,Lee, Doo Sung Elsevier 2018 Biomaterials Vol.185 No.-
<P><B>Abstract</B></P> <P>Despite the tremendous potential of DNA-based cancer vaccines, their efficacious delivery to antigen presenting cells to stimulate both humoral and cellular response remains a major challenge. Although electroporation-based transfection has improved performance, an optimal strategy for safe and pain-free vaccination technique remains elusive. Herein, we report a smart DNA vaccine delivery system in which nanoengineered DNA vaccine was laden on microneedles (MNs) assembled with layer-by-layer coating of ultra-pH-responsive OSM-(PEG-PAEU) and immunostimulatory adjuvant poly(I:C), a synthetic double stranded RNA. Transcutaneous application of MN patches onto the mice skin perforate the stratum corneum with minimal cell damage; subsequent disassembly at the immune-cell-rich epidermis/dermis allows the release of adjuvants and DNA vaccines, owing to the ultra-sharp pH-responsive nature of OSM-(PEG-PAEU). The released adjuvant and DNA vaccine can enhance dendritic cell maturation and induce type I interferons, and thereby produce antigen-specific antibody that can achieve the antibody-dependent cell-mediated cytotoxicity (ADCC) and CD8<SUP>+</SUP> T cell to kill cancer cells. Strikingly, transcutaneous application of smart vaccine formulation in mice elicited 3-fold greater frequencies of Anti-OVA IgG1 serum antibody and 3-fold excess of cytotoxic CD8<SUP>+</SUP> T cell than soluble DNA vaccine formulation. As a consequence, the formulation rejected the murine B16/OVA melanoma tumors in C57BL/6 mice through the synergistic activation of antigen-specific ADCC and cytotoxic CD8<SUP>+</SUP> T cells. The maneuvered use of vaccine and adjuvant poly(I:C) in MNs induces humoral and cellular immunity, which provides a promising vaccine technology that shows improved efficacy, compliance, and safety.</P>
Duong, Huu Thuy Trang,Thambi, Thavasyappan,Yin, Yue,Kim, Seong Han,Nguyen, Thanh Loc,Phan, V.H. Giang,Kim, Jaeyun,Jeong, Ji Hoon,Lee, Doo Sung Elsevier 2020 Biomaterials Vol.230 No.-
<P><B>Abstract</B></P> <P>Cancer vaccines that elicit a robust and durable antitumor response show great promise in cancer immunotherapy. Nevertheless, low immunogenicity and weak immune response limit the application of cancer vaccines. To experience next generation cancer vaccines that elicit robust, durable, and anti-tumor T cell response, herein we design injectable smart hydrogels (ISHs) that self-assemble into a cellular microenvironment-like microporous network using a simple hypodermic needle injection, to localize the immune cells and program host cells. ISHs, composed of levodopa- and poly(ε-caprolactone-<I>co</I>-lactide)ester-functionalized hyaluronic acid (HA-PCLA), are loaded with immunomodulatory factor (OVA expressing plasmid, pOVA)-bearing nano-sized polyplexes and granulocyte-macrophage colony-stimulating factor (GM-CSF) as dendritic cell (DC) enhancement factor. Subcutaneous administration of ISHs effectively localized immune cells, and controlled the delivery of immunomodulatory factors to recruit immune cells. The microporous network allowed the recruitment of a substantial number of DCs, which was 6-fold higher than conventional PCLA counterpart. The locally released nano-sized polyplexes effectively internalized to DCs, resulting in the presentation of tumor-specific OVA epitope, and subsequent activation of CD4<SUP>+</SUP> T cells and generation of OVA-specific serum antibody. By the controlled release of nano-sized polyplexes and GM-CSF through a single subcutaneous injection, the ISHs effectively eliminated B16/OVA melanoma tumors in mice. These ISHs can be administered using a minimal invasive technique that could bypass the need for extracorporeal training of cells <I>ex vivo</I>, and provide sustained release of cancer vaccines for immunomodulation. These important findings suggest that ISHs can serve as powerful biomaterials for cancer immunotherapy.</P>
Giang Phan, V.H.,Duong, Huu Thuy Trang,Thambi, Thavasyappan,Nguyen, Thanh Loc,Turabee, Md. Hasan,Yin, Yue,Kim, Seong Han,Kim, Jaeyun,Jeong, Ji Hoon,Lee, Doo Sung IPC Science and Technology Press 2019 Biomaterials Vol.195 No.-
<P><B>Abstract</B></P> <P>Lymphoid organs, which are populated by dendritic cells (DCs), are highly specialized tissues and provide an ideal microenvironment for T-cell priming. However, intramuscular or subcutaneous delivery of vaccine to DCs, a subset of antigen-presenting cells, has failed to stimulate optimal immune response for effective vaccination and need for adjuvants to induce immune response. To address this issue, we developed an in situ-forming injectable hybrid hydrogel that spontaneously assemble into microporous network upon subcutaneous administration, which provide a cellular niche to host immune cells, including DCs. In situ-forming injectable hybrid hydrogelators, composed of protein-polymer conjugates, formed a hydrogel depot at the close proximity to the dermis, resulting in a rapid migration of immune cells to the hydrogel boundary and infiltration to the microporous network. The biocompatibility of the watery microporous network allows recruitment of DCs without a DC enhancement factor, which was significantly higher than that of traditional hydrogel releasing chemoattractants, granulocyte-macrophage colony-stimulating factor. Owing to the sustained degradation of microporous hydrogel network, DNA vaccine release can be sustained, and the recruitment of DCs and their homing to lymph node can be modulated. Furthermore, immunization of a vaccine encoding amyloid-β fusion proteinbearing microporous network induced a robust antigen-specific immune response in vivo and strong recall immune response was exhibited due to immunogenic memory. These hybrid hydrogels can be administered in a minimally invasive manner using hypodermic needle, bypassing the need for cytokine or DC enhancement factor and provide niche to host immune cells. These findings highlight the potential of hybrid hydrogels that may serve as a simple, yet multifunctional, platform for DNA vaccine delivery to modulate immune response.</P>
Le, Thai Minh Duy,Duong, Huu Thuy Trang,Thambi, Thavasyappan,Giang Phan, V.H.,Jeong, Ji Hoon,Lee, Doo Sung American Chemical Society 2018 Biomacromolecules Vol.19 No.8
<P>Despite great potential, the delivery of genetic materials into cells or tissues of interest remains challenging owing to their susceptibility to nuclease degradation, lack of permeability to the cell membrane, and short in vivo half-life, which severely restrict their widespread use in therapeutics. To surmount these shortcomings, we developed a bioinspired in situ-forming pH- and temperature-sensitive injectable hydrogel depot that could control the delivery of DNA-bearing polyplexes for versatile biomedical applications. A series of multiblock copolymer, comprised of water-soluble poly(ethylene glycol) (PEG) and pH- and temperature-responsive poly(sulfamethazine ester urethane) (PSMEU), has been synthesized as in situ-forming injectable hydrogelators. The free-flowing PEG-PSMEU copolymer sols at high pH and room temperature (pH 8.5, 23 °C) were transformed to stable gel at the body condition (pH 7.4, 37 °C). Physical and mechanical properties of hydrogels, including their degradation rate and viscosity, are elegantly controlled by varying the composition of urethane ester units. Subcutaneous administration of free-flowing PEG-PSMEU copolymer sols to the dorsal region of Sprague-Dawley rats instantly formed hydrogel depot. The degradation of the hydrogel depot was slow at the beginning and found to be bioresorbable after two months. Cationic protein or DNA-bearing polyplex-loaded PEG-PSMEU copolymer sols formed stable gel and controlled its release over 10 days in vivo. Owing to the presence of urethane linkages, the PEG-PSMEU possesses excellent adhesion strength to wide range of surfaces including glass, plastic, and fresh organs. More importantly, the hydrogels effectively adhered on human skin and peeled easily without eliciting an inflammatory response. Subcutaneous implantation of PEG-PSMEU copolymer sols effectively sealed the ruptured skin, which accelerated the wound healing process as observed by the skin appendage morphogenesis. The bioinspired in situ-forming pH- and temperature-sensitive injectable adhesive hydrogel may provide a promising platform for myriad biomedical applications as controlled delivery vehicle, adhesive, and tissue regeneration.</P> [FIG OMISSION]</BR>
Folate decorated hollow spheres of microporous organic networks as drug delivery materials
Jang, June Young,Duong, Huu Thuy Trang,Lee, Sang Moon,Kim, Hae Jin,Ko, Yoon-Joo,Jeong, Ji Hoon,Lee, Doo Sung,Thambi, Thavasyappan,Son, Seung Uk The Royal Society of Chemistry 2018 Chemical communications Vol.54 No.29
<P>Hollow and microporous organic network spheres decorated with folic acids (H-MON-FA) were prepared using silica templates by the Sonogashira coupling of organic building blocks and successive post-synthetic modifications. The drug (DOX) delivery performance of H-MON-FA to cancer cells was studied.</P>
Yue Yin,Thanh Loc Nguyen,Bo Wang,Huu Thuy Trang Duong,이두성,김지흥,김재윤,정지훈 한국공업화학회 2019 Journal of Industrial and Engineering Chemistry Vol.80 No.-
The activation and maturation of dendritic cells are critical in immunotherapy, and the potency of DCs isassociated with high levels of antigen presentation on major histocompatibility complex (MHC) class Iand II and the expression of costimulatory signals. Graphene oxide (GO) and its derivatives have manyexcellent physicochemical properties, including large and hydrophobic surface available for interactingwith hydrophobic or aromatic drugs via p–p stacking forces,flexibility of the chemical modification onthe surfaces, and capacity of DC activation. In this study, we designed a simple strategy to achieve the codeliveryof a DNA vaccine and hydrophobic immune adjuvant (R848) and to enhance the adjuvanticity ofR848 via the synergistic effect of GO and R848. Thiolated low-molecular-weight polyethylenimine(TPEI1.8) was crosslinked with 4-aminothiophenol-modified GO (TGO) via the formation of disulfidebonds. Thus, TGO with its assembled TPEI1.8 could not only load R848 but also electrostatically interactwith the DNA vaccine. Owing to the reducibility of the disulfide bond in the cellular environment, theDNA vaccine could be readily released. This system can significantly enhance the DNA transfection, theexpression of the costimulatory signal, and the level of antigen presentation to MHC class I DCs for theiractivation and maturation.