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Gujrati, Vipul,Kim, Sunghyun,Kim, Sang-Hyun,Min, Jung Joon,Choy, Hyon E,Kim, Sun Chang,Jon, Sangyong American Chemical Society 2014 ACS NANO Vol.8 No.2
<P>Advances in genetic engineering tools have contributed to the development of strategies for utilizing biologically derived vesicles as nanomedicines for achieving cell-specific drug delivery. Here, we describe bioengineered bacterial outer membrane vesicles (OMVs) with low immunogenicity that can target and kill cancer cells in a cell-specific manner by delivering small interfering RNA (siRNA) targeting kinesin spindle protein (KSP). A mutant <I>Escherichia coli</I> strain that exhibits reduced endotoxicity toward human cells was engineered to generate OMVs displaying a human epidermal growth factor receptor 2 (HER2)-specific affibody in the membrane as a targeting ligand. Systemic injection of siRNA-packaged OMVs caused targeted gene silencing and induced highly significant tumor growth regression in an animal model. Importantly, the modified OMVs were well tolerated and showed no evidence of nonspecific side effects. We propose that bioengineered OMVs have great potential as cell-specific drug-delivery vehicles for treating various cancers.</P><P><B>Graphic Abstract</B> <IMG SRC='http://pubs.acs.org/appl/literatum/publisher/achs/journals/content/ancac3/2014/ancac3.2014.8.issue-2/nn405724x/production/images/medium/nn-2013-05724x_0007.gif'></P><P><A href='http://pubs.acs.org/doi/suppl/10.1021/nn405724x'>ACS Electronic Supporting Info</A></P>
Gujrati, Vipul,Lee, Miriam,Ko, Young-Joon,Lee, Sangeun,Kim, Daejin,Kim, Hyungjun,Kang, Sukmo,Lee, Soyoung,Kim, Jinjoo,Jeon, Hyungsu,Kim, Sun Chang,Jun, Youngsoo,Jon, Sangyong National Academy of Sciences 2016 PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF Vol.113 No.3
<P>Despite the appreciable success of synthetic nanomaterials for targeted cancer therapy in preclinical studies, technical challenges involving their large-scale, cost-effective production and intrinsic toxicity associated with the materials, as well as their inability to penetrate tumor tissues deeply, limit their clinical translation. Here, we describe biologically derived nanocarriers developed from a bioengineered yeast strain that may overcome such impediments. The budding yeast Saccharomyces cerevisiae was genetically engineered to produce nanosized vacuoles displaying human epidermal growth factor receptor 2 (HER2)-specific affibody for active targeting. These nanosized vacuoles efficiently loaded the anticancer drug doxorubicin (Dox) and were effectively endocytosed by cultured cancer cells. Their cancer-targeting ability, along with their unique endomembrane compositions, significantly enhanced drug penetration in multicellular cultures and improved drug distribution in a tumor xenograft. Furthermore, Dox-loaded vacuoles successfully prevented tumor growth without eliciting any prolonged immune responses. The current study provides a platform technology for generating cancer-specific, tissue-penetrating, safe, and scalable biological nanoparticles for targeted cancer therapy.</P>
Yoo, Jisang,Lee, DaeYong,Gujrati, Vipul,Rejinold, N. Sanoj,Lekshmi, Kamali Manickavasagam,Uthaman, Saji,Jeong, Chanuk,Park, In-Kyu,Jon, Sangyong,Kim, Yeu-Chun Elsevier 2017 Journal of controlled release Vol.246 No.-
<P><B>Abstract</B></P> <P>Cell-penetrating peptides (CPPs) have been widely used to deliver nucleic acid molecules. Generally, CPPs consisting of short amino acid sequences have a linear structure, resulting in a weak complexation and low transfection efficacy. To overcome these drawbacks, a novel type of CPP is required to enhance the delivery efficacy while maintaining its safe use at the same time.</P> <P>Herein, we report that a bioreducible branched poly-CPP structure capable of responding to reducing conditions attained both outstanding delivery effectiveness and selective gene release in carcinoma cells. Branched structures provide unusually strong electrostatic attraction between DNA and siRNA molecules, thereby improving the transfection capability through a tightly condensed form. We designed a modified type of nona-arginine (mR9) and synthesized a branched-mR9 (B-mR9) using disulfide bonds. A novel B-mR9/pDNA polyplex exhibited redox-cleavability and high transfection efficacy compared to conventional CPPs, with higher cell viability as well. B-mR9/VEGF siRNA polyplex exhibited significant serum stability and high gene-silencing effects <I>in vitro</I>. Furthermore, the B-mR9 polyplex showed outstanding tumor accumulation and inhibition ability <I>in vivo</I>. The results suggest that the bioreducible branched poly CPP has great potential as a gene delivery platform.</P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>
Self-assembled nanoparticles comprising aptide–SN38 conjugates for use in targeted cancer therapy
Kim, Hyungjun,Lee, Yonghyun,Kang, Sukmo,Choi, Minsuk,Lee, Soyoung,Kim, Sunghyun,Gujrati, Vipul,Kim, Jinjoo,Jon, Sangyong IOP 2016 Nanotechnology Vol.27 No.48
<P>Self-assembled nanoparticles (NPs) have been intensively utilized as cancer drug delivery carriers because hydrophobic anticancer drugs may be efficiently loaded into the particle cores. In this study, we synthesized and evaluated the therapeutic index of self-assembled NPs chemically conjugated to a fibronectin extra domain B-specific peptide (APT<SUB>EDB</SUB>) and an anticancer agent SN38. The APT<SUB>EDB</SUB>–SN38 formed self-assembled structures with a diameter of 58?±?3 nm in an aqueous solution and displayed excellent drug loading, solubility, and stability properties. A pharmacokinetic study revealed that the blood circulation half-life of SN38 following injection of the APT<SUB>EDB</SUB>–SN38 NPs was markedly higher than that of the small molecule CPT-11. The APT<SUB>EDB</SUB>–SN38 NPs delivered SN38 to tumor sites by both passive and active targeting. Finally, the APT<SUB>EDB</SUB>–SN38 NPs exhibited potent antitumor activities and low toxicities against EDB-expressing tumors (LLC, U87MG) in mice. This system merits further preclinical and clinical investigations for SN38 delivery.</P>
Kang, S.,Ahn, S.,Lee, J.,Kim, J.Y.,Choi, M.,Gujrati, V.,Kim, H.,Kim, J.,Shin, E.C.,Jon, S. Elsevier Science Publishers 2017 Journal of controlled release Vol.256 No.-
<P>Although it has been shown that the size of nanoparticle-based vaccines is a key determining factor for the induction of immune responses, few studies have provided detailed analyses of thresholds or critical sizes of nanoparticle vaccines. Here we report effects of the size of gold nanoparticle (GNP)-based vaccines on their efficiency of delivery to lymph nodes (LNs) and induction of CD8(+) T-cell responses. We further propose a threshold size of GNPs for use as an effective vaccine. To examine the effects of GNP size, we synthesized GNPs with diameters of 7, 14 and 28 nm, and then conjugated them with recombinant ovalbumin (OVA) as a model antigen. The resulting OVA-GNPs had hydrodynamic diameter (HD) of similar to 10, 22, and 33 nm for 7, 14 and 28 nm GNPs, respectively and exhibited a size-dependent increase in cellular uptake by dendritic cells (DCs) and subsequent T-cell cross-priming and activation. Upon injection into a mouse footpad, both 22-and 33-nm OVAGNPs showed much higher delivery efficiency to draining LNs than did 10-nm OVA-GNPs. An ex vivo restimulation assay using OVA as an antigen revealed that frequencies of OVA-specific CD8(+) T cells were higher in mice immunized with 22-and 33-nm OVA-GNPs than in those immunized with 10-nm OVA-GNPs; moreover, these cells were shown to be poly-functional. In a tumor-prevention study, 22-nm OVA-GNPs showed greater antitumor efficacy, and higher infiltration of CD8+ T-cells and greater tumor cell apoptosis and cell death than 10-nm OVA-GNPs. Taken together, our results suggest that the size threshold for induction of potent cellular responses and T-cell poly-functionality by GNPs lies between 10 nm and 22 nm, and highlight the importance of nanoparticle size as a critical parameter in designing and developing nanoparticle-based vaccines.</P>