Biological Weapons and Nuclear Deterrence in the Pandemic Era

Richard Pilch,Miles Pomper 동아시아재단 2021 Global Asia Vol.16 No.2

Synthesis and Biological Evaluation of Substrate-Based Imaging Agents for the Prostate-Specific Membrane Antigen

변영주,Mrudula Pullambhatla,Haofan Wang,Ronnie C. Mease,Martin G. Pomper 한국고분자학회 2013 Macromolecular Research Vol.21 No.5

Prostate-specific membrane antigen (PSMA) is an attractive target for the imaging of prostate cancer (PCa) due to the elevated expression on the surface of prostate tumor cells. Most PSMA-targeted low molecular weight imaging agents are inhibitors of PSMA. We have synthesized a series of substrate-based PSMA-targeted imaging agents by mimicking poly-γ-glutamyl folic acid, an endogenous substrate of PSMA. In vitro the γ-linked polyglutamate conjugates proved to be better substrates than the corresponding α-linked glutamates. However, in vivo imaging studies of γ-ray-emitting and γ-linked glutamates did not demonstrate selective uptake in PSMA-positive over PSMA-negative tumors. Subsequent chromatographic studies and in silico molecular dynamics simulations indicated that hydrolysis of the substrates is slow and access to the enzymatic active site is limited. These results inform the design of future substrate-based imaging agents for PSMA.

PEGylated TRAIL ameliorates experimental inflammatory arthritis by regulation of Th17 cells and regulatory T cells

Park, Jong-Sung,Oh, Yumin,Park, Ogyi,Foss, Catherine A.,Lim, Sung Mook,Jo, Dong-Gyu,Na, Dong Hee,Pomper, Martin G.,Lee, Kang Choon,Lee, Seulki Elsevier 2017 Journal of controlled release Vol.267 No.-

<P><B>Abstract</B></P> <P>TNF-related apoptosis-inducing ligand (TRAIL) is a death ligand that can induce apoptosis in cells expressing its cognate death receptors (DRs). Previously, we demonstrated the therapeutic potential of recombinant human TRAIL in experimental rheumatoid arthritis (RA) models. However, the mechanisms of how DR-mediated apoptosis elicits these actions is not known. Here, we show that systemically administering a potent, long-acting PEGylated TRAIL (TRAIL<SUB>PEG</SUB>) is profoundly anti-rheumatic against two complementary experimental RA mouse models, collagen-induced arthritis (CIA) and collagen antibody-induced arthritis (CAIA), <I>via</I> targeting IL-17 secreting Th17 cells and regulatory T cells (Treg). Systemic administration of TRAIL<SUB>PEG</SUB> after disease onset ameliorated the severity of inflammatory arthritis including arthritis indices, paw thickness, cartilage damage and neutrophil infiltration in both CIA and CAIA models. Additionally, the levels of inflammatory molecules (p-p65, ICAM-1, Cox-2, MMP3, and iNOS), pro-inflammatory cytokines (TNF-α, IL-1β, IFN-γ, IL-6, IL-17) and accumulation of activated macrophages were significantly reduced after the TRAIL<SUB>PEG</SUB> treatment. Importantly, TRAIL<SUB>PEG</SUB> decreased the number of pro-inflammatory Th17 cells in inflamed arthritic joints through TRAIL-induced apoptosis while increasing anti-inflammatory Treg population <I>in vivo</I>. These results suggest that TRAIL<SUB>PEG</SUB> ameliorates autoimmunity by targeting the Th 17-Tregs axis, making it a promising candidate drug for the treatment of RA.</P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>

State-of-the-art in design rules for drug delivery platforms: Lessons learned from FDA-approved nanomedicines

Dawidczyk, C.M.,Kim, C.,Park, J.H.,Russell, L.M.,Lee, K.H.,Pomper, M.G.,Searson, P.C. Elsevier Science Publishers 2014 Journal of controlled release Vol.187 No.-

The ability to efficiently deliver a drug to a tumor site is dependent on a wide range of physiologically imposed design constraints. Nanotechnology provides the possibility of creating delivery vehicles where these design constraints can be decoupled, allowing new approaches for reducing the unwanted side effects of systemic delivery, increasing targeting efficiency and efficacy. Here we review the design strategies of the two FDA-approved antibody-drug conjugates (Brentuximab vedotin and Trastuzumab emtansine) and the four FDA-approved nanoparticle-based drug delivery platforms (Doxil, DaunoXome, Marqibo, and Abraxane) in the context of the challenges associated with systemic targeted delivery of a drug to a solid tumor. The lessons learned from these nanomedicines provide an important insight into the key challenges associated with the development of new platforms for systemic delivery of anti-cancer drugs.

Delivery of tumor-homing TRAIL sensitizer with long-acting TRAIL as a therapy for TRAIL-resistant tumors

Oh, Y.,Swierczewska, M.,Kim, T.H.,Lim, S.M.,Eom, H.N.,Park, J.H.,Na, D.H.,Kim, K.,Lee, K.C.,Pomper, M.G.,Lee, S. Elsevier Science Publishers 2015 Journal of controlled release Vol.220 No.2

Tumor necrosis factor-related apoptosis inducing ligand (TRAIL) has attracted great interest as a cancer therapy because it selectively induces death receptor (DR)-mediated apoptosis in cancer cells while sparing normal tissue. However, recombinant human TRAIL demonstrates limited therapeutic efficacy in clinical trials, possibly due to TRAIL-resistance of primary cancers and its inherent short half-life. Here we introduce drug delivery approaches to maximize in vivo potency of TRAIL in TRAIL-resistant tumor xenografts by (1) extending the half-life of the ligand with PEGylated TRAIL (TRAIL<SUB>PEG</SUB>) and (2) concentrating a TRAIL sensitizer, selected from in vitro screening, in tumors via tumor-homing nanoparticles. Antitumor efficacy of TRAIL<SUB>PEG</SUB> with tumor-homing sensitizer was evaluated in HCT116 and HT-29 colon xenografts. Western blot, real-time PCR, immunohistochemistry and cell viability assays were employed to investigate mechanisms of action and antitumor efficacy of the combination. We discovered that doxorubicin (DOX) sensitizes TRAIL-resistant HT-29 colon cancer cells to TRAIL by upregulating mRNA expression of DR5 by 60% in vitro. Intravenously administered free DOX does not effectively upregulate DR5 in tumor tissues nor demonstrate synergy with TRAIL<SUB>PEG</SUB> in HT-29 xenografts, but rather introduces significant systemic toxicity. Alternatively, when DOX was encapsulated in hyaluronic acid-based nanoparticles (HAC/DOX) and intravenously administered with TRAIL<SUB>PEG</SUB>, DR-mediated apoptosis was potentiated in HT-29 tumors by upregulating DR5 protein expression by 70% and initiating both extrinsic and intrinsic apoptotic pathways with reduced systemic toxicity compared to HAC/DOX or free DOX combined with TRAIL<SUB>PEG</SUB> (80% vs. 40% survival rate; 75% vs. 34% tumor growth inhibition). This study demonstrates a unique approach to overcome TRAIL-based therapy drawbacks using sequential administration of a tumor-homing TRAIL sensitizer and long-acting TRAIL<SUB>PEG</SUB>.

Molecular Imaging of CXCL12 Promoter-driven HSV1-TK Reporter Gene Expression

Lina Alon,Dara L. Kraitchman,Michael Schär,Angel Cortez,Nirbhay N. Yadav,Rebecca Krimins,Peter V. Johnston,Michael T. McMahon,Peter C. M. van Zijl,Sridhar Nimmagadda,Martin G. Pomper,Jeff W. M. Bulte 한국생물공학회 2018 Biotechnology and Bioprocess Engineering Vol.23 No.2

The C-X-C motif chemokine 12 (CXCL12, SDF1a) and its receptor, CXCR4, play a fundamental role in several biological processes, including hematopoiesis, cardiogenesis, cancer progression, and stem cell migration. Noninvasive monitoring of CXCL12 is highly desirable for optimizing strategies that combine mobilization of therapeutic cells to combat cancer or to assist in cardiac tissue repair after myocardial infarction. Here, we report on an MRI reporter gene system for directly monitoring CXCL12 expression in vivo. Glioma cells and human adipose-derived stem cells (hADSC) were transduced with the herpes simplex virus type-1-thymidine kinase (HSV1- tk) reporter gene expressed under the CXCL12 promoter. HSV1-tk expression resulted in accumulation of the PET tracer [125I]FIAU in vitro and in vivo and induced cell death after ganciclovir treatment. Furthermore, the results show that conditional expression of the reporter gene can be induced by hypoxia in transduced cells. Transduced hADSC were incubated with the CEST MRI probe 5-methyl-5, 6- dihydrothymidine (5-MDHT) and transplanted into swine heart. Transplanted cells were clearly visible on Chemical Exchange Saturation Transfer (CEST) MRI using a 3T clinical scanner. Therefore, we conclude that it is possible to image CXCL12 expression with MRI in a large animal model, opening up a possible route to clinical translation.

Nano-sized metabolic precursors for heterogeneous tumor-targeting strategy using bioorthogonal click chemistry <i>in vivo</i>

Lee, Sangmin,Jung, Seulhee,Koo, Heebeom,Na, Jin Hee,Yoon, Hong Yeol,Shim, Man Kyu,Park, Jooho,Kim, Jong-Ho,Lee, Seulki,Pomper, Martin G.,Kwon, Ick Chan,Ahn, Cheol-Hee,Kim, Kwangmeyung IPC Science and Technology Press 2017 Biomaterials Vol.148 No.-

<P><B>Abstract</B></P> <P>Herein, we developed nano-sized metabolic precursors (Nano-MPs) for new tumor-targeting strategy to overcome the intrinsic limitations of biological ligands such as the limited number of biological receptors and the heterogeneity in tumor tissues. We conjugated the azide group-containing metabolic precursors, triacetylated <I>N</I>-azidoacetyl-<SMALL> <I>D</I> </SMALL>-mannosamine to generation 4 poly(amidoamine) dendrimer backbone. The nano-sized dendrimer of Nano-MPs could generate azide groups on the surface of tumor cells homogeneously regardless of cell types via metabolic glycoengineering. Importantly, these exogenously generated ‘artificial chemical receptors’ containing azide groups could be used for bioorthogonal click chemistry, regardless of phenotypes of different tumor cells. Furthermore, in tumor-bearing mice models, Nano-MPs could be mainly localized at the target tumor tissues by the enhanced permeation and retention (EPR) effect, and they successfully generated azide groups on tumor cells <I>in vivo</I> after an intravenous injection. Finally, we showed that these azide groups on tumor tissues could be used as ‘artificial chemical receptors’ that were conjugated to bioorthogonal chemical group-containing liposomes via <I>in vivo</I> click chemistry in heterogeneous tumor-bearing mice. Therefore, overall results demonstrated that our nano-sized metabolic precursors could be extensively applied to new alternative tumor-targeting technique for molecular imaging and drug delivery system, regardless of the phenotype of heterogeneous tumor cells.</P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>