Cathepsin B-Overexpressed Tumor Cell Activatable Albumin-Binding Doxorubicin Prodrug for Cancer-Targeted Therapy

Prodrugs are bioreversible medications that should undergo an enzymatic or chemical transformation in the tumor microenvironment to release active drugs, which improve cancer selectivity to reduce toxicities of anticancer drugs. However, such approaches have been challenged by poor therapeutic efficacy attributed to a short half-life and low tumor targeting. Herein, we propose cathepsin B-overexpressed tumor cell activatable albumin-binding doxorubicin prodrug, Al-ProD, that consists of a albumin-binding maleimide group, cathepsin B-cleavable peptide (FRRG), and doxorubicin. The Al-ProD binds to in situ albumin, and albumin-bound Al-ProD indicates high tumor accumulation with prolonged half-life, and selctively releases doxorubicin in cathepsin B-overexpressed tumor cells, inducing a potent antitumor efficacy. Concurrently, toxicity of Al-ProD toward normal tissues with innately low cathepsin B expression is significantly reduced by maintaining an inactive state, thereby increasing the safety of chemotherapy. This study offers a promising approach for effective and safe chemotherapy, which may open new avenues for drug design and translational medicine.

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Design Strategy for the EPR Tumor-Targeting of 1,2-Bis(sulfonyl)-1-alkylhydrazines

Molecules ◽

10.3390/molecules26020259 ◽

2021 ◽

Vol 26 (2) ◽

pp. 259

Author(s):

Philip G. Penketh ◽

Hugh S Williamson ◽

Raymond P. Baumann ◽

Krishnamurthy Shyam

Keyword(s):

Tumor Cell ◽

Solid Tumor ◽

Half Life ◽

Design Strategy ◽

Chemical Kinetic ◽

Tumor Target ◽

Ph Gradients ◽

Tumor Cell Membrane ◽

Epr Effect ◽

Normal Tissues

A design strategy for macromolecular prodrugs is described, that are expected to exhibit robust activity against most solid tumor types while resulting in minimal toxicities to normal tissues. This approach exploits the enhanced permeability, and retention (EPR) effect, and utilizes carefully engineered rate constants to selectively target tumor tissue with short-lived cytotoxic moieties. EPR based tumor accumulation (half-life ~ 15 h) is dependent upon the ubiquitous abnormal solid tumor capillary morphology and is expected to be independent of individual tumor cell genetic variability that leads to resistance to molecularly targeted agents. The macromolecular sulfonylhydrazine-based prodrugs hydrolyze spontaneously with long half-life values (~10 h to >300 h dependent upon their structure) resulting in the majority of the 1,2-bis(sulfonyl)-1-alkylhydrazines (BSHs) cytotoxic warhead being released only after tumor sequestration. The very short half-life (seconds) of the finally liberated BSHs localizes the cytotoxic stress to the tumor target site by allowing insufficient time for escape. Thus, short lifespan anticancer species are liberated, and exhibit their activity largely within the tumor target. The abnormal tumor cell membrane pH gradients favor the uptake of BSHs compared to that of normal cells, further enhancing their selectivity. The reliance on physicochemical/chemical kinetic parameters and the EPR effect is expected to reduce response variability, and the acquisition of resistance.

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Striking a Balance between Carbonate/Carbamate Linkage Bond- and Reduction-Sensitive Disulfide Bond-Bearing Linker for Tailored Controlled Release: In Situ Covalent-Albumin-Binding Gemcitabine Prodrugs Promote Bioavailability and Tumor Accumulation

Journal of Medicinal Chemistry ◽

10.1021/acs.jmedchem.8b00293 ◽

2018 ◽

Vol 61 (11) ◽

pp. 4904-4917 ◽

Cited By ~ 10

Author(s):

Huicong Zhang ◽

Kuanglei Wang ◽

Kexin Na ◽

Dan Li ◽

Zhenbao Li ◽

...

Keyword(s):

Controlled Release ◽

Disulfide Bond ◽

Albumin Binding ◽

Tumor Accumulation

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Detection and clinical relevance of hematogenous tumor cell dissemination in patients with ductal carcinoma in situ

Senologie - Zeitschrift für Mammadiagnostik und -therapie ◽

10.1055/s-0033-1347541 ◽

2013 ◽

Vol 10 (02) ◽

Author(s):

M Banys ◽

I Gruber ◽

S Becker ◽

N Krawczyk ◽

R Kurth ◽

...

Keyword(s):

Tumor Cell ◽

Ductal Carcinoma In Situ ◽

Clinical Relevance ◽

Carcinoma In Situ ◽

Ductal Carcinoma ◽

Tumor Cell Dissemination ◽

Cell Dissemination

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Metastatic Tumor Cell Behavior In Situ

10.21236/ada336000 ◽

1997 ◽

Author(s):

John Condeelis

Keyword(s):

Tumor Cell ◽

Metastatic Tumor ◽

Cell Behavior ◽

Metastatic Tumor Cell ◽

Tumor Cell Behavior

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Metastatic Tumor Cell Behavior in Situ

10.21236/ada361604 ◽

1998 ◽

Author(s):

John Condeelis

Keyword(s):

Tumor Cell ◽

Metastatic Tumor ◽

Cell Behavior ◽

Metastatic Tumor Cell ◽

Tumor Cell Behavior

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Adherence of platelets to in situ albumin-binding surfaces under flow conditions: role of surface-adsorbed albumin

Biomedical Materials ◽

10.1088/1748-6041/7/4/045007 ◽

2012 ◽

Vol 7 (4) ◽

pp. 045007 ◽

Cited By ~ 2

Author(s):

Sanjukta Guha Thakurta ◽

Robert Miller ◽

Anuradha Subramanian

Keyword(s):

Albumin Binding ◽

Flow Conditions

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TMOD-24. GENERATION AND CHARACTERIZATION OF A NOVEL TRANSGENIC IDO REPORTER MOUSE FOR IDO POSTTRANSLATIONAL MODIFICATION ANALYSIS IN SITU

Neuro-Oncology ◽

10.1093/neuonc/noaa215.974 ◽

2020 ◽

Vol 22 (Supplement_2) ◽

pp. ii233-ii233

Author(s):

April Bell ◽

Lijie Zhai ◽

Erik Ladomersky ◽

Kristen Lauing ◽

Lakshmi Bollu ◽

...

Keyword(s):

Mouse Model ◽

Tumor Cell ◽

Central Nervous System Tumor ◽

Post Translational Modifications ◽

Reporter Mouse ◽

C Terminus ◽

Human Gbm

Abstract Glioblastoma (GBM) is the most common and aggressive primary central nervous system tumor in adults with a median survival of 14.6 months. GBM is a potently immunosuppressive cancer due in-part to the prolific expression of immunosuppressive indoleamine 2,3 dioxygenase 1 (IDO). Tumor cell IDO facilitates the intratumoral accumulation of regulatory T cells (Tregs; CD4+CD25+FoxP3+). Although immunosuppressive IDO activity is canonically characterized by the conversion of tryptophan into kynurenine, we have utilized transgenic and syngeneic mouse models and mutant glioma lines to demonstrate that tumor cell IDO increases Treg accumulation independent of tryptophan metabolism. Here, we address the gap in our understanding of IDO signaling activity in vivo. Subcutaneously-engrafted human GBM expressing human IDO-GFP cDNA was isolated from immunodeficient humanized NSG-SGM3 mice. The tumor was immunoprecipitated for the GFP tag using GFP-TRAP followed by mass spectrometry which revealed a novel methylation site on a lysine residue at amino acid 373 in the IDO C-terminus region. Western blot analysis of IDO protein also revealed the presence of tyrosine phosphorylation. Additionally, we recently created a new transgenic IDO reporter mouse model whereby endogenous IDO is fused to GFP via a T2A linker (IDO→GFP). This model allows for the isolation of IDO+ cells in real-time and without causing cell death, thereby creating the opportunity for downstream molecular analysis of in situ-isolated GFP+ cells. Collectively, our work suggests that IDO non-enzyme activity may involve the post-translational modifications we recently identified. As IDO activity may differ between in vitro and in vivo modeling systems, we will use the new IDO→GFP reporter mouse model for an improved mechanistic understanding of how immunosuppressive IDO facilitates Treg accumulation in vivo.

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In-Situ Cosmogenic 14C: Production and Examples of its Unique Applications in Studies of Terrestrial and Extraterrestrial Processes

Radiocarbon ◽

10.1017/s0033822200041394 ◽

2001 ◽

Vol 43 (2B) ◽

pp. 731-742 ◽

Cited By ~ 8

Author(s):

D Lal ◽

A J T Jull

Keyword(s):

Half Life ◽

Earth Science ◽

Chemical Properties ◽

Radioactive Isotopes ◽

Earth’S Atmosphere ◽

The Earth ◽

Wide Range ◽

History Of ◽

Earth's Atmosphere

Nuclear interactions of cosmic rays produce a number of stable and radioactive isotopes on the earth (Lai and Peters 1967). Two of these, 14C and 10Be, find applications as tracers in a wide variety of earth science problems by virtue of their special combination of attributes: 1) their source functions, 2) their half-lives, and 3) their chemical properties. The radioisotope, 14C (half-life = 5730 yr) produced in the earth's atmosphere was the first to be discovered (Anderson et al. 1947; Libby 1952). The next longer-lived isotope, also produced in the earth's atmosphere, 10Be (half-life = 1.5 myr) was discovered independently by two groups within a decade (Arnold 1956; Goel et al. 1957; Lal 1991a). Both the isotopes are produced efficiently in the earth's atmosphere, and also in solids on the earth's surface. Independently and jointly they serve as useful tracers for characterizing the evolutionary history of a wide range of materials and artifacts. Here, we specifically focus on the production of 14C in terrestrial solids, designated as in-situ-produced 14C (to differentiate it from atmospheric 14C, initially produced in the atmosphere). We also illustrate the application to several earth science problems. This is a relatively new area of investigations, using 14C as a tracer, which was made possible by the development of accelerator mass spectrometry (AMS). The availability of the in-situ 14C variety has enormously enhanced the overall scope of 14C as a tracer (singly or together with in-situ-produced 10Be), which eminently qualifies it as a unique tracer for studying earth sciences.

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