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

Molecules ◽  
2021 ◽  
Vol 26 (2) ◽  
pp. 259
Author(s):  
Philip G. Penketh ◽  
Hugh S Williamson ◽  
Raymond P. Baumann ◽  
Krishnamurthy Shyam

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.

Pharmaceutics ◽  
2021 ◽  
Vol 14 (1) ◽  
pp. 83
Author(s):  
Hanhee Cho ◽  
Man Kyu Shim ◽  
Suah Yang ◽  
Sukyung Song ◽  
Yujeong Moon ◽  
...  

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.


Biomaterials ◽  
2014 ◽  
Vol 35 (9) ◽  
pp. 2952-2960 ◽  
Author(s):  
Liang Han ◽  
Mingming Liu ◽  
Deyong Ye ◽  
Ning Zhang ◽  
Ed Lim ◽  
...  

2019 ◽  
Vol 18 (4) ◽  
pp. 1051-1100
Author(s):  
Lenka Molčanová ◽  
Dominika Janošíková ◽  
Stefano Dall´Acqua ◽  
Karel Šmejkal

2011 ◽  
Vol 2 (3) ◽  
pp. 419-422 ◽  
Author(s):  
VESNA BUCAN ◽  
CLAUDIA Y.U. CHOI ◽  
ANDREA LAZARIDIS ◽  
PETER M. VOGT ◽  
KERSTIN REIMERS

1982 ◽  
Vol 68 (5) ◽  
pp. 365-371 ◽  
Author(s):  
Ornella Marelli ◽  
Alberto Mantovani ◽  
Paola Franco ◽  
Angelo Nicotin

Murine leukemic cells, after in vivo treatment with antineoplastic drugs, have been shown to express new antigenic specificities that were not detectable on parental cells and that were heritable after the withdrawal of drug treatment. A study was conducted of macrophage antitumor activity triggered by LY/DTIC cells, a subline of LY murine lymphoma, antigenically altered by the drug DTIC. In vitro non-specific inhibition of tumor cell growth was exhibited by spleen and peritoneal macrophages from mice previously challenged with viable LY/DTIC. Peritoneal macrophages from LY/DTIC immune animals showed moderate, although significant lytic activity against unrelated tumor target cells. Supernatants from mixed lymphocyte-tumor cell cultures, in which LY/DTIC immune lymphocytes and LY/DTIC tumor cells had been cultured, rendered normal macrophages non-specifically growth inhibitory for tumor cells.


Leukemia ◽  
2009 ◽  
Vol 23 (7) ◽  
pp. 1270-1277 ◽  
Author(s):  
A Furuhata ◽  
M Murakami ◽  
H Ito ◽  
S Gao ◽  
K Yoshida ◽  
...  

2020 ◽  
Vol 326 ◽  
pp. 297-309 ◽  
Author(s):  
Jingyao Gan ◽  
Guangsheng Du ◽  
Chunting He ◽  
Min Jiang ◽  
Xingyue Mou ◽  
...  

2020 ◽  
Vol 38 (6) ◽  
pp. 595-600
Author(s):  
Yu Zhang ◽  
Miao‐Deng Liu ◽  
Chu‐Xin Li ◽  
Bin Li ◽  
Xian‐Zheng Zhang

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