FCCC LOGO Faculty Publications
Mondal UK , Doroba K , Shabana AM , Adelberg R , Alam MR , Supuran CT , Ilies MA
PEG Linker Length Strongly Affects Tumor Cell Killing by PEGylated Carbonic Anhydrase Inhibitors in Hypoxic Carcinomas Expressing Carbonic Anhydrase IX
Int J Mol Sci. 2021 Jan 23;22(3)
PMID: 33498779    PMCID: PMC7866101   
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Hypoxic tumors overexpress membrane-bound isozymes of carbonic anhydrase (CA) CA IX and CA XII, which play key roles in tumor pH homeostasis under hypoxia. Selective inhibition of these CA isozymes has the potential to generate pH imbalances that can lead to tumor cell death. Since these isozymes are dimeric, we designed a series of bifunctional PEGylated CA inhibitors (CAIs) through the attachment of our preoptimized CAI warhead 1,3,4-thiadiazole-2-sulfonamide to polyethylene glycol (PEG) backbones with lengths ranging from 1 KDa to 20 KDa via a succinyl linker. A detailed structure-thermal properties and structure-biological activity relationship study was conducted via differential scanning calorimetry (DSC) and via viability testing in 2D and 3D (tumor spheroids) cancer cell models, either CA IX positive (HT-29 colon cancer, MDA-MB 231 breast cancer, and SKOV-3 ovarian cancer) or CA IX negative (NCI-H23 lung cancer). We identified PEGylated CAIs DTP1K 28, DTP2K 23, and DTP3.4K 29, bearing short and medium PEG backbones, as the most efficient conjugates under both normoxic and hypoxic conditions, and in the tumor spheroid models. PEGylated CAIs did not affect the cell viability of CA IX-negative NCI-H23 tumor spheroids, thus confirming a CA IX-mediated cell killing for these potential anticancer agents.
1422-0067 Mondal, Utpal K Doroba, Kate Shabana, Ahmed M Adelberg, Rachel Alam, Md Raqibul Supuran, Claudiu T Orcid: 0000-0003-4262-0323 Ilies, Marc A Orcid: 0000-0003-0694-411x R03EB026189/NH/NIH HHS/United States 2020/Edward N. & Della Thome Memorial Foundation/ Journal Article Int J Mol Sci. 2021 Jan 23;22(3):1120. doi: 10.3390/ijms22031120.