PEG Linker Length Strongly Affects Tumor Cell Killing by PEGylated Carbonic Anhydrase Inhibitors in Hypoxic Carcinomas Expressing Carbonic Anhydrase IX

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 ar...

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Published in:International journal of molecular sciences 2021-01, Vol.22 (3), p.1120
Main Authors: Mondal, Utpal K, Doroba, Kate, Shabana, Ahmed M, Adelberg, Rachel, Alam, Md Raqibul, Supuran, Claudiu T, Ilies, Marc A
Format: Article
Language:English
Subjects:
Antibiotics
Biological activity
Biological properties
Breast cancer
Carbon dioxide
Carbonic anhydrase
Carcinoma
Cell culture
Cell death
Cell viability
Colon
Colon cancer
Differential scanning calorimetry
Homeostasis
Hypoxia
inhibitor
Inhibitors
Isoenzymes
Lung cancer
Medical prognosis
Ovarian cancer
PEG
Pharmaceutical sciences
Polyethylene glycol
polymer conjugate
Spheroids
Sulfonamides
Thiadiazoles
tumor
Tumors
Two dimensional models
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Summary: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 , , and , 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.
ISSN:1422-0067
1661-6596
1422-0067
DOI:10.3390/ijms22031120