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Volume 22
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10.3390/ijms22031120
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Article

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

by
Utpal K. Mondal
1,
Kate Doroba
1,
Ahmed M. Shabana
1,2,
Rachel Adelberg
1,
Md. Raqibul Alam
1,
Claudiu T. Supuran
3 and
Marc A. Ilies
1,*
1
Department of Pharmaceutical Sciences, Moulder Center for Drug Discovery Research, Temple University School of Pharmacy, 3307 N Broad Street, Philadelphia, PA 19140, USA
2
Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Cairo University, Cairo 11562, Egypt
3
NEUROFARBA Department, Pharmaceutical Sciences Section, Universita degli Studi di Firenze, Polo Scientifico, via Ugo Schiff no. 6, 50019 Sesto Fiorentino (Florence), Italy
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2021, 22(3), 1120; https://doi.org/10.3390/ijms22031120
Submission received: 28 December 2020 / Revised: 20 January 2021 / Accepted: 21 January 2021 / Published: 23 January 2021
(This article belongs to the Special Issue 25th Anniversary of IJMS: Advances in Biochemistry)
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Abstract

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.
Keywords: tumor; hypoxia; carbonic anhydrase; inhibitor; polymer conjugate; PEG; sulfonamide tumor; hypoxia; carbonic anhydrase; inhibitor; polymer conjugate; PEG; sulfonamide

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MDPI and ACS Style

Mondal, U.K.; Doroba, K.; Shabana, A.M.; Adelberg, R.; Alam, M.R.; Supuran, C.T.; Ilies, M.A. 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, 22, 1120. https://doi.org/10.3390/ijms22031120

AMA Style

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. International Journal of Molecular Sciences. 2021; 22(3):1120. https://doi.org/10.3390/ijms22031120

Chicago/Turabian Style

Mondal, Utpal K., Kate Doroba, Ahmed M. Shabana, Rachel Adelberg, Md. Raqibul Alam, Claudiu T. Supuran, and Marc A. Ilies. 2021. "PEG Linker Length Strongly Affects Tumor Cell Killing by PEGylated Carbonic Anhydrase Inhibitors in Hypoxic Carcinomas Expressing Carbonic Anhydrase IX" International Journal of Molecular Sciences 22, no. 3: 1120. https://doi.org/10.3390/ijms22031120

APA Style

Mondal, U. K., Doroba, K., Shabana, A. M., Adelberg, R., Alam, M. R., Supuran, C. T., & Ilies, M. A. (2021). PEG Linker Length Strongly Affects Tumor Cell Killing by PEGylated Carbonic Anhydrase Inhibitors in Hypoxic Carcinomas Expressing Carbonic Anhydrase IX. International Journal of Molecular Sciences, 22(3), 1120. https://doi.org/10.3390/ijms22031120

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