Development of potent nanosized carbonic anhydrase inhibitor for targeted therapy of hypoxic solid tumors

Nanosized molecularly designed carbonic anhydrase inhibitor for targeted therapy of hypoxic solid tumors. Created with BioRender.com. [Display omitted] •Molecularly designed carbonic anhydrase (CA) inhibitors limit tumor progression.•Molecular docking enabled design of selective inhibitor of human C...

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Published in:International journal of pharmaceutics 2023-01, Vol.631, p.122537-122537, Article 122537
Main Authors: Eldehna, Wagdy M., El Hassab, Mahmoud A., Abdelshafi, Nahla A., Eissa, Rana A., Diab, Nadeen H., Mohamed, Ekram H., Oraby, Mamdouh A., Al-Rashood, Sara T., Eissa, Rana G., Elsayed, Zainab M., Nocentini, Alessio, Supuran, Claudiu T., Elsabahy, Mahmoud, Eissa, Noura G.
Format: Article
Language:English
Subjects:
Animals
Antigens, Neoplasm
Carbonic anhydrase
Carbonic Anhydrase Inhibitors - pharmacology
Carbonic Anhydrases - metabolism
Carbonic Anhydrases - therapeutic use
HIF-1α
Humans
Hypoxia
Hypoxia - drug therapy
Hypoxic solid tumors
Liposomes - therapeutic use
Mice
MMP-2
Nanoparticles
Neoplasms - drug therapy
Niosomes
Tumor Microenvironment
VEGF
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Summary:Nanosized molecularly designed carbonic anhydrase inhibitor for targeted therapy of hypoxic solid tumors. Created with BioRender.com. [Display omitted] •Molecularly designed carbonic anhydrase (CA) inhibitors limit tumor progression.•Molecular docking enabled design of selective inhibitor of human CA isoform.•Nanosized CA inhibitor exhibited profound and sustained antitumor activity in vivo. Overexpression of two carbonic anhydrase (CA) isoforms, CA IX and XII, in several hypoxic solid tumors provides an extracellular hypoxic microenvironment, interferes with extra- and intracellular pH regulation, thus favoring hypoxic tumor cell survival, proliferation and metastasis. In the current study, a selective inhibitor for human CA isoforms IX and XII (isatin-bearing sulfonamide, WEG-104), was incorporated into nanosized spherical niosomes at high encapsulation efficiency to allow for an enhanced and sustained antitumor activity. In vivo, administration of WEG-104 that is either free (10 mg/kg) or loaded into niosomes (5 mg/kg) into a mice model of Ehrlich ascites solid tumor resulted in comparable efficacy in terms of reduction of tumor weight and volume. Administration of WEG-104-loaded niosomes (10 mg/kg) exhibited superior antitumor activity compared to the free drug, evidenced by reduced tumor weight and volume, marked reduction in the activity of CA IX and XII, and suppression of HIF-1α and MMP-2. Moreover, prominent increase of caspase 3 and pronounced decrease in VEGF immune expression were observed in the treated animals. Hence, loading of molecularly designed compounds that targets CAs in hypoxic solid tumors into nanosized delivery systems provided an auspicious strategy for limiting solid tumor progression and malignancy.
ISSN:0378-5173
1873-3476
DOI:10.1016/j.ijpharm.2022.122537