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

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, adminis-tration 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. Admin-istration 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-1 alpha 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.

Automated summary

In this study, a selective inhibitor for human CA isoforms IX and XII was incorporated into nanosized niosomes to enhance its antitumor activity. In a mice model of Ehrlich ascites solid tumor, administration of the niosomes loaded with the inhibitor exhibited superior antitumor activity compared to the free drug, as evidenced by reduced tumor weight and volume, decreased activity of CA IX and XII, and suppression of HIF-1 alpha and MMP-2. Furthermore, there was an increase in caspase 3 activity and a decrease in VEGF immune expression in the treated animals.