Engineering pH-responsive niosomes with ergosterol and CHEMS for controlled carfilzomib release: insights from in vitro and in vivo studies.

OBJECTIVE

Carfilzomib (CFZ), a selective proteasome inhibitor, was encapsulated in pH-responsive niosomes to enhance its stability and targeted delivery.

SIGNIFICANCE: This formulation aims to improve the controlled release and therapeutic efficacy of CFZ while minimizing systemic toxicity.

METHODS

Niosomes were prepared via thin-film hydration using ergosterol, CHEMS, Span 60, and Tween 60. The lipid film was hydrated with PBS (pH 7.4) containing CFZ in DMSO at 60 °C, followed by sonication to form unilamellar vesicles. The formulation was characterized for encapsulation efficiency, particle size, drug release, cytotoxicity, and in vivo toxicity.

RESULTS

Encapsulation efficiency reached 89.82%, with particle size increasing slightly from 323 nm (empty niosomes) to 334 nm (CFZ-loaded). In vitro release was pH-dependent, with 74.39% of CFZ released at pH 5.4 versus 54.55% at pH 7.4. CFZ-loaded niosomes exhibited enhanced cytotoxicity against breast cancer cells (IC₅。 = 0.0415 µM) compared to free CFZ (IC₅。 = 0.0714 µM). A synergistic effect with doxorubicin was observed (combination index <1). In vivo studies showed no significant toxicity at 1 and 2 mg/kg doses. However, 4 mg/kg caused elevations in liver enzymes, BUN, and creatinine, with histopathological signs of liver and kidney damage.

CONCLUSIONS

The CFZ-loaded niosomal system demonstrated optimal size, pH-responsive release, and superior anticancer activity. These findings highlight its potential as an effective carrier for controlled proteasome inhibitor delivery.