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Published on: May 14, 2021
Lactoferrin-modified niclosamide lipid nanocarriers reprogram ferroptosis and antioxidant networks for breast cancer
Rana K Mahmoud1, Riham M El-Moslemany1, Basant A Abou-Taleb2
1Department of Pharmaceutics, Faculty of Pharmacy, Alexandria University, Alexandria, Egypt.
Abstract:
Repurposing niclosamide (Nic), an FDA-approved anthelmintic with emerging anticancer potential, offers a promising strategy for breast cancer therapy. However, its clinical translation is limited by poor solubility and bioavailability. In this study, Nic was encapsulated into bioactive Nigella sativa incorporated nanostructured lipid carriers (Nic-NLC) and further functionalized with lactoferrin (LF-Nic-NLC) to enhance the tumor-specific targeting and cellular uptake. The selected LF-Nic-NLC showed a particle size of 133.43 ± 0.8 nm and a zeta potential of -10.7 ± 0.3 mV with high entrapment efficiency exceeding 99 % and sustained drug release. In-vitro studies on MDA-MB-231 cells showed potent cytotoxic effect (IC50 6.826 µg/mL), improved internalization (7.9-fold increase compared to coumarin 6), reduced migration (30.61 ± 4.51 % wound closure) and enhanced apoptotic effect. Moreover, LF-Nic-NLC demonstrated an efficient antitumor activity following both oral and intraperitoneal administration when tested in an Ehrlich ascites mammary tumor model. Results indicated strong tumor growth inhibition. The histopathological assessment using the Miller-Payne grading system revealed grade 4-5, indicating marked to near-complete tumor regression. At the molecular level, Nic-based therapies enhanced ferroptotic signaling, evidenced by increased transferrin receptor and ALOX15, along with suppression of DHODH, NRF2, and oncogenic miR-522, thereby promoting lipid peroxidation and ferroptotic vulnerability. Concurrently, VEGF downregulation and p53 upregulation reflected additional anti-angiogenic and pro-apoptotic effects. Collectively, the lactoferrin-functionalized Nic-NLC produced the most robust antitumor response, with superior ferroptosis induction, redox modulation, and anti-angiogenic activity.
Insights
Lactoferrin-functionalized nanostructured lipid carriers carrying niclosamide show potent breast cancer treatment effects. This novel formulation enhances drug delivery, inhibits tumor growth, and induces cancer cell death via ferroptosis and apoptosis.
Area of Science:
- Nanotechnology
- Drug Delivery
- Cancer Therapy
Background:
- Repurposing niclosamide (Nic) for breast cancer therapy is promising but limited by poor solubility and bioavailability.
- Novel drug delivery systems are needed to improve Nic's clinical efficacy.
Purpose of the Study:
- To develop and evaluate lactoferrin-functionalized nanostructured lipid carriers (LF-Nic-NLC) for enhanced breast cancer treatment.
- To investigate the in vitro and in vivo antitumor activity and molecular mechanisms of LF-Nic-NLC.
Main Methods:
- Niclosamide was encapsulated into Nigella sativa incorporated nanostructured lipid carriers and functionalized with lactoferrin (LF-Nic-NLC).
- Characterization of LF-Nic-NLC particle size, zeta potential, entrapment efficiency, and drug release.
- In vitro studies on MDA-MB-231 cells assessed cytotoxicity, cellular uptake, migration, and apoptosis.
- In vivo antitumor activity was evaluated in an Ehrlich ascites mammary tumor model.
- Molecular mechanisms including ferroptosis, angiogenesis, and apoptosis signaling pathways were analyzed.
Main Results:
- LF-Nic-NLC exhibited optimal physicochemical properties with high drug entrapment and sustained release.
- In vitro studies demonstrated potent cytotoxicity, enhanced cellular uptake, reduced migration, and increased apoptosis in cancer cells.
- LF-Nic-NLC significantly inhibited tumor growth in vivo, leading to marked tumor regression.
- Molecular analysis revealed enhanced ferroptosis, suppressed oncogenic pathways, downregulated VEGF, and upregulated p53.
Conclusions:
- Lactoferrin-functionalized niclosamide-loaded nanostructured lipid carriers represent a promising strategy for effective breast cancer therapy.
- The enhanced antitumor efficacy is attributed to improved drug delivery, ferroptosis induction, anti-angiogenic effects, and pro-apoptotic activity.
