Tocopherol-human serum albumin nanoparticles enhance lapatinib delivery and overcome doxorubicin resistance in breast cancer

Abstract

Introduction: HER2, a tyrosine kinase receptor, is amplified in HER2-positive breast cancer, driving cell signaling and growth. Aim: This study aimed to combat multidrug resistance in Dox-insensitive breast adenocarcinoma by creating a nanoformulation therapy with a tyrosine kinase inhibitor. Methodology: Human serum albumin (HSA) was conjugated with α-D-tocopherol succinate to form nanoaggregates loaded with lapatinib (Lapa). Results: The resulting Lapa@HSA(VE) NPs were 117.2 nm in size and demonstrated IC50 values of 10.25 μg/ml on MCF7 (S) and 8.02 μg/ml on MCF7 (R) cell lines. Conclusion: Lapa@HSA(VE) NPs showed no hepatotoxicity, unlike free Lapa, as seen in acute toxicity studies in rats.

Article highlights

• α-D-tocopherol succinate (vitamin E) was conjugated to human serum albumin (HSA).

• The HSA-VE conjugate formed nanoparticles (NPs) by self-assembly without any external cross-linker and loaded Lapatinib (Lapa).

• The NPs were characterized thoroughly.

• Time-dependent uptake of NPs was observed in tested sensitive and resistant human breast cancer cell lines (MCF-7).

• The nanomedicine displayed enhanced cytotoxicity in breast cancer cell lines compared with free drugs at higher concentrations.

• Lapa@HSA(VE) NPs caused significantly higher reactive oxygen species (ROS) generation and mitochondrial depolarization in tested breast cancer cell lines compared with free Lapa.

• In vivo pharmacokinetic data showed sustained drug release from nanoformulation with decreased systemic clearance, and in vivo, toxicity study revealed that the nanoformulation considerably reduced hepatotoxicity compared with free Lapa.

Keywords: :

• cancer
• HER2 positive
• lapatinib
• multi-drug resistance
• nanoparticles

Supplemental material

Supplemental data for this article can be accessed at https://doi.org/10.1080/17435889.2024.2359357

Acknowledgments

The authors are grateful to the Central Analytical Laboratory at the Birla Institute of Technology and Science (BITS) (Pilani, Hyderabad Campus, India) for providing the instrumentation facilities such as XRD, DSC, FACS, and SEM for nanoparticle characterizations.

Author contributions

M Paul: methodology, validation, investigation, data curation, writing – original draft preparation, editing. S Das: methodology, validation, investigation, data curation, writing – original draft preparation, editing. B Ghosh: conceptualization, validation, writing – reviewing and editing, supervision. S Biswas: conceptualization, validation, writing – reviewing and editing, supervision.

Financial disclosure

The work was funded by the Indian Council of Medical Research, Government of India, to S Biswas through grant number 2021-8945/F1. M Paul acknowledges the Indian Council of Medical Research (ICMR) for providing a senior research fellowship. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Competing interests disclosure

The authors have no competing interests or relevant affiliations with any organization or entity with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Writing disclosure

No writing assistance was utilized in the production of this manuscript.

Ethical conduct of research

The toxicity test adhered to protocols approved by the Animal Ethics Committee of BITS PILANI HYDERABAD CAMPUS (BITS-Hyd-IAEC-2022-12).

Additional information

Funding

The work was funded by the Indian Council of Medical Research, Government of India, to S Biswas through grant number 2021-8945/F1. M Paul acknowledges the Indian Council of Medical Research (ICMR) for providing a senior research fellowship.