A novel HER2 targeting nanoagent self-assembled from affibody-epothilone B conjugate for cancer therapy

Area of Science:

• Biomedical Engineering
• Nanotechnology
• Oncology

Background:

• Epothilone B (Epo B) shows promise as an antitumor agent but suffers from poor selectivity and narrow therapeutic windows.
• Affibody proteins offer precise targeting of cancer cells overexpressing specific receptors.
• Reactive oxygen species (ROS) are implicated in tumor microenvironments.

Purpose of the Study:

• To develop a targeted nanoagent for improved cancer therapy by conjugating Epothilone B with an Affibody.
• To create a drug delivery system that releases Epothilone B in response to tumor-specific conditions like high ROS levels.
• To evaluate the efficacy and safety of the novel nanoagent in HER2-positive cancer models.

Main Methods:

• Self-assembly of a core-shell nanoagent (Z-E ADCN) using a thioketal (tk) linker to conjugate ZHER2:342 Affibody with Epothilone B.
• Encapsulation of Epothilone B within the Affibody corona to form the nanoagent.
• In vitro and in vivo evaluation of Z-E ADCN targeting, drug release, and anticancer efficacy in HER2-positive tumor models.

Main Results:

• The Z-E ADCN demonstrated enhanced targeting and accumulation in HER2-positive tumors.
• The nanoagent was internalized via HER2 receptor-mediated endocytosis.
• Epothilone B release was triggered by high ROS levels within cancer cells, leading to significant tumor growth inhibition.
• Reduced side effects were observed in normal organs due to targeted drug delivery.

Conclusions:

• The developed ZHER2:342-Epo B Affibody-Drug Conjugate Nanoagent (Z-E ADCN) offers a promising strategy for targeted cancer therapy.
• The ROS-sensitive linker and Affibody targeting enhance drug delivery and reduce systemic toxicity.
• Z-E ADCN exhibits potent anticancer efficacy in HER2-positive tumor models, highlighting its clinical potential.