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Designed ferritin nanocages displaying trimeric TRAIL and tumor-targeting peptides confer superior anti-tumor
Jae Do Yoo1, Sang Mun Bae2, Junyoung Seo1
1Department of Biochemistry and Cell Biology, Cell and Matrix Research Institute, School of Medicine, Kyungpook National University, Daegu, 41944, Republic of Korea.
Abstract:
TRAIL is considered a promising target for cancer therapy because it mediates activation of the extrinsic apoptosis pathway in a tumor-specific manner by binding to and trimerizing its functional receptors, DR4 or DR5. Although recombinant human TRAIL has shown high potency and specificity for killing cancer cells in preclinical studies, it has failed in multiple clinical trials for several reasons, including a very short half-life mainly caused by instability of the monomeric form of TRAIL and rapid renal clearance of the off-targeted TRAIL. To overcome such obstacles, we developed a TRAIL-active trimer nanocage (TRAIL-ATNC) that presents the TRAIL ligand in its trimer-like conformation by connecting it to a triple helix sequence that links to the threefold axis of the ferritin nanocage. We also ligated the tumor-targeting peptide, IL4rP, to TRAIL-ATNC to enhance tumor targeting. The developed TRAIL-ATNCIL4rP showed enhanced agonistic activity compared with monomeric TRAIL. The in vivo serum half-life of TRAIL-ATNCIL4rP was ~ 16-times longer than that of native TRAIL. As a consequence of these properties, TRAIL-ATNCIL4rP exhibited efficacy as an anti-tumor agent in vivo against xenograft breast cancer as well as orthotopic pancreatic cancer models, highlighting the promise of this system for development as novel therapeutics against cancer.
Insights
We developed a novel TRAIL-active trimer nanocage (TRAIL-ATNC) with a tumor-targeting peptide. This enhanced TRAIL delivery system shows improved stability and anti-tumor efficacy in preclinical cancer models.
Area of Science:
- Biotechnology
- Cancer Therapeutics
- Nanomedicine
Background:
- Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) targets cancer cells via apoptosis but faces clinical limitations.
- Short serum half-life and off-target clearance of monomeric TRAIL hinder its therapeutic potential.
- Developing stable, tumor-specific TRAIL delivery systems is crucial for effective cancer therapy.
Purpose of the Study:
- To engineer a novel TRAIL-based therapeutic with enhanced stability and tumor-targeting capabilities.
- To evaluate the anti-tumor efficacy of the engineered TRAIL system in preclinical cancer models.
Main Methods:
- Development of a TRAIL-active trimer nanocage (TRAIL-ATNC) presenting TRAIL in a trimeric conformation.
- Conjugation of a tumor-targeting peptide (IL4rP) to TRAIL-ATNC for enhanced tumor specificity.
- Assessment of TRAIL-ATNCIL4rP activity, serum half-life, and in vivo anti-tumor efficacy in breast and pancreatic cancer models.
Main Results:
- TRAIL-ATNCIL4rP demonstrated enhanced agonistic activity compared to monomeric TRAIL.
- The engineered nanocage exhibited a significantly longer in vivo serum half-life (approximately 16-fold increase).
- TRAIL-ATNCIL4rP showed significant anti-tumor efficacy in xenograft breast and orthotopic pancreatic cancer models.
Conclusions:
- TRAIL-ATNCIL4rP represents a promising nanotherapeutic platform overcoming limitations of native TRAIL.
- The system's enhanced stability, tumor targeting, and potent anti-cancer activity highlight its therapeutic potential.
- This approach offers a novel strategy for developing effective cancer therapeutics.
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