Designed ferritin nanocages displaying trimeric TRAIL and tumor-targeting peptides confer superior anti-tumor efficacy

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.

Engineering Self-Assembling Protein Nanoparticles for Therapeutic Delivery

“…Currently, the most straightforward nanoparticle design method is top-down adaptation of an existing, naturally evolved viral capsid or cellular protein nanocontainer. , Natural protein nanoparticles like ferritins, encapsulins, and lumazine synthases evolved over billions of years to serve highly specialized biological functions in specific environments, with many functionalities that would be virtually impossible to design using current methods. (Table ).…”

Cancer nanotechnology: current status and perspectives

“…Multiple drugs may be engineered to be released simultaneously or in specific sequence depending on kinetics and mechanism of action, with drug release occuring through degradation of the carrier, drug desorption, diffusion through the nanoparticle matrix, or by triggered release [ 62 , 63 ]. Specific targeting utilizes a nanocarrier or drug conjugate tethered with specific molecules that have high affinity for cancerous cells and lower affinity for healthy cells, lowering the likelihood of systemic toxicity [ 64 , 65 ]. Antibody drug conjugates currently improve targeting, but targeted delivery of a nanocarrier may incorporate a higher dosage of drug and typically have more versatility for targeting modes using dynamic nanomaterials [ 66 , 67 ].…”

“…However, it struggles to move past preclinical because of a short half-life and rapid renal clearance of the off-targeted TRAIL [ 213 ]. A new development of a TRAIL-active trimer ferritin nanocage (TRAIL-ATNC) has 16 times longer serum half-life while maintaining anti-tumor efficacy in vivo in xenograft breast cancer and orthotopic pancreatic models [ 64 ]. Nanoformulation has the potential to improve PK/PD parameters for any therapeutic, opening the door to drug repurposing [ 214 ].…”

“…The incorporation of Cu 2+ into BP@Cu nanostructures further enables chemodynamic therapy-enhanced PTT. Moreover, by employing 64 Cu 2+ , PET imaging can be achieved for in vivo real-time and quantitative tracking.…”

Construction and validation of a prognostic risk model for breast cancer based on protein expression

“…In human breast cancer, cathepsin D (CTSD), IL4 receptor (IL4R), mucin-1 (MUC1, CD227), and serine protease 3 (PRSS3) may serve as valuable biomarkers for the diagnosis and treatment of breast cancer [20][21][22][23]. Breast cancer is divided into different types based on pathology features.…”