A Dual-Targeting Ferritin Drug Carrier for Synergistic Pro-Hydrophobic Drug Co-Loading

Ferritin is an iron-storage protein found in human cells with a unique shell-nucleus structure, where the outer shell is self-assembled from 24 subunits to form a protein cage and the inner lumen can be loaded with therapeutic drugs. The researchers found that human heavy chain ferritin recognizes the tumor marker molecule, transferrin receptor 1 (TfR1/CD71), without the need to couple to a targeting ligand, and recently discovered the existence of a temperature-controlled drug channel on ferritin, which opens when warmed and allows hydrophilic small molecules (e.g., epoxystilbene, oxaliplatin, gemcitabine, irinotecan, etc.) to be loaded into the protein cage. This important finding addresses the limited efficiency of ferritin in loading hydrophilic drugs.

However, it is often difficult to obtain good therapeutic effects with a single drug in the clinic. The combined application of pro-hydrophobic chemotherapeutic drugs demonstrates superior synergistic therapeutic effects, but there is currently no clinical nano-delivery system capable of delivering pro-hydrophobic chemotherapeutic drugs simultaneously. To this end, researchers have explored new strategies for co-loading nanocarriers with pro-hydrophobic chemotherapeutic drugs for synergistic therapy based on ferritin drug carriers.

In addition, current studies have shown that the therapeutic efficiency of single-targeted drug carriers is usually limited due to differences in the expression and specificity of tumor marker molecules on different tumor cells. Dual targeting of drug carriers can further improve the specific binding ability of carriers to tumor cells and the ability of drug penetration into tumor cells. In response to the above problems, researchers have developed an amphiphilic-hydrophobic drug co-loaded ferritin drug carrier (Am-PNCage) with dual tumor-targeting properties, which achieves effective delivery of amphiphilic-hydrophobic antitumor drugs and synergistic antitumor effects.

To construct a pro-hydrophobic drug co-loading ferritin drug vector with dual targeting, researchers genetically engineered a functional motif consisting of a hydrophobic peptide-hydrophilic peptide-RGD peptide to replace the fifth helix of the subunit of human heavy-chain ferritin, which achieved the display of the peptide's functional motif on the outer surface of the ferritin cage. The dual-targeting properties of the Am-PNCage were derived from the intrinsic human heavy-chain ferritin's CD71 targeting ability and the integrin ɑvβ3 targeting ability of the RGD peptide displayed on the outer surface of the protein cage. Through the hydrophilic drug channel of heavy chain ferritin and the hydrophobic peptide displayed on the outer surface of the cage, hydrophilic epothilone and hydrophobic camptothecin were loaded into the inner cavity and the outer surface of the nanocage, respectively, triggering different release mechanisms and exhibiting temporally and spatially controllable cascade release kinetics of the drugs. The Am-PNCage nanocarriers not only prolonged the half-life of the small molecule drugs to reduce the side effects but also promoted the drug targeting to tumor cells through dual-targeting. targeting to promote the affinity and permeability of drugs to tumor cells, and can cross the blood-brain barrier to aggregate effectively in brain tumors. The drug-loaded Am-PNCage can improve the therapeutic effect on tumors, especially malignant and drug-resistant tumors, through a synergistic cascade drug release strategy. Therefore, Am-PNCage can be used as a novel ferritin drug carrier platform for synergistic pro-hydrophobic drug co-loading and targeted combination chemotherapy.

References

1. Wang Z.; et al. Bioengineered dual‐targeting protein nanocage for stereoscopical loading of synergistic hydrophilic/hydrophobic drugs to enhance anticancer efficacy. Advanced Functional Materials. 2021, 31(29): 2102004.
2. Ning C.; et al. Co-encapsulation of hydrophilic and hydrophobic drugs into human H chain ferritin nanocarrier enhances antitumor efficacy. ACS Biomaterials Science & Engineering. 2023, 9(5): 2572-2583.