Ferritin Nanoparticle Drug Carrier with MMP Cleavage and PAS Masking
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Solution Overview
Problem
Current therapies face challenges in selectively releasing therapeutic agents at diseased areas due to low drug binding capacity and short plasma half-life of native heavy chain human ferritin (HFt) nanoparticles, which also exhibit ferroxidase activity that can inhibit osteogenesis and cause adverse effects.
Innovation Solution
Genetic modification of HFt by adding a matrix metalloproteinase (MMP) cleavage site and a polypeptide sequence rich in proline, serine, and alanine (PAS) to enhance drug encapsulation and plasma half-life, while maintaining tumor cell recognition and avoiding ferroxidase activity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If native heavy chain human ferritin (HFt) nanoparticles are used as drug carriers, then they can cross biological barriers and bind to tumor cells, but they exhibit low drug binding capacity and short plasma half-life
Solution Approach 1:
The HFt protein structure is segmented by introducing a cleavable peptide sequence that separates the stable core (HFt) from the functional domain (PAS polypeptide). This segmentation allows the core to maintain structural integrity and tumor targeting, while the functional domain can be optimized for drug binding and circulation stability.
Solution Approach 2:
The invention creates a composite structure by fusing HFt with a PAS-rich polypeptide sequence. This composite material combines the tumor-targeting properties of HFt with the circulation-stabilizing and drug-binding properties of PAS sequences, achieving both long plasma half-life and high drug binding capacity.
2Reliability
If native HFt is used as a drug carrier, then it can be internalized by tumor cells, but it has a very short plasma half-life (2-3 hours)
Solution Approach 1:
The PAS-rich polypeptide acts as an intermediary that mediates between the HFt core and the physiological environment. It provides a protective interface that extends plasma half-life while preserving the tumor cell internalization capability of the HFt core through the cleavable peptide linker.
Solution Approach 2:
The invention changes the physicochemical parameters of the HFt surface by adding PAS sequences, which alter the protein's interaction with plasma proteins and cellular components. This parameter change extends plasma half-life from 2-3 hours to potentially much longer durations while maintaining tumor targeting.
3Quantity of substance
If native HFt is used, then it can bind certain drugs, but the binding yield is low which restricts clinical development
Solution Approach 1:
The PAS sequences are pre-installed on the HFt surface before drug administration. This preliminary action creates pre-formed high-capacity binding sites that dramatically increase drug binding yield when the nanovector encounters the drug, eliminating the need for complex drug loading procedures.
4Reliability
If native HFt is used as a drug carrier, then it can cross biological barriers, but its ferroxidase activity inhibits osteoblast development and causes osteoporosis
Solution Approach 1:
The harmful ferroxidase activity is extracted or removed from the HFt structure by using variant forms (vHFt) that lack this activity. The essential functions (tumor targeting, barrier crossing) are preserved while the harmful function is selectively eliminated through genetic modification.
Data Source
AI summary
A fusion protein based on the heavy chain of human ferritin is described, which includes at the N terminus of the protein at least one metalloproteinase cleavage sequence and a PAS polypeptide that acts as a masking polymer that increases the protein-drug stability, as well as a nanoparticle composed of multiple monomers of said fusion protein, a nucleic acid encoding for said fusion protein, and diagnostic and therapeutic applications thereof.