Brain-Targeted Nanoparticle Linkers for BBB Drug Delivery
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Solution Overview
Problem
The blood-brain barrier (BBB) poses a significant challenge for delivering therapeutic and diagnostic agents to the brain, as nearly all high and low molecular weight drugs struggle to cross, limiting effective treatments and diagnostics for neurodegenerative disorders.
Innovation Solution
A nano-delivery system comprising a core nanoparticle conjugated through polymeric linkers to a brain-internalizing transporter moiety and a therapeutic or diagnostic agent, where the relative lengths and molecular weights of the linkers significantly impact penetration, allowing stable conjugation and efficient BBB crossing.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If drugs are administered to cross the blood-brain barrier, then therapeutic and diagnostic agents can reach the brain, but nearly all high and low molecular weight drugs are unable to cross the BBB
Solution Approach 1:
The patent uses a nanoparticle as an intermediary carrier to transport therapeutic and diagnostic agents across the BBB. The nanoparticle is conjugated with a brain-internalizing transporter moiety (such as insulin or transferrin) that mediates active transport through the BBB, enabling drugs that normally cannot cross the barrier to be delivered efficiently to the brain while maintaining versatility with multiple drug types.
2Stability of the object's composition
If polymeric linkers are used to conjugate therapeutic agents to the nanoparticle, then stable conjugation is achieved, but the therapeutic agent may lose its activity
Solution Approach 1:
The patent applies different polymeric linkers with different lengths (first and second polymeric linkers of substantially different lengths) to different conjugation sites on the nanoparticle. The first linker conjugates the brain-internalizing transporter moiety while the second linker conjugates the therapeutic agent, allowing each linker to be optimized for its specific function and minimizing interference with therapeutic agent activity while maintaining stable conjugation.
3Ease of manufacture
If the same polymeric linker length is used for conjugating transporter and therapeutic agent, then manufacturing is simplified, but BBB penetration efficiency is reduced
Solution Approach 1:
The patent deliberately introduces asymmetry by using polymeric linkers of substantially different lengths for conjugating the brain-internalizing transporter moiety versus the therapeutic agent. This asymmetric design optimizes BBB penetration efficiency by allowing the shorter linker to position the therapeutic agent optimally for transport while the longer linker provides sufficient spacing for the transporter moiety to interact with BBB transporters, resolving the contradiction between manufacturing simplicity and penetration efficiency.
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The system enables efficient delivery of various molecules, including antibodies and peptides, into the brain while maintaining the therapeutic agent's activity, facilitating treatment and diagnosis of brain-related diseases without the need for linker detachment.
Implementation Method 1
functionalized with angiopep-2, a specific ligand of low density lipoprotein receptor-related protein-1 (LRP1), which could mediate the system to penetrate blood brain barrier
Implementation Method 2
conjugated through a first polymeric linker to a brain-internalizing transporter moiety, and is further conjugated to a second polymeric linker capable of binding a therapeutic or diagnostic agent
Data Source
AI summary
The present invention provides a generic platform for delivering molecules with low blood-brain barrier (BBB) penetration into the brain. The nano-delivery system is based on a core nanoparticle which is conjugated through a first polymeric linker to a brain-internalizing transporter moiety, and is further conjugated to a second polymeric linker bound to an active agent selected from a biologically active molecule or a labeling molecule. Further provided is a process for preparation of the nano-delivery system. The present invention further provides pharmaceutical compositions comprising the nano-delivery system and its use in therapeutic and/or diagnostic methods.