Dendritic Polyglycerol Derivative with Cleavable Linkers
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Solution Overview
Problem
Current anti-inflammatory compounds like dendritic polyglycerol sulfate (dPGS) face issues with biocompatibility and biodistribution due to ionic interactions with serum proteins, leading to accumulation in organs like the liver and spleen, and potential side effects such as heparin-induced thrombocytopenia and infections.
Innovation Solution
A polyglycerol derivative with a dendritic backbone and covalently bound negatively charged groups, such as sulfates, sulfonates, or phosphates, linked via cleavable moieties like carbamate, ester, or amide groups, which allows for adjustable degradation and improved biodistribution by forming a core-shell structure that can be targeted and cleared.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If dendritic polyglycerol sulfate (dPGS) is used as an anti-inflammatory compound, then strong anti-inflammatory activity is achieved, but accumulation in liver and spleen occurs leading to poor biodistribution
Solution Approach 1:
The patent divides the dPGS molecule into two segments: a stable dendritic polyglycerol core that provides anti-inflammatory activity, and a degradable sulfate shell that can be cleaved off. This segmentation allows the core to remain active while the shell can be metabolized to improve biodistribution and reduce organ accumulation.
Solution Approach 2:
The sulfate groups are extracted as a separate degradable shell component that can be removed from the system through metabolic pathways. This extraction of the potentially harmful sulfate shell while retaining the beneficial core resolves the contradiction between activity and biodistribution.
2Reliability
If heparin is used as an anticoagulant and anti-inflammatory agent, then high anti-inflammatory properties are achieved, but severe side effects occur such as heparin-induced thrombocytopenia and infections
Solution Approach 1:
The patent creates a disposable-like molecular structure where the sulfate shell is designed to be temporary and degradable. This short-living shell provides the necessary anti-inflammatory effect temporarily, then degrades to eliminate side effects, unlike permanent heparin molecules that cause cumulative side effects.
Solution Approach 2:
The degradable sulfate shell acts as an intermediary that provides the necessary charge and anti-inflammatory activity temporarily, then degrades into harmless byproducts. This intermediary approach avoids the persistent harmful effects of heparin while maintaining therapeutic benefits.
3Reliability
If dPGS is administered intravenously, then strong binding affinity to L- and P-selectin is achieved, but ionic interactions with serum proteins lead to aggregate formation and increased hydrodynamic diameter
Solution Approach 1:
The patent introduces dynamic characteristics to the sulfate shell, making it degradable and adaptable. The shell can dynamically adjust its structure and eventually degrade, preventing permanent aggregation and allowing the molecule to maintain optimal hydrodynamic properties throughout its biological journey.
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 polyglycerol derivative exhibits enhanced biological activity and reduced anticoagulant effects, minimizing organ accumulation and side effects, while maintaining strong anti-inflammatory properties and complement inhibition, making it suitable for long-term inflammatory disease treatment.
Implementation Method 1
the linker is chosen from the group consisting of moieties being or comprising a carbamate group, an ester group, an orthoester group, an amide group, a disulfide bridge group, an acetal group, an imine group and combinations thereof
Data Source
AI summary
It is provided a polyglycerol derivative, comprising a dendritic polyglycerol backbone and at least one substituent in the nature of a covalently bound negatively charged group chosen from the group consisting of sulfates, sulfonates, phosphates, phosphonates, bisphosphonates, carboxylates and combinations thereof. The substituent is bound to the polyglycerol backbone via a linker, the linker being chosen from the group consisting of moieties being or comprising a carbamate group, an ester group, an orthoester group, an amide group, a disulfide bridge group, an acetal group, an imine group and combinations thereof.