Payload-Polymer-Protein Conjugates for Solubility and Targeting
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Solution Overview
Problem
Current conjugates of payload molecules with proteins, such as cytotoxic drugs and antibodies, face issues with inefficient delivery, stability, and impaired pharmacokinetic properties due to suboptimal solubility and linkage to random positions on proteins, which affect their activity and specificity.
Innovation Solution
A conjugate is developed using a polymer with hydroxyl groups linked to payload molecules through a linker group, allowing for controlled release and improved stability, solubility, and targeted delivery by incorporating specific linker chemistries like click conjugation and lysosomal hydrolase-cleavable groups.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Stability of the object's composition
If payload molecules are conjugated to proteins using conventional chemistries, then the conjugate can be formed, but the aqueous solubility of the conjugate deteriorates
Solution Approach 1:
A polymer intermediary containing multiple hydroxyl groups is introduced between the payload molecule and the protein. This polymer acts as a mediating structure that provides multiple conjugation sites while maintaining aqueous solubility through its hydroxyl groups, thus resolving the contradiction between forming stable conjugates and maintaining solubility
Solution Approach 2:
The invention creates a composite structure consisting of payload molecules, polymer with hydroxyl groups, and protein components. This composite architecture combines the advantages of each component: the payload provides therapeutic activity, the polymer provides solubility and multiple attachment points, and the protein provides targeting specificity
2Stability of the object's composition
If payload molecules are conjugated to random positions on proteins, then the conjugate can be formed, but the specificity of the protein towards its target deteriorates
Solution Approach 1:
The polymer intermediary is designed with specific functional groups at defined positions, creating local quality differences that enable selective conjugation. The hydroxyl groups on the polymer can be selectively modified to attach payload molecules at specific locations, preventing random conjugation that would impair protein specificity
3Stability of the object's composition
If payload molecules are conjugated to proteins, then the conjugate can be formed, but the activity of the payload molecule deteriorates
Solution Approach 1:
The polymer serves as a protective intermediary that separates the payload molecule from direct interaction with the protein structure. This intermediate layer allows the conjugate to form stably while preserving the payload's active sites and functionality, preventing activity loss that occurs with direct conjugation
Solution Approach 2:
The conjugate structure is designed to be dynamic, allowing the payload molecule to maintain its functional conformation. The polymer linker provides flexibility that enables the payload to adopt the necessary orientation for activity while remaining stably attached to the protein
4Stability of the object's composition
If payload molecules are conjugated to proteins, then the conjugate can be formed, but the conjugate may not be efficiently delivered to its target due to suboptimal solubility
Solution Approach 1:
The composite structure combines the hydrophilic polymer with hydroxyl groups with the payload and protein components. This composite material exhibits optimized solubility properties that enhance circulation stability and target delivery efficiency, resolving the contradiction between forming stable conjugates and achieving efficient delivery
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 conjugate achieves enhanced payload molecule delivery and release, maintaining activity and specificity, thereby improving therapeutic efficacy against cancer cells.
Implementation Method 1
A conjugate is developed using a polymer with hydroxyl groups linked to payload molecules through a linker group
Implementation Method 2
lysosomal hydrolase-cleavable groups
Data Source
AI summary
The present invention relates to a conjugate represented by the formula [D—L—Y—(CH2)n-0]m-P—T wherein T is a protein; P is a polymer selected from the group consisting of dextran, mannan, pullulan, hyaluronic acid, hydroxyethyl starch, chondroitin sulphate, heparin, heparin sulphate, polyalkylene glycol, Ficoll, polyvinyl alcohol, amylose, amylopectin, chitosan, cyclodextrin, pectin and carrageenan, or a derivative thereof; m is at least 1; n is in the range of 1 to 10; each Y is independently selected from the group consisting of S, NH and 1,2,3-triazolyl, wherein 1,2,3-triazolyl is optionally substituted; each L is independently absent or comprises a linker group covalently joining D and Y; and each D is a payload molecule.