Water-Soluble Carrier-Linked Prodrugs for High Drug Loading
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Solution Overview
Problem
Current carrier-linked prodrugs face challenges such as low drug loading, interpatient variability in enzymatic cleavage, and limited water solubility, which affect the efficacy and convenience of drug administration.
Innovation Solution
A water-soluble carrier-linked prodrug with a branching core, poly(ethylene glycol)-based polymeric chains, branched moieties, and reversible prodrug linkers, allowing for high drug loading and controlled release, enhancing bioavailability and reducing administration volume.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Stability of the object's composition
If non-covalent encapsulation is used to prevent burst release, then drug release control is improved, but conformationally sensitive drugs are rendered dysfunctional and side reactions occur
Solution Approach 1:
The patent introduces a covalent linker as an intermediary between the carrier and drug, replacing non-covalent encapsulation. This covalent connection maintains stable drug release control while preserving drug functionality by avoiding the structural constraints and side reactions associated with hydrophobic encapsulation.
Solution Approach 2:
The patent replaces the mechanical/physical encapsulation system (non-covalent binding via van der Waals contacts) with a chemical system (covalent bonding through linker molecules). This substitution eliminates the harmful mechanical constraints on conformationally sensitive drugs while maintaining controlled release through enzymatic or chemical cleavage of the linker.
2Speed
If enzymatic cleavage is used for prodrug activation, then cleavage rate is accelerated in vivo, but interpatient variability increases
Solution Approach 1:
The patent changes the activation mechanism from enzyme-dependent to pH-dependent or redox-dependent cleavage. By utilizing the stable pH gradient between tumor microenvironment (acidic) and blood circulation (neutral), or the unique redox environment, the patent achieves fast and predictable prodrug activation that is independent of variable enzyme levels across different patients.
3Device complexity
If one drug molecule is conjugated to one carrier moiety, then prodrug activation is simplified, but administration volume increases
Solution Approach 1:
The patent merges multiple drug molecules onto a single carrier moiety through multiple linker attachments. This creates a multi-functional prodrug structure where one carrier delivers multiple drug payloads, thereby reducing the total administration volume required to achieve therapeutic drug dosage while maintaining manageable structural complexity.
4Quantity of substance
If dendrimers are used to achieve high drug loading, then drug capacity increases, but water solubility decreases
Solution Approach 1:
The patent creates a composite prodrug structure combining a carrier moiety with multiple drug molecules through linker chemistry. This composite approach achieves high drug loading capacity while maintaining water solubility by selecting water-soluble carrier backbones and appropriate linkers, avoiding the insolubility problem inherent in dendrimer structures.
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 prodrug provides a sustained-release dosage form with high drug loading and increased water solubility, improving bioavailability and reducing interpatient variability, thus enhancing therapeutic efficacy and convenience.
Implementation Method 1
non-enzymatic hydrolytic degradable, i.e. cleavable, under physiological conditions (aqueous buffer at pH 7.4, 37°C) with half-lives ranging from, for example, one hour to three months
Implementation Method 2
the poly(ethylene glycol)-based (PEG-based) polymeric chain allows for increased water-solubility
Data Source
AI summary
The present invention relates to water-soluble carrier-linked prodrugs of formula (I), wherein B, A and Hyp form the carrier, B is a branching core, each A is independently a poly(ethylene glycol)-based polymeric chain, each Hyp is independently a branched moiety, each SP is independently a spacer moiety, each L is independently a reversible prodrug linker moiety, each D is independendly a biologically active moiety, each x is independently 0 or 1, each m is independently an integer of from 2 to 64, n is an integer from 3 to 32; or the pharmaceutically acceptable salt thereof. It further relates to pharmaceutical compositions comprising said water-soluble carrier-linked prodrugs, their use asmedicament or diagnostic, and methods of treatment.