Reversibly Crosslinked Polymer Vesicles for Cytosolic Drug Delivery
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Solution Overview
Problem
Current methods face challenges in efficiently delivering cyclic dinucleotides (CDNs) to cytosolic compartments of tumor-associated cells for cancer immunotherapy due to poor localization, hindering their potential as therapeutics and vaccine adjuvants.
Innovation Solution
Development of reversibly crosslinked endosomolytic polymer vesicles, specifically diblock copolymers with a hydrophilic block and a block containing amine and hydrophobic monomers, which self-assemble into pH-responsive vesicles that destabilize at endosomal pH to release CDNs or other active agents into the cytosol.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If CDNs are administered directly to tumor-associated cells, then the therapeutic potential and vaccine adjuvant effects can be achieved, but poor localization in cytosolic compartments prevents effective delivery
Solution Approach 1:
The patent uses pH-responsive polymer vesicles as intermediary carriers to transport CDNs from the extracellular environment through endosomes to the cytosol. The vesicles protect CDNs during transit and facilitate their release at the target location through pH-triggered disassembly, solving the localization problem without requiring direct administration of free CDNs
Solution Approach 2:
The patent exploits pH parameter changes between different cellular compartments (neutral extracellular pH vs. acidic endosomal pH) to control vesicle stability and CDN release. The vesicles remain stable at physiological pH but disassemble in acidic endosomes, enabling spatiotemporal control of drug delivery and improving cytosolic localization efficiency
2Stability of the object's composition
If stable polymer vesicles are used for drug delivery, then protection and controlled release are improved, but endosomal escape and cytosolic delivery become difficult
Solution Approach 1:
The patent creates dynamically responsive vesicles that change their stability properties in response to pH changes. The vesicles are stable under physiological conditions for protection and controlled release, but become unstable and disassemble in acidic endosomal environments to enable escape and cytosolic delivery. This dynamic behavior resolves the contradiction between stability and endosomal escape
Solution Approach 2:
The patent utilizes pH-induced phase transitions in the polymer vesicle structure. At neutral pH, the vesicles maintain an intact bilayer structure for stability. Upon exposure to acidic pH in endosomes, the vesicles undergo structural phase transition and disassemble, releasing their cargo into the cytosol. This phase transition mechanism enables both stable delivery and efficient endosomal escape
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
Enhances the delivery and potency of CDNs and other active agents, such as STING agonists, by facilitating their release into the cytosol, thereby improving cancer immunotherapy outcomes and antigen presentation, as demonstrated by increased type I interferon production and tumor regression in murine models.
Implementation Method 1
self-assemble into pH-responsive vesicles that destabilize at endosomal pH to release CDNs or other active agents into the cytosol
Implementation Method 2
diblock copolymers with a hydrophilic block and a block containing amine and hydrophobic monomers, which self-assemble into pH-responsive vesicles
Data Source
AI summary
A diblock copolymer, polymer vesicle, and method of forming a polymer vesicle are provided. The diblock polymer includes a hydrophilic first block and a second block including amine containing monomers and hydrophobic monomers. The polymer vesicle includes a diblock copolymer with a hydrophilic first block and a second block including amine containing monomers and hydrophobic monomers, and at least one active agent loaded in the polymer vesicle. The second block forms an inner hydrophobic domain of a vesicle membrane and the hydrophilic block forms a corona facing the exterior and aqueous interior of the vesicle membrane, the corona providing an outer shell that stabilizes the vesicle in aqueous media. The method of forming the polymer vesicle includes synthesizing the diblock copolymer through a polymerization technique selected from the group consisting of addition polymerization, condensation polymerization, and a combination thereof, providing at least one active agent, and assembling the polymer vesicle, the diblock copolymer including a hydrophilic first block and a second block with amine containing monomers and hydrophobic monomers.