PLGA Particles with pH-Responsive Polymer for Endosomal Escape
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Current particulate formulations within phagocytosable size ranges often result in therapeutic agents becoming entrapped within endosomes, failing to reach their intracellular targets due to phagocytosis, leading to reduced therapeutic efficacy.
Innovation Solution
Development of particles comprising a composite material of poly(lactide-co-glycolide) (PLGA) and a membrane-destabilizing agent, such as poly(alkylacrylic acid) polymer, which destabilizes endosomes at acidic pH, allowing for the release of active agents into the target cell cytoplasm.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If particles are taken up by phagocytes, then intracellular delivery is enabled, but therapeutic agents become entrapped within endosomes and fail to reach target
Solution Approach 1:
The patent utilizes pH parameter changes to trigger membrane destabilization. The poly(alkylacrylic acid) polymer remains stable at physiological pH but destabilizes endosomal membranes at acidic endosomal pH, enabling controlled release of therapeutic agents from endosomes into the cytoplasm
Solution Approach 2:
The patent employs composite particles combining PLGA (poly(lactide-co-glycolide)) with poly(alkylacrylic acid) polymer. This composite structure provides both biocompatibility/biodegradability from PLGA and pH-dependent membrane destabilization from the poly(alkylacrylic acid) component, resolving the contradiction between reliable cellular uptake and avoidance of endosomal entrapment
2Reliability
If membrane-destabilizing agent is added to enable endosomal escape, then cytosolic delivery is improved, but particle stability may be compromised
Solution Approach 1:
The poly(alkylacrylic acid) polymer exhibits pH-dependent conformational changes, transitioning from a hydrophilic soluble conformation at physiological pH to a hydrophobic conformation at acidic pH. This parameter change enables the polymer to remain inert during circulation while actively destabilizing endosomal membranes upon cellular uptake
Solution Approach 2:
The patent converts the potentially harmful effect of membrane destabilization into a beneficial controlled release mechanism. The pH-triggered membrane disruption is transformed from a destabilizing defect into a targeted delivery advantage, enabling therapeutic agents to escape endosomes only under the specific acidic conditions of the endosomal compartment
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 intracellular delivery of therapeutic agents by facilitating their escape from endosomal compartments, thereby improving therapeutic potential and immune responses, as demonstrated by increased T-cell proliferation and antigen-specific responses.
Implementation Method 1
the membrane-destabilizing agent reversibly switches from a hydrophilic soluble conformation to less soluble hydrophobic confirmation or vice versa in response to the change of pH from physiological pH value to that of the endosomal pH value
Data Source
AI summary
Embodiments of the present disclosure include particles, methods of making particles, methods of delivering an active agent using the particle, and the like.