Engineered Hemichannels in Vesicles for Calcium-Switched Cargo Delivery
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Solution Overview
Problem
Small biologic compounds such as peptides and polynucleotides face challenges in clinical translation due to rapid degradation and neutralization upon administration, necessitating effective delivery methods.
Innovation Solution
Development of engineered connexin 43 polypeptides with modified c-terminal regions, engineered hemichannels, and engineered vesicles that are responsive to calcium concentration but not pH changes, allowing for controlled cargo delivery using calcium switches and esterase-mediated cleavage of ester bonds.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If small biologic compounds are administered directly, then they can provide new therapies, but they are prone to rapid degradation and neutralization
Solution Approach 1:
The patent uses engineered vesicles as intermediary carriers to protect small biologic compounds from degradation. The vesicles encapsulate the cargo compounds and deliver them to target cells, preventing direct exposure to degrading environments while maintaining therapeutic efficacy.
Solution Approach 2:
The patent modifies the chemical parameters of biologic compounds by conjugating them to carrier molecules or encapsulating them in vesicles. This changes their physical-chemical properties to resist degradation while maintaining their biological activity and target-specific functionality.
2Ease of operation
If engineered hemichannels are made responsive to calcium concentration, then controlled cargo delivery is enabled, but the system becomes more complex
Solution Approach 1:
The patent creates dynamic hemichannels that can change their state (open/closed) in response to calcium concentration changes. This dynamic behavior allows controlled cargo delivery without complex mechanical switching mechanisms, using the natural calcium sensitivity of the engineered connexin 43 polypeptides.
Solution Approach 2:
The engineered hemichannels self-regulate their opening and closing based on calcium concentration without requiring external control mechanisms. The system uses the endogenous calcium signaling of cells to automatically control cargo release, eliminating the need for complex external control systems.
3Adaptability or versatility
If modified connexin 43 polypeptides are engineered with non-functional c-terminus, then pH responsiveness is eliminated, but calcium responsiveness is maintained
Solution Approach 1:
The patent applies local quality modification by specifically altering the c-terminal region of connexin 43 polypeptides while leaving other regions intact. This localized modification eliminates pH responsiveness in the c-terminus while preserving calcium responsiveness in other domains of the protein.
Solution Approach 2:
The patent segments the functional domains of connexin 43 by treating the c-terminal region differently from the rest of the polypeptide. The c-terminus is engineered with non-functional residues to remove pH sensitivity, while the N-terminal and transmembrane domains retain calcium sensitivity and channel-forming capability.
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 stability and efficacy of peptide and polynucleotide delivery by protecting them from degradation, enabling targeted treatment of conditions like diabetic ulcers and myocardial infarction.
Implementation Method 1
the engineered hemichannel of is responsive to calcium concentration
Implementation Method 2
esterase-mediated cleavage of ester bonds
Data Source
AI summary
Described herein are engineered hemichannels, engineered vesicles that can contain the one or more of the engineered hemichannels, pharmaceutical formulations thereof, and uses thereof. In some aspects, the engineered vesicles can include one or more cargo molecules. Also described herein are methods of loading the engineered vesicles. In some aspects, loading of one or more cargo molecules engineered vesicles can be optionally via an engineered hemichannel contained in the engineered vesicle.