Molecular Delivery System for Oligonucleotide Trans-Membrane Transport
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Solution Overview
Problem
There is an unmet need for effective delivery systems that can transport large and heavily electrically-charged oligonucleotide drugs (OD) across hydrophobic phospholipid membranes into cells, as existing technologies struggle to efficiently achieve this.
Innovation Solution
A novel molecular delivery system (MDS) is developed, comprising chemical moieties that, when conjugated to cargo drugs like OD, facilitate the delivery of these drugs across phospholipid membranes into cells, where they can exert their biological activity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If oligonucleotide drugs are used for therapeutic purposes, then biological activity (gene silencing) is achieved, but delivery across phospholipid membranes into cells is inefficient due to large size and heavy electrical charge
Solution Approach 1:
The patent employs cell-penetrating peptides (CPPs) as intermediary carriers that temporarily associate with the oligonucleotide drug to facilitate its passage across the hydrophobic phospholipid membrane. The CPP acts as a mediator that bridges the incompatibility between the charged macromolecule and the hydrophobic membrane barrier, enabling delivery without permanently altering the OD structure.
Solution Approach 2:
The invention creates a composite delivery system where the oligonucleotide drug is conjugated to or complexed with cell-penetrating peptide moieties. This composite structure combines the therapeutic functionality of the OD with the membrane-translocating capability of the CPP, achieving both delivery efficiency and biological activity.
2Reliability
If the oligonucleotide drug is made larger and more charged to enhance biological activity, then therapeutic efficacy is improved, but the ability to cross hydrophobic membranes deteriorates
Solution Approach 1:
The cell-penetrating peptide serves as an intermediary that protects the charged oligonucleotide from the hydrophobic membrane environment during translocation. The CPP's amphipathic nature allows it to interface with both the charged OD and the hydrophobic lipid bilayer, mediating passage without requiring reduction of the OD's charge or size.
Solution Approach 2:
The invention alters the physicochemical parameters of the delivery system by conjugating the OD with CPPs that have opposite charge characteristics and different hydrophobicity. This parameter change in the composite structure enables membrane crossing while preserving the original OD's biological activity parameters.
3Productivity
If a delivery system is designed to transport macromolecular drugs across membranes, then delivery efficiency is improved, but the system complexity and synthesis difficulty increase
Solution Approach 1:
The delivery system is segmented into distinct functional modules: the oligonucleotide drug moiety and the cell-penetrating peptide moiety. These segments can be synthesized separately using established methodologies and then coupled together, simplifying the overall manufacturing process compared to de novo synthesis of a fully integrated complex delivery system.
Solution Approach 2:
The cell-penetrating peptide moiety serves as a universal delivery vehicle that can be conjugated to different oligonucleotide drugs with varying sequences and functions. This multi-functional approach allows the same CPP scaffold to deliver various therapeutic ODs, reducing the need to develop separate delivery systems for each drug and thereby simplifying manufacturing.
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 MDS enables efficient trans-membrane delivery of macromolecular ODs, allowing them to exert biological activities such as gene silencing both in vitro and in vivo.
Implementation Method 1
comprising red-ox-sensitive cleavable group, that is stable at the extracellular compartment, but undergoes efficient cleavage in the reductive conditions that prevail in the cytoplasm
Data Source
AI summary
The Invention provides a novel delivery system for delivery of drugs across biological membranes. It provides novel chemical conjugates that comprise said delivery system, methods for synthesis of said compounds, and methods for utilization of said delivery system, among others, for delivery of genetic drugs into tissues and cells, in vitro, ex vivo, and in vivo, for the treatment of various medical disorders.