Guanidinylated Polymyxin B Derivatives for Intracellular Cargo Delivery

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Solution Overview

Problem

High molecular weight and highly charged biomolecules, such as proteins and liposomes, face limited cellular uptake due to biological barriers, hindering their therapeutic delivery to intended targets.

Innovation Solution

Derivatives of polymyxin B, specifically guanidinylated polymyxin B, are used as molecular transporters to facilitate the intracellular delivery of cargo by forming conjugates with these molecules, utilizing cell surface heparan sulfate and caveolae-mediated pathways for uptake.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If high molecular weight and highly charged biomolecules are used as therapeutic agents, then therapeutic potential is improved, but cellular uptake is limited

Engineering Contradiction:

Improvetherapeutic potentialVSAvoidcellular uptake

Core Design Contradiction:

ReliabilityVSProductivity

Solution Approach 1:

The patent employs polymyxin B derivatives as intermediary transporter molecules that mediate the cellular uptake of large biomolecules. These derivatives interact with cell surface heparan sulfate to facilitate the internalization of cargo such as proteins, liposomes, and oligonucleotides, thereby resolving the contradiction between therapeutic potential and cellular uptake efficiency

Inventive Principle:

Principle #24Intermediary (Mediator)

Solution Approach 2:

The patent modifies the chemical structure of polymyxin B by changing parameters such as charge distribution and molecular configuration to enhance cellular uptake. The derivatives are designed with optimized properties that allow them to interact more effectively with cell surface heparan sulfate, thereby improving the uptake of high molecular weight biomolecules while maintaining their therapeutic activity

Inventive Principle:

Principle #35Parameter changes

2Productivity

If polymyxin B is used as a transporter, then cellular uptake is enhanced, but neurotoxicity and nephrotoxicity are observed

Engineering Contradiction:

Improvecellular uptakeVSAvoidneurotoxicity and nephrotoxicity

Core Design Contradiction:

ProductivityVSObject-affected harmful factors

Solution Approach 1:

The patent applies local quality modification by creating site-specific derivatives of polymyxin B with tailored properties. The derivatives are designed to interact specifically with heparan sulfate at the cell surface while having modified regions that reduce toxic effects in neural and renal tissues, thereby achieving enhanced uptake without proportionally increasing neurotoxicity and nephrotoxicity

Inventive Principle:

Principle #3Local quality

Solution Approach 2:

The patent systematically modifies parameters of polymyxin B structure to optimize the balance between cellular uptake efficiency and toxicity. By changing molecular parameters such as charge distribution, hydrophobicity, and molecular size in specific derivatives, the patent achieves enhanced uptake while mitigating harmful effects in sensitive tissues

Inventive Principle:

Principle #35Parameter changes

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

These transporters effectively deliver large biomolecules and liposomal assemblies into mammalian cells at nanomolar concentrations, enhancing intracellular uptake and cytosolic delivery, potentially as novel drug delivery vehicles.

Implementation Method 1

utilizing cell surface heparan sulfate and caveolae-mediated pathways for uptake

Methodology Applied

Scientific EffectCell surface heparan sulfate interaction:

Implementation Method 2

utilizing cell surface heparan sulfate and caveolae-mediated pathways for uptake

Methodology Applied

Scientific EffectCaveolae-mediated endocytosis:

Data Source

PatentUS10449230B2Polymyxin derived cell penetrating scaffolds

Publication Date: 2019.10.22 RGT UNIV OF CALIFORNIA

AI summary

Provided are transporters based on polymyxin B. Also provided are methods of using the transporters for intracellular delivery of cargo and methods of enhancing intracellular uptake of cargo.