Nucleic Acid Delivery Construct for KRAS-Targeted Hematologic Tumors
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Solution Overview
Problem
Existing nucleic acid delivery systems struggle to effectively target hematologic malignancies, particularly RAS-mutated multiple myeloma, due to the difficulty in introducing nucleic acids into suspended cells and the lack of an effective therapeutic agent.
Innovation Solution
A nucleic acid delivery construct composed of cationic artificial nucleic acids with hydrophilic polymers and ligands, assembled through electrostatic interactions, is used to deliver miR-143 or its analogs to regulate the K-RAS network, inhibiting proliferation of hematologic malignancies.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional nucleic acid delivery systems are used, then delivery to solid tumors may be achieved, but delivery to hematologic malignancies (suspended cells) is difficult and ineffective
Solution Approach 1:
The patent modifies the delivery system parameters by incorporating hydrophilic polymers and ligands onto the nucleic acid construct surface, changing its physical-chemical properties to enable effective interaction with and uptake by hematologic malignancy cells, thereby resolving the delivery effectiveness issue for suspended cells
Solution Approach 2:
The patent introduces ligands as intermediary molecules that mediate between the nucleic acid delivery construct and hematologic malignancy cells, facilitating specific binding and internalization, thus enabling effective delivery to cell types that were previously difficult to target
2Reliability
If miR-143 is delivered to regulate K-RAS network, then proliferation of hematologic malignancies is inhibited, but the complexity of delivering nucleic acids to suspended cells increases
Solution Approach 1:
The patent merges multiple functional components (nucleic acid, hydrophilic polymer, ligand) into a single integrated delivery construct, combining delivery and therapeutic functions in one system, which simplifies the overall delivery process while maintaining therapeutic effectiveness
Solution Approach 2:
The nucleic acid delivery construct is designed with multi-functionality, serving both as a delivery vehicle and as a therapeutic agent, reducing the need for separate components and simplifying the treatment approach while achieving effective proliferation inhibition
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 construct effectively inhibits the growth of hematologic malignancies by delivering miR-143, demonstrating significant inhibitory effects on various hematologic cancer cell lines, including leukemia and multiple myeloma, by regulating the K-RAS network.
Implementation Method 1
a nucleic acid analog represented by formula (1) and a nucleic acid to be delivered are assembled with each other through electrostatic interaction
Data Source
Figure 1a~1d
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AI summary
The present disclosure is a nucleic acid delivery construct used for treatment of a hematologic malignancy, the nucleic acid delivery construct having an assembly structure in which a nucleic acid analog represented by the following formula (1) and a nucleic acid to be delivered containing a microRNA that regulates a network of the oncogene KRAS are assembled with each other through electrostatic interaction. Wherein N represents a cationic artificial nucleic acid, H represents a hydrophilic polymer, S1 represents a spacer 1, S2 represents a spacer 2, and L represents a ligand; N has structural units in which a base is bonded to a hexose selected from ribose and deoxyribose, linking structures linking two of the structural units, and a backbone structure having cationic groups; and the cationic artificial nucleic acid is capable of assembling through electrostatic interaction between a phosphate group of the nucleic acid to be delivered and the cationic group.