CpG-free plasmid with PBAE nanoparticles for targeted gene therapy
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Solution Overview
Problem
Current nucleic acid delivery methods for cancer therapy face challenges in achieving selective targeting of cancer cells while minimizing toxicity and ensuring effective delivery of therapeutic agents to hepatocellular carcinoma (HCC) and prostate cancer cells.
Innovation Solution
A composition comprising a nucleic acid molecule encoding a mutant thymidine kinase protein linked to an alpha-fetoprotein (AFP) gene promoter, combined with biodegradable poly(beta-amino ester) (PBAE) nanoparticles, which facilitates selective transfection and therapeutic action in AFP-producing cancer cells, along with the use of ganciclovir or valganciclovir and imaging agents like 9-(4-(18)F-fluoro-3-[hydroxymethyl]butyl) guanine ((18)F-FHBG for diagnostic and therapeutic purposes.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If nucleic acid therapeutics are designed for selective expression in cancer cells using cancer-specific promoters, then transcriptional targeting is improved, but safe and effective nucleic acid delivery remains challenging
Solution Approach 1:
The patent uses PBAE nanoparticles as an intermediary delivery vehicle to transport transcriptionally targeted nucleic acids. The nanoparticles serve as a mediator between the therapeutic nucleic acid and the target cancer cell, enabling safe and effective delivery while maintaining transcriptional targeting through the use of cancer-specific promoters like AFP promoter for HCC and PSA promoter for prostate cancer
Solution Approach 2:
The invention employs composite material design by combining PBAE nanoparticles with transcriptionally targeted nucleic acids. This composite approach integrates the delivery capabilities of nanoparticles with the selective expression properties of cancer-specific promoters, achieving both safe delivery and reliable transcriptional targeting simultaneously
2Reliability
If biodegradable poly(beta-amino ester) nanoparticles are used for selective transfection of HCC cells, then transfection selectivity is improved, but toxicity and liver failure risks increase
Solution Approach 1:
The patent applies local quality by using cancer-specific promoters that are actively expressed only in certain cancer cell types. The AFP promoter targets HCC cells specifically, while the PSA promoter targets prostate cancer cells, thereby achieving transfection selectivity without causing widespread toxicity. This localized genetic expression minimizes harmful effects on healthy tissues
Solution Approach 2:
The PBAE nanoparticles are designed to be biodegradable and transiently active. They deliver the therapeutic nucleic acid to the target cell and then degrade, avoiding long-term persistence in the body. This disposable nature reduces cumulative toxicity and eliminates the need for prolonged exposure to the delivery vehicle itself
3Productivity
If CpG dinucleotides are present in the nucleic acid sequence, then gene expression is improved, but immunogenicity and inflammation increase
Solution Approach 1:
The patent extracts and removes CpG dinucleotides from the nucleic acid sequence while maintaining gene expression functionality. By eliminating these immunogenic sequences, the invention prevents TLR9 activation and associated inflammatory responses, thereby reducing immunogenicity without sacrificing the productivity of gene expression through alternative promoter designs and nucleic acid modifications
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 solution enables targeted gene delivery and therapeutic efficacy specifically to cancer cells with minimal toxicity, allowing for effective treatment and diagnosis of HCC and prostate cancer while maintaining low cytotoxicity in healthy cells.
Implementation Method 1
Biodegradable poly(beta-amino) ester (PBAE) nanoparticles have been developed for biomaterial-based selective transfection of HCC cells
Implementation Method 2
PBAE nanoparticles...facilitates selective transfection and therapeutic action in AFP-producing cancer cells
Implementation Method 3
nucleic acid molecule encoding a mutant thymidine kinase (TK) protein...therapeutic agents is ganciclovir (GCV) or valganciclovir
Implementation Method 4
the one or more imaging agents is 9-(4-(18)F-fluoro-3-[hydroxymethyl]butyl) guanine ((18)F-FHBG)...taking an image, which in more certain aspects, is a positron emission tomography (PET) image
Data Source
AI summary
A DNA plasmid useful for diagnostic and therapeutic gene therapy is disclosed. Improvements to gene therapy methods known in the art are provided to ensure cancer-targeting, high efficacy, and long durability of expression. The DNA plasmid is combined with compositions of polymeric nanoparticles for non-viral gene therapy to treat cancer, including hepatocellular carcinoma and prostate cancer.