PSMA-Targeted LPEI-PEG Polyplexes With Defined PEG Conjugation
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Current chemotherapeutic agents face inefficiencies in targeting and uptake by tumors, leading to non-specific uptake by healthy cells and toxicity, while polyplexes comprising linear polyethyleneimine (LPEI) suffer from aggregation and interaction with serum proteins, and random PEG conjugation results in heterogeneous vectors with undefined structure-activity relationships.
Innovation Solution
The development of PSMA-targeting conjugates with specifically defined discrete molecular weight PEG fragments connected through chemoselective reactions, forming linear and homogeneous LPEI-PEG conjugates, which are further combined with a targeting fragment to enhance selective delivery of nucleic acids to cancer cells.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If PEG is conjugated to LPEI by formation of covalent bonds between electrophilic PEG fragment(s) and secondary amines in LPEI backbone, then PEG shielding and biocompatibility are improved, but conjugate homogeneity and structural definition deteriorate due to random and branched conjugation
Solution Approach 1:
The LPEI polymer is segmented into discrete repeating units with specific functional groups positioned at defined locations. This segmentation allows for controlled conjugation at specific sites rather than random bonding, enabling homogeneous linear conjugates with defined PEG inclusion density while maintaining the biocompatibility benefits of PEG shielding.
Solution Approach 2:
The invention introduces local quality by positioning electrophilic PEG fragments at specific locations within the LPEI structure rather than allowing random distribution. This creates defined conjugation sites that produce homogeneous linear conjugates with consistent structure-activity relationships, while the PEG fragments continue to provide local shielding and biocompatibility at their specific positions.
2Reliability
If multiple PEG fragments are bonded orthogonally to LPEI fragment with random synthesis, then PEG shielding effect is enhanced, but structure-activity relationship definition and conjugate characterization deteriorate
Solution Approach 1:
The LPEI polymer is pre-functionalized with specific electrophilic groups at defined positions before PEG conjugation. This preliminary action ensures that PEG fragments are incorporated in a controlled manner at predetermined locations, resulting in homogeneous linear conjugates with well-defined structures and consistent shielding effects, eliminating the need for complex post-synthesis characterization.
3Reliability
If LPEI polyplexes are used for nucleic acid delivery, then selective delivery to cancer cells is achieved, but aggregation and interaction with serum proteins occur
Solution Approach 1:
The invention introduces PEG fragments as intermediary molecules between the LPEI polyplex and the surrounding biological environment. These PEG fragments act as a protective shield that prevents direct interactions between the positively charged LPEI and negatively charged serum proteins or other cellular components, thereby reducing aggregation and non-specific interactions while maintaining the targeting specificity of the polyplex for cancer cells.
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 conjugates achieve consistent and predictable ratios of LPEI to PEG, ensuring reduced heterogeneity and maintaining or increasing biological activity, including selective delivery and high expression of pharmaceutically active peptides or proteins in targeted cancer cells.
Implementation Method 1
LPEI is protonated at physiological pH and therefore carries a net positive charge. When LPEI is incubated with a nucleic acid, which carries a net negative charge at physiological pH, LPEI and the nucleic acid can form polyplexes that are held together by electrostatic interaction.
Implementation Method 2
the chemoselective bonding of the LPEI fragments to the specifically defined discrete PEG fragments can take place using any suitable chemical precursors that can form a chemoselective bond. In preferred embodiments, the chemoselective bonding of the LPEI fragments to the specifically defined discrete PEG fragments takes place by means of a [3+2] cycloaddition between an azide and an alkyne or alkene leading to a 1,2,3-triazole or a 4,5-dihydro-1H-[1,2,3]triazole.
Data Source
AI summary
The present invention relates to polyplexes comprising linear conjugates of LPEI and PEG. The LPEI and PEG fragments of the linear conjugates are preferably linked by a [3+2]cycloaddition between an azide and an alkene or an alkyne to produce a 1, 2, 3 triazole or a 4,5-dihydro-1H-[1,2,3]triazole. The linear conjugates are further conjugated to a targeting fragment capable of binding to prostate specific membrane antigen (PSMA) to enable selective interaction with a particular cell type. The conjugates can form polyplexes with therapeutic agents such as nucleic acids to deliver the therapeutic agents to cells.