Development of Dendrimers as Gene Delivery System
In order to avoid the immune response caused by viral vectors, scientists start averting their attention to non-viral vectors given their high efficiency and large insert capacity. Dendrimers are highly branched polymer-based macromolecules which have a spherical and symmetrical structure in precise size, and the terminal group function. Creative Biolabs has years of experience in providing gene therapy services, with multiple dendrimers available for your convenience.
Dendrimers Introduction
Dendrimers have unique molecular structures and properties, making them attractive materials for the development of nanomedicine. The key characteristics, such as clear structure and high ratio of multivalent surface portion to molecular volume, also make these nanoscale materials of great interest for developing synthetic (non-viral) carriers for therapeutic nucleic acids. Reasonable development of such carriers requires establishing a connection between the morphology and physicochemical properties of dendritic macromolecular structures and corresponding nucleic acid complexes, as well as establishing a connection with the biological properties of these systems at the cellular and systemic levels.
Dendrimer Structure
Dendrimers contain three regions: a central core, branches emanating from the core, and terminal function groups. Dendrimers bind to genetic material for gene delivery. Because of their nanometric size, dendrimers can interact specifically and effectively with membranes and proteins. Here, we provide a variety of methods to functionalize the surface of the dendrimers to meet different demands of our worldwide customers.
Figure 1 Schematized third-generation dendrimer, showing its main structural features.1
Core Services at Creative Biolabs
At Creative Biolabs, we are at the forefront of innovating gene delivery solutions, leveraging our deep expertise in dendrimer chemistry and gene therapy. Our comprehensive services are meticulously designed to accelerate the development of novel biomedical discoveries, ensuring precision, efficiency, and safety in your research endeavors.
Custom Synthesis and Functionalization of Dendrimer
We can also do custom synthesis of a variety of dendrimers such as PAMAM, PPI, PLL, carbosilane, phosphorus dendrimers and a number of generations. Our advanced functionalization services allow for precise surface modification with a wide array of biocompatible materials.
Gene Delivery System Development
In addition to dendrimers, Creative Biolabs also provides comprehensive services for the development of other non-viral and viral gene delivery systems, including multi complex and viral vectors (adenovirus, lentivirus, adenovirus, etc.). Our integrated platform ensures that you can obtain the most effective delivery strategy for therapeutic genes.
Diverse Dendrimer Portfolio
We offer a robust selection of commercially relevant dendrimers, including multiple generations of amine-terminated PAMAM dendrimers (G0-G10) and Dendrigraft poly(L-lysine) (DGLs, G2-G5), allowing researchers to select the optimal platform based on their specific research demands.
Characterization and Optimization
We provide a wide range of characterization services for dendritic macromolecular nucleic acid complexes (dendritic complexes), including size, zeta potential, stability, and encapsulation efficiency. Our expert team also assists in optimizing complex formation and transfection conditions in vitro and in vivo to maximize therapeutic efficacy while minimizing off target effects and toxicity.
Our Dendrimers Conjugated with Biocompatible Materials
- Dendrimer conjugated with PEG - The PEGylation of dendrimers offers many advantages, including better gene delivery, high transfection efficiency, low cytotoxicity and reduced immunogenicity both in vitro and in vivo.
- Dendrimer conjugated with CDs - Cyclodextrins (CDs) are a type of non-toxic and non-immunogenic oligosaccharide. PAMAM dendrimers with CDs synergize the proton sponge effect to promote the release of complexes in the cytosol.
- Dendrimers conjugated with amino acids - L-phenylalanine-modified dendrimers can enhance gene translocation to improve transduction efficiency.
Major Dendrimer Types for Gene Delivery Applications
Various types of dendrimers have been explored for gene delivery, each with unique structural features and physicochemical properties that affect their interactions with nucleic acids, cellular uptake, and biocompatibility. The selection of dendrimers usually depends on the specific therapeutic application and required delivery characteristics.
| Dendrimer Type | Core Structure | Surface Groups | Advantages | Limitations |
|---|---|---|---|---|
| PAMAM | Ammonia/EDA | Amino hydroxyl | High transfection efficiency, commercial availability | Cytotoxicity at higher generations |
| PPI (DAB) | Butylenediamine | Amino | Excellent endosomal buffering capacity | Higher inherent cytotoxicity |
| PAMAM-OH | Ethylenediamine | Hydroxyl | Reduced cytotoxicity | Lower DNA binding affinity |
| Triazine-based | Variable | Variable | Highly tunable properties | Complex synthesis |
| Carbosilane | Silicon core | Variable | High stability, versatile functionality | Limited biodegradability |
Our Dendrimer Synthesis Methods
Divergent Method
This method involves forming dendrimers from the core, distilling with reagents containing at least two protective branching sites, and then eliminating the protective groups. The released active sites form the first generation of dendrimers. By repeating this process, dendrimers of the desired size can be obtained.
Convergent Growth Process
The second method for synthesizing dendritic polymers is the convergent growth process, which starts from the periphery of the dendritic polymer and gradually moves inward by connecting surface active units together. Therefore, connect enough branches to appropriate cores to produce complete dendrimers. Polyarylene ether dendrites are typically synthesized using this technique.
Frequently Asked Questions
Q: Are dendrimers suitable for delivery to hard-to-reach tissues in the body, such as the brain?
A: Yes, targeted modifications. For example, dendrimers that bind to transferrin (a ligand for transferrin receptors expressed on brain endothelial cells) can cross the blood-brain barrier (BBB). A 2022 study by Brain reported that transferrin PEG PAMAM dendrimers deliver siRNA to mouse glioblastoma cells, reducing tumor volume by 50%. Creative Biolabs focuses on designing BBB penetrating dendrimers.
Q: Can dendrimers simultaneously deliver multiple nucleic acids (such as mRNA+siRNA)?
A: Yes, it is. The multivalent surface and lumen of dendrimers can jointly transport multiple payloads. For example, PEI dendrimers (G4) can complex Cas9 mRNA (through electrostatic interactions) and gRNA (through intraluminal encapsulation). A study by Advanced Materials showed that this co delivery system achieved a gene editing efficiency of 70% in HeLa cells, while the efficiency of sequential delivery was 40%. Creative Biolabs provides customized co delivery formulas tailored to customer payloads.
Q: Can dendrimers adapt to different types of nucleic acids (such as siRNA, mRNA, pDNA)? Do different nucleic acids need structural adjustment?
A: Dendrimers have the ability to adapt to all mainstream nucleic acid types, but require targeted structural adjustments based on the molecular weight, charge characteristics, and stability requirements of the nucleic acid
- siRNA (small interfering RNA, approximately 13kDa): Dendrimers have small molecular weight and high negative charge density, requiring high surface cation density to form stable complexes.
- mRNA (messenger RNA, ~500-2000kDa): a branched large molecule with high molecular weight, highly sensitive to degradation, requiring complex stability and lumen protection. Typically, mid to high generation dendrimers with large lumens (such as G5-G6 PLL) are chosen, and disulfide linkers (reduction sensitive type in cytoplasm) are used to achieve controlled release of mRNA.
- pDNA (plasmid DNA, ~3-10 kbp): Dendrimers have a large molecular weight and complex structure, requiring stronger chelating ability and endosome escape efficiency.
Q: How to reduce the toxicity of dendrimers in biomedical applications?
A: Toxicity can be significantly reduced through various surface functionalization strategies. Common methods include PEGylation (binding with polyethylene glycol), acylation, and binding with neutral or anionic groups, amino acids, or carbohydrates. These modifications reduce net positive charges, decrease non-specific interactions, improve biocompatibility, enhance in vivo safety, while typically maintaining or improving gene delivery efficiency.
We're Here to Help
Creative Biolabs has been committed to surface functionalization and charge improvement in a variety of ways to efficiently deliver DNA or RNA with little or no toxicity. We offer one-stop services about the development of dendrimers as a gene delivery system. Please feel free to contact us for more details and our scientists will tailor the most reasonable scheme for your projects.
Reference
- Caminade A M. Dendrimers, an emerging opportunity in personalized medicine? Journal of Personalized Medicine, 2022, 12(8): 1334. https://doi.org/10.3390/jpm12081334 (Distributed under Open Access license CC BY 4.0, without modification.)
