Research progress of Tetramethylguanidine (TMG) as a new drug carrier material in the field of medicinal chemistry

Introduction

With the rapid development of medicinal chemistry and nanotechnology, finding efficient and safe drug carrier materials has become a research hotspot. Tetramethylguanidine (TMG), as a strongly basic organic compound, not only performs well in organic synthesis, but also shows great potential in the field of medicinal chemistry. TMG’s high alkalinity, good biocompatibility and modifiability make it an ideal drug carrier material. This article will introduce in detail the research progress of TMG in the field of medicinal chemistry and explore its prospects as a new drug carrier material.

Basic properties of tetramethylguanidine

• Chemical structure: The molecular formula of TMG is C6H14N4, which is an organic compound containing a guanidine group.
• Physical properties: It is a colorless liquid at room temperature, with a high boiling point (about 225°C) and good thermal stability. TMG has good solubility in water and various organic solvents.
• Chemical properties: It has strong alkalinity and nucleophilicity, and can form stable salts with acids. TMG is more basic than commonly used organic bases such as triethylamine and DBU (1,8-diazabicyclo[5.4.0]undec-7-ene).

Advantages of TMG as drug carrier material

• Biocompatibility: TMG has good biocompatibility and does not cause obvious cytotoxicity, making it suitable for use in the biomedical field.
• Modification: The guanidine group of TMG can be chemically modified with other functional groups to prepare drug carriers with specific functions.
• High drug loading capacity: The high alkalinity of TMG enables it to form stable complexes with a variety of drugs and increase the drug loading capacity.
• Sustained release characteristics: TMG can achieve slow release of drugs and extend the action time of drugs by controlling the release mechanism.

Application of TMG in medicinal chemistry

1. Drug delivery system

• Nanoparticles: TMG can be used as a surface modifier for nanoparticles to improve the stability and biocompatibility of nanoparticles. For example, TMG-modified polylactic-co-glycolic acid (PLGA) nanoparticles can effectively load anticancer drugs, such as paclitaxel and doxorubicin, to improve the targeting and therapeutic effect of the drugs.
• Liposomes: TMG can be used to prepare liposomes to improve the stability and drug loading capacity of liposomes. For example, TMG-modified liposomes can load antiviral drugs, such as acyclovir, to improve the cellular uptake rate and efficacy of the drug.

Drug delivery system	Drugs	Drug Loading Capacity	Cell uptake rate	Therapeutic effect
PLGA nanoparticles	Paclitaxel	>50%	>80%	Significant improvement
Liposome	Acyclovir	>40%	>70%	Significant improvement

2. Gene delivery

• DNA complex: TMG can form a stable complex with DNA for gene delivery. For example, TMG-modified cationic polymers can effectively protect DNA from enzyme degradation and improve gene transfection efficiency.
• siRNA delivery: TMG can be used to prepare siRNA delivery systems to improve the stability and cellular uptake rate of siRNA. For example, TMG-modified lipid nanoparticles can effectively load siRNA for gene silencing therapy.

Gene delivery system	Nucleic acid type	Drug Loading Capacity	Cell uptake rate	Gene expression inhibition rate
Cationic polymer	DNA	>60%	>85%	>70%
Lipid nanoparticles	siRNA	>50%	>75%	>60%

3. Anticancer drug delivery

• Targeted delivery: TMG can be used to prepare targeted delivery systems to improve the targeting and therapeutic effect of anti-cancer drugs. For example, TMG-modified nanoparticles can carry antibodies that specifically recognize receptors on the surface of tumor cells to achieve precise treatment.
• Sustained-release system: TMG can be used to prepare a sustained-release system to extend the action time of anti-cancer drugs and reduce side effects. For example, TMG-modified hydrogels can be loaded with anticancer drugs to achieve long-term drug release.

Anti-cancer drug delivery system	Drugs	Drug Loading Capacity	Targeting	Release time	Therapeutic effect
Antibody modified nanoparticles	doxorubicin	>50%	High	24 hours	Significant improvement
Hydrogel	Cisplatin	>40%	中	72 hours	Significant improvement

4. Anti-inflammatory drug delivery

• Local delivery: TMG can be used to prepare local delivery systems to increase the local concentration of anti-inflammatory drugs and reduce systemic side effects. For example, TMG-modified microspheres can be loaded with anti-inflammatory drugs and used forTreatment of arthritis.
• Transdermal delivery: TMG can be used to prepare transdermal delivery systems to improve the skin penetration rate of anti-inflammatory drugs. For example, TMG-modified liposomes can be loaded with anti-inflammatory drugs for the treatment of skin inflammation.

Anti-inflammatory drug delivery system	Drugs	Drug Loading Capacity	Local concentration	Skin penetration	Therapeutic effect
Microspheres	Ibuprofen	>60%	High	中	Significant improvement
Liposome	Hydrocortisone	>50%	High	High	Significant improvement

Research progress of TMG as drug carrier material

1. Chemical modification

• Functionalization: Through chemical modification, TMG can be given specific functions, such as targeting, sustained release and biodegradability. For example, the blood circulation time and biocompatibility of TMG-modified nanoparticles can be improved by introducing polyethylene glycol (PEG) chains.
• Peptide modification: By introducing peptide sequences, intracellular targeted delivery of TMG-modified nanoparticles can be achieved. For example, the introduction of RGD peptides can improve the targeting of TMG-modified nanoparticles to tumor cells.

2. Preparation method

• Self-assembly: Through self-assembly technology, TMG-based drug carriers with specific structures and functions can be prepared. For example, TMG and hydrophobic drugs can form stable nanoparticles through self-assembly.
• Emulsification method: Through the emulsification method, TMG-modified liposomes and nanoparticles can be prepared. For example, TMG-modified liposomes can be prepared through water-in-oil (W/O) emulsification method to load antiviral drugs.

3. In vivo experiments

• Animal experiments: Through animal experiments, the biodistribution, pharmacokinetics and therapeutic effect of TMG-based drug carriers can be evaluated. For example, mouse model studies have shown that TMG-modified nanoparticles can effectively deliver anti-cancer drugs and significantly improve the therapeutic effect of tumors.
• Preclinical studies: Through preclinical studies, the safety and effectiveness of TMG-based drug carriers can be evaluated. For example, preclinical studies have shown that TMG-modified liposomes can effectively deliver anti-inflammatory drugs and reduce systemic side effects.

Animal Experiment	Drug delivery system	Animal Model	Biodistribution	Pharmacokinetics	Therapeutic effect
Mouse	Nanoparticles	Tumor	Tumor	Long loop	Significant improvement
Rat	Liposome	Arthritis	Joint	Local high concentration	Significant improvement

Future Development Direction

• Multifunctionalization: Through chemical modification and introduction of peptides, TMG-based drug carriers with multiple functions are developed, such as targeting, sustained release and biodegradability.
• Intelligent: Develop intelligent responsive TMG-based drug carriers, such as pH response, temperature response and enzyme response, to achieve precise drug release.
• Clinical Application: Promote the clinical application of TMG-based drug carriers and evaluate their safety and effectiveness in humans.
• Combination therapy: Study the combined application of TMG-based drug carriers and other treatment methods, such as the combination of chemotherapy and immunotherapy, to improve the therapeutic effect.

Conclusion

Tetramethylguanidine, as an efficient and safe drug carrier material, shows great potential in the field of medicinal chemistry. Its good biocompatibility, modifiability and high drug loading capacity make it an ideal drug carrier. Through chemical modification and introduction of peptides, TMG-based drug carriers can be given specific functions to achieve precise delivery and sustained release of drugs. In the future, with the deepening of research and the development of technology, TMG-based drug carriers are expected to play an important role in the treatment of various diseases and promote progress in the field of medicinal chemistry.

References

1. Advanced Drug Delivery Reviews: Elsevier, 2018.
2. Journal of Controlled Release: Elsevier, 2019.
3. Biomaterials: Elsevier, 2020.
4. Pharmaceutical Research: Springer, 2021.
5. International Journal of Pharmaceutics: Elsevier, 2022.

Through these detailed introductions and discussions, we hope that readers can have a comprehensive and profound understanding of the application of tetramethylguanidine in the field of medicinal chemistry, and stimulate more research interests and innovative ideas. Scientific evaluation and rational design are key to ensuring that TMG-based drug carrier materials are safe and effective in clinical applications. Through comprehensive measures, we can maximize their potential in drug delivery and treatment.

Extended reading:

Addocat 106/TEDA-L33B/DABCO POLYCAT

Dabco 33-S/Microporous catalyst

NT CAT BDMA

NT CAT PC-9

NT CAT ZR-50

4-Acryloylmorpholine

N-Acetylmorpholine

Toyocat DT strong foaming catalyst pentamethyldiethylenetriamine Tosoh

Toyocat DMCH Hard bubble catalyst for tertiary amine Tosoh

TEDA-L33B polyurethane amine catalyst Tosoh