Azido-PEG24-NHS ester compound integrates the azido group, a functional moiety known for its biorthogonal click chemistry applications, with PEG (polyethylene glycol), a polymer widely recognized for improving drug solubility and stability. The NHS ester group, or N-hydroxysuccinimide ester, is highly reactive towards amine groups, making it an excellent candidate for conjugation with drugs, peptides, or proteins. This unique combination facilitates the creation of sophisticated drug delivery systems that can target specific cells or tissues, thereby optimizing the therapeutic outcomes while minimizing side effects. One of the primary advantages of using Azido-PEG24-NHS ester in drug delivery is its ability to form stable conjugates with biologically active molecules. The PEG24 spacer provides a substantial hydrophilic chain that enhances the solubility and circulation time of the conjugated drugs in the bloodstream. This prolonged circulation is crucial for maintaining therapeutic concentrations of the drug over extended periods, which is particularly beneficial for treating chronic conditions. Moreover, the azido group allows for subsequent functionalization via click chemistry, enabling the attachment of various targeting ligands, imaging agents, or therapeutic molecules. This modularity and ease of functionalization make Azido-PEG24-NHS ester a powerful tool in the development of multifunctional drug delivery systems. The NHS ester component of Azido-PEG24-NHS ester is particularly noteworthy for its reactivity towards primary amines. This characteristic allows for the straightforward attachment of the compound to a wide range of drugs, peptides, and proteins, forming stable amide bonds. This reactivity not only simplifies the conjugation process but also ensures the stability of the resulting drug conjugate, which is crucial for maintaining the integrity and efficacy of the therapeutic agent throughout its delivery journey. The ability to create such stable linkages is particularly important in the context of targeted drug delivery, where the precision and stability of the drug-carrier complex can significantly impact therapeutic outcomes.
Figure 1. N-terminal biotin-PEG24 modification of peptides. (Dharmatti R, et al. 2019)
In practical applications, Azido-PEG24-NHS ester has shown remarkable potential in enhancing the delivery and efficacy of anticancer drugs, peptides, and proteins. For instance, when conjugated with chemotherapeutic agents, this compound can improve the drugs' selectivity towards cancer cells, thereby reducing the toxicity to healthy tissues. The enhanced permeability and retention (EPR) effect facilitated by the PEG component further aids in the preferential accumulation of the drug in tumor tissues. This effect is particularly valuable in oncology, where maximizing the concentration of the drug in the tumor while minimizing its presence in healthy tissues can lead to more effective treatments with fewer side effects. Beyond oncology, Azido-PEG24-NHS ester is also being explored in the delivery of biologics, such as peptides and proteins. The ability to enhance the stability and solubility of these macromolecules is crucial for their therapeutic efficacy, as many biologics are inherently unstable and prone to degradation in the biological environment. By conjugating these biologics with Azido-PEG24-NHS ester, researchers can improve their pharmacokinetic profiles, increasing their half-life and bioavailability. This improvement can lead to more sustained therapeutic effects and potentially lower dosing frequencies, which can enhance patient compliance and overall treatment outcomes. Moreover, the versatility of the azido group in Azido-PEG24-NHS ester enables the incorporation of imaging probes, which can assist in monitoring the biodistribution and therapeutic response in real-time. This capability is invaluable in both preclinical and clinical settings, as it allows researchers and clinicians to track the delivery and efficacy of the drug in vivo. Real-time tracking can provide critical insights into the pharmacokinetics and pharmacodynamics of the drug, enabling the optimization of dosing regimens and the identification of potential issues early in the treatment process. Such insights can be pivotal in the development of new therapeutics and in the personalization of treatment plans for individual patients.
The application of Azido-PEG24-NHS ester extends beyond drug delivery to include diagnostics and theranostics. In diagnostics, the azido group can be used to attach imaging agents that allow for the visualization of specific biomarkers or pathological conditions. For example, conjugating Azido-PEG24-NHS ester with a fluorescent dye or a radiolabel can enable the detection of tumors, infections, or other disease states with high specificity and sensitivity. In theranostics, the same principles are applied to create multifunctional agents that can simultaneously diagnose and treat diseases. This dual functionality can enhance the precision and effectiveness of medical interventions, offering a more integrated approach to patient care. In the realm of personalized medicine, Azido-PEG24-NHS ester offers promising potential. By enabling the precise targeting and delivery of therapeutic agents, this compound can facilitate the development of treatments tailored to the specific genetic and molecular profiles of individual patients. This precision can enhance the efficacy of treatments and reduce the likelihood of adverse effects, aligning with the goals of personalized medicine to provide more effective and safer therapeutic options. The ability to conjugate a wide range of drugs and biologics with Azido-PEG24-NHS ester, coupled with its modularity and ease of functionalization, makes it a valuable tool in the customization of treatment strategies.
Alternate Names:
Azido-PEG24-N-hydroxysuccinimide ester
Azido-PEG24-activated ester
Azido-PEG24-NHS
Azido-polyethylene glycol 24-NHS ester
References:
1. Dharmatti R, et al. Enhancement of Binding Affinity of Folate to Its Receptor by Peptide Conjugation. Int J Mol Sci. 2019, 20(9):2152.
Efficient synthesis of diverse heterobifunctionalized clickable oligo(ethylene glycol) linkers: potential applications in bioconjugation and targeted drug delivery
Org Biomol Chem
Authors: Goswami LN, Houston ZH, Sarma SJ, Jalisatgi SS, Hawthorne MF.
Abstract
Herein we describe the sequential synthesis of a variety of azide-alkyne click chemistry-compatible heterobifunctional oligo(ethylene glycol) (OEG) linkers for bioconjugation chemistry applications. Synthesis of these bioorthogonal linkers was accomplished through desymmetrization of OEGs by conversion of one of the hydroxyl groups to either an alkyne or azido functionality. The remaining distal hydroxyl group on the OEGs was activated by either a 4-nitrophenyl carbonate or a mesylate (-OMs) group. The -OMs functional group served as a useful precursor to form a variety of heterobifunctionalized OEG linkers containing different highly reactive end groups, e.g., iodo, -NH(2), -SH and maleimido, that were orthogonal to the alkyne or azido functional group. Also, the alkyne- and azide-terminated OEGs are useful for generating larger discrete poly(ethylene glycol) (PEG) linkers (e.g., PEG(16) and PEG(24)) by employing a Cu(I)-catalyzed 1,3-dipolar cycloaddition click reaction. The utility of these clickable heterobifunctional OEGs in bioconjugation chemistry was demonstrated by attachment of the integrin (α(v)β(3)) receptor targeting peptide, cyclo-(Arg-Gly-Asp-D-Phe-Lys) (cRGfKD) and to the fluorescent probe sulfo-rhodamine B. The synthetic methodology presented herein is suitable for the large scale production of several novel heterobifunctionalized OEGs from readily available and inexpensive starting materials.
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