t-Boc-Aminooxy-PEG3-Acid is a bifunctional molecule that combines the protective t-Boc (tert-butyloxycarbonyl) group, an aminooxy moiety, and a triethylene glycol (PEG3) linker. The t-Boc group serves as a protecting group for the aminooxy functionality, preventing premature reactions during the synthesis and handling of the compound. Upon removal of the t-Boc group under mild acidic conditions, the aminooxy group becomes highly reactive, facilitating the formation of oxime linkages with carbonyl-containing compounds. This reaction is particularly valuable in bioconjugation processes, enabling the stable attachment of drugs, targeting ligands, or other bioactive molecules to carrier systems such as liposomes, polymers, or nanoparticles. The incorporation of a PEG3 linker in t-Boc-Aminooxy-PEG3-Acid further enhances its utility in drug delivery applications. Polyethylene glycol (PEG) is well-known for its biocompatibility and ability to improve the solubility and stability of conjugated molecules. The PEG3 spacer provides sufficient flexibility and distance between the drug and carrier, reducing steric hindrance and potential interference with biological interactions. This property is crucial for maintaining the bioactivity of conjugated drugs and ensuring efficient delivery to target sites. Additionally, the PEGylation can reduce immunogenicity and prolong the circulation time of drug conjugates, thereby enhancing their therapeutic efficacy. In summary, t-Boc-Aminooxy-PEG3-Acid represents a versatile and effective tool in the realm of drug delivery. Its unique combination of a protective t-Boc group, reactive aminooxy functionality, and biocompatible PEG3 linker allows for precise and stable conjugation of therapeutic agents to various delivery systems. By leveraging these properties, researchers can develop advanced drug delivery platforms that offer improved targeting, stability, and therapeutic outcomes.
Figure 1. Monodispersed Linear PEGs. (Kazushi Kinbara, et al. 2018)
The versatility of t-Boc-Aminooxy-PEG3-Acid in drug delivery systems stems from its pivotal role in bioconjugation chemistry. Bioconjugation involves the covalent bonding of biomolecules to various carriers or other biomolecules, facilitating targeted delivery and controlled release of therapeutics. The aminooxy group in t-Boc-Aminooxy-PEG3-Acid is particularly suited for this purpose due to its ability to form stable oxime bonds with aldehyde or ketone groups, a reaction known as oxime ligation. This bio-orthogonal reaction is highly specific and occurs under mild conditions, making it ideal for linking sensitive biological molecules without compromising their function. In practical applications, t-Boc-Aminooxy-PEG3-Acid can be employed to conjugate drugs to targeting ligands, such as antibodies or peptides, that recognize and bind to specific cell surface receptors. This targeted approach enhances the accumulation of therapeutic agents at the desired site, minimizing off-target effects and reducing systemic toxicity. For example, in cancer therapy, drugs conjugated to tumor-specific antibodies via t-Boc-Aminooxy-PEG3-Acid can achieve higher concentrations in tumor tissues compared to non-targeted therapies, thereby improving therapeutic outcomes and reducing side effects. Moreover, the PEG3 linker plays a crucial role in optimizing the pharmacokinetics of the conjugated drugs. The hydrophilic nature of PEG increases the solubility of hydrophobic drugs, facilitating their formulation in aqueous environments and improving their bioavailability. The length of the PEG3 spacer also helps in reducing steric hindrance, allowing the conjugated drug to interact more effectively with its biological target. Additionally, PEGylation can shield the drug conjugate from recognition and clearance by the immune system, thereby extending its half-life in the bloodstream and enhancing its therapeutic efficacy.
The unique properties of t-Boc-Aminooxy-PEG3-Acid have led to its application in a variety of drug delivery systems, each designed to address specific therapeutic challenges. One notable application is in the development of antibody-drug conjugates (ADCs). ADCs combine the high specificity of antibodies for target antigens with the potent cytotoxicity of small-molecule drugs. By linking the drug to the antibody via t-Boc-Aminooxy-PEG3-Acid, researchers can ensure a stable and controlled release of the drug at the target site, maximizing its therapeutic effect while minimizing systemic exposure and toxicity. In addition to ADCs, t-Boc-Aminooxy-PEG3-Acid is also used in the design of polymer-drug conjugates. These systems utilize biocompatible polymers as carriers for drugs, providing a controlled release mechanism and improving the pharmacokinetic profile of the drug. The aminooxy group of t-Boc-Aminooxy-PEG3-Acid allows for the efficient conjugation of drugs to the polymer backbone via oxime ligation, creating stable and effective drug delivery vehicles. These polymer-drug conjugates can be tailored to release the drug in response to specific physiological conditions, such as pH or enzymatic activity, ensuring that the drug is released at the desired site of action. Liposomes represent another promising application of t-Boc-Aminooxy-PEG3-Acid in drug delivery. Liposomes are spherical vesicles composed of lipid bilayers that can encapsulate both hydrophilic and hydrophobic drugs. By functionalizing the surface of liposomes with t-Boc-Aminooxy-PEG3-Acid, researchers can attach targeting ligands or other functional molecules, enhancing the specificity and efficacy of the liposomal drug delivery system. The PEG3 linker helps in reducing the opsonization and clearance of liposomes by the mononuclear phagocyte system, thereby prolonging their circulation time and improving the bioavailability of the encapsulated drug.
Alternate Names:
t-Boc-Aminooxy-PEG3-Carboxylic Acid
t-Boc-Aminooxy-PEG3-COOH
Boc-Aminooxy-PEG3-Acid
Boc-Oxyamine-PEG3-Acid
References:
1. Kazushi Kinbara, et al. Monodisperse engineered PEGs for bio-related applications. Polymer Journal. 2018, volume 50, pages689–697.
Application of Monodisperse PEGs in Pharmaceutics: Monodisperse Polidocanols
Mol Pharm
Authors: Yu Z, Bo S, Wang H, Li Y, Yang Z, Huang Y, Jiang ZX.
Abstract
Polydisperse PEGs are ubiquitously used in pharmaceutical industry and biomedical research. However, the monodispersity in PEGs may play a role in the development of safe and effective PEGylated small molecular drugs. Here, to avoid the polydispersity in polidocanol, the active ingredient in a clinically used drug, a macrocyclic sulfate-based strategy for the efficient and scalable synthesis of monodisperse polidocanols, their sulfates, and their methylated derivatives, was developed. TLC and HPLC analysis indicated a complex mixture in regular polidocanol and high purities in monodisperse polidocanols and their derivatives. Assay on HUVEC, L929, and HePG2 cells showed that monodisperse polidocanols have much higher cytotoxicity and safety than that of regular polidocanol. It was found that the monodispersity of PEGs in polidocanols is crucial for achieving the optimal therapeutic results. Therefore, based on this case study, it would be beneficial to optimize PEGylated small molecular drugs with monodisperse PEGs in pharmaceutical research and development.
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