In intelligent drug delivery systems, pH-responsive carriers have garnered significant attention for their ability to achieve precise drug release in different physiological microenvironments (such as tumor tissues, inflamed sites, or the digestive tract). Fmoc-Arg(Pbf)-OH (fluorenylmethoxycarbonyl-arginine-tert-butylfluorobenzenesulfonyl), an arginine-containing amino acid derivative, can be chemically modified to bind with pH-responsive carriers through functional groups in its structure, endowing carriers with unique charge-converting or degradable properties. The design logic in pH-responsive carriers is analyzed below from three aspects: design concepts, action mechanisms, and application advantages.
I. Structural Characteristics of Fmoc-Arg(Pbf)-OH and Basis for pH Responsiveness
1. pH Sensitivity of Key Functional Groups
Guanidino group in arginine side chain: The guanidino group of arginine (Arg) has a pKa of approximately 12.4, remaining protonated and positively charged at physiological pH (7.4). In strongly acidic environments (e.g., tumor microenvironment pH 6.0–6.5, gastric acid environment pH 1–3), it retains positive charge but enables responsive release via cleavage of covalent bonds with the carrier backbone.
Acid sensitivity of protective groups: Pbf (tert-butylfluorobenzenesulfonyl), the protective group for the arginine side chain, is stable under neutral or weakly alkaline conditions but gradually detaches in strongly acidic conditions (e.g., pH < 4), exposing free guanidino groups. This enhances charge changes or hydrophilicity of the carrier, promoting structural disassembly.
2. Binding Modes with Carriers
Covalent conjugation to polymer backbones: The carboxyl group of the Fmoc group reacts with amino or hydroxyl groups of polymers like polylactic-co-glycolic acid (PLGA) or polyethylene glycol (PEG) to form ester or amide bonds, constructing a "drug-Fmoc-Arg(Pbf)-OH-carrier" complex. These covalent bonds are stable at neutral pH but break under acidic conditions due to Pbf protective group detachment and ester bond hydrolysis, releasing the drug.
Assembly into pH-responsive nanoparticles: Fmoc-Arg(Pbf)-OH can co-modify the carrier surface with other pH-sensitive units (such as imine bonds, hydrazone bonds). Through charge changes (e.g., from positive to neutral) or hydrophilic-lipophilic transitions, it achieves disassembly of nanoparticles in acidic environments, accelerating drug release.
II. Design Strategies and Action Mechanisms of pH-Responsive Carriers
1. pH-Responsive Release Based on Charge Conversion
Tumor microenvironment targeting: The weakly acidic environment of tumor tissues (pH 6.0–6.5) promotes partial detachment of the Pbf protective group in Fmoc-Arg(Pbf)-OH, exposing positively charged guanidino groups. This enhances the binding capacity of carriers to negatively charged receptors on tumor cell surfaces, while the carrier backbone disassembles due to charge repulsion, releasing the drug. For example, when Fmoc-Arg(Pbf)-OH modifies a polylysine (PLL) carrier, guanidine protonation increases at pH 6.5, shifting the carrier from hydrophobic to hydrophilic, with drug release rate 3–5 times higher than at pH 7.4.
Digestive tract-targeted delivery: In oral medications, Fmoc-Arg(Pbf)-OH-modified carriers resist degradation by gastric acid (pH 1–3)—the Pbf protective group remains partially attached, maintaining carrier stability. Upon entering the intestine (pH 6.5–7.5), as pH increases, the Pbf protective group gradually detaches, enhancing carrier charge, binding to intestinal mucosal cells, and releasing the drug to improve oral bioavailability.
2. Carrier Degradation Based on Chemical Bond Cleavage
Introduction of acid-sensitive bonds: Linking Fmoc-Arg(Pbf)-OH to the carrier main chain via imine bonds (pH-sensitive) leads to imine bond hydrolysis under acidic conditions, accompanied by Pbf protective group detachment, prompting rapid carrier degradation through dual actions. For instance, introducing Fmoc-Arg(Pbf)-OH as a linker in PEG-polycaprolactone (PCL) copolymers shows imine bond hydrolysis rate at pH 5.5 is 10 times that at pH 7.4, with drug release exceeding 80% within 24 hours, compared to only 20% under neutral conditions.
III. Application Advantages and Challenges of Fmoc-Arg(Pbf)-OH-Modified Carriers
1. Advantages
Dual response mechanism: The synergistic effect of Pbf protective group acid sensitivity and arginine guanidino charge properties enables carriers to exhibit stepwise responses under different pH gradients, enhancing precision in targeted drug release.
Biocompatibility and degradability: As a natural amino acid, arginine-modified carriers can be gradually metabolized by in vivo enzymes, reducing long-term toxicity risks and suiting long-term drug administration scenarios.
Multifunctional modification: The positive charge of guanidino groups can further bind to nucleic acids (e.g., siRNA) or negatively charged drugs, achieving integrated "carriage-release" via pH response—for example, in constructing gene therapy vectors.
2. Challenges and Improvement Directions
Regulation of pH response thresholds: Current pH responses of Fmoc-Arg(Pbf)-OH are mainly focused on strongly acidic (pH < 4) or weakly acidic (pH 6.0–6.5) environments. Responsiveness to near-neutral inflamed sites (e.g., atherosclerotic plaque pH 6.8–7.2) requires optimization, achievable by introducing other pH-sensitive groups (such as phthalimide) to adjust response thresholds.
In vivo stability and immunogenicity: The Fmoc group as a protective group may trigger mild immune reactions, requiring improvement by shortening modification chain lengths or replacing it with more biocompatible protective groups (e.g., Boc-tert-butoxycarbonyl).
IV. Conclusion
Fmoc-Arg(Pbf)-OH provides a design paradigm of "chemical modification-microenvironment response-precise drug release" for pH-responsive drug delivery systems through its acid-sensitive protective groups and charge-responsive moieties. Its core lies in leveraging the pH-dependent charge changes and chemical bond cleavage properties of arginine derivatives to achieve carrier disassembly and drug release at specific physiological sites, offering new technical pathways for tumor-targeted therapy, oral drug delivery, and other fields. Future efforts should further optimize response thresholds and biocompatibility to advance clinical translation.
