L-valine-modified nanoparticles

As an essential amino acid, L-valine, with its hydrophobic side chain (isopropyl group) and polar amino/carboxyl groups, serves as an ideal ligand for modifying the surface of nanoparticles, exhibiting unique application value in drug controlled-release systems. This modification not only improves the biocompatibility of nanoparticles but also enables precise drug delivery and controlled release through mechanisms such as targeted recognition and environmental responsiveness.

I. Enhancing Biocompatibility and Stability of Nanoparticles

L-valine modification significantly improves the biocompatibility of nanoparticles. Its polar groups (-NH₂, -COOH) increase the surface hydrophilicity of nanoparticles, reducing non-specific adsorption with plasma proteins and lowering the probability of rapid clearance by the reticuloendothelial system (e.g., liver, spleen), thereby extending circulation time. Meanwhile, the hydrophobic side chain regulates the surface energy of nanoparticles, preventing aggregation and enhancing their dispersion stability in physiological solutions (e.g., blood, extracellular fluid), laying the foundation for long-acting controlled drug release. For example, after modifying the surface of poly(lactic-co-glycolic acid) (PLGA) nanoparticles with L-valine, their half-life in simulated body fluid can be extended by 2-3 times, and the hemolysis rate of red blood cells is reduced to below 5%, meeting the basic requirements for intravenous administration.

II. Targeted Drug Delivery and Promotion of Cellular Internalization

L-valine-modified nanoparticles can achieve targeted delivery through specific binding to amino acid transporters on cell surfaces (e.g., LAT1, the L-type amino acid transporter 1). Many tumor cells (e.g., liver cancer, breast cancer cells) require large amounts of amino acids for rapid proliferation, and the expression of LAT1 on their cell membranes is significantly higher than that on normal cells. When L-valine on the nanoparticle surface binds to LAT1, the nanoparticles can be preferentially internalized by tumor cells through active transport mechanisms, increasing drug accumulation at the lesion site. For example, doxorubicin-loaded L-valine-modified liposomes show a 3-fold higher targeting efficiency to tumor tissues in a mouse model of lung cancer compared to unmodified liposomes, with significantly reduced toxicity to normal tissues. In addition, this active transport mechanism can enhance the ability of nanoparticles to cross biological barriers, such as the blood-brain barrier (where LAT1 is highly expressed in brain nerve cells), providing a new approach for drug delivery in central nervous system diseases (e.g., glioma).

III. Regulation of Environment-Responsive Controlled Drug Release

The molecular structure of L-valine is sensitive to environmental stimuli such as pH and enzymes, endowing nanoparticles with "intelligent" drug release properties.

pH-responsive release: In the tumor microenvironment (weakly acidic, pH 6.0-6.5) or intracellular lysosomes (pH 4.5-5.0), the amino group of L-valine is protonated, causing changes in the surface charge of nanoparticles, triggering structural disintegration or pore opening, and accelerating drug release. For example, L-valine-modified mesoporous silica nanoparticles have a drug release rate of less than 10% in a neutral environment, while reaching over 80% within 24 hours under pH 5.0 conditions.

Enzyme-responsive release: After nanoparticles enter cells, intracellular peptidases or proteases can hydrolyze the linkages (e.g., peptide bonds) between L-valine and the nanoparticle skeleton, triggering drug release. This enzyme-dependent release can further increase the effective concentration of drugs in target cells and reduce off-target effects.

IV. Combination Therapy and Multifunctional Integration

L-valine-modified nanoparticles can achieve combination therapy through functional integration. For example, co-loading chemotherapeutic drugs and photothermal agents into L-valine-modified nanoparticles allows targeted delivery to tumor sites via L-valine, while photothermal effects under near-infrared irradiation destroy tumor cell structures and promote drug release, achieving synergistic effects of chemotherapy and photothermal therapy. In addition, the presence of L-valine can reduce the toxicity of nanoparticles to immune cells, providing a potential platform for the combination of immunotherapy and targeted chemotherapy.

L-valine-modified nanoparticles exhibit high efficiency and low toxicity in drug controlled-release systems through optimizing biocompatibility, enhancing targeting, and enabling environment-responsive drug release. They have significant innovative value, especially in tumor therapy and cross-barrier drug delivery. Future research can further explore their synergistic modification with other functional ligands to expand therapeutic scenarios for more complex diseases.