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<p>Breast cancer therapy is often hindered by non-specific drug distribution, minimal tumor accumulation, and systemic toxicity. Gefitinib, an epidermal growth factor receptor (EGFR) and tyrosine kinase inhibitor, has shown efficacy in treating EGFR-expressing breast cancers. But, its clinical use is restricted owing to inadequate solubility and lower bioavailability, alongside off-target effects. In this study, a pH-responsive lipid conjugate, folic acid (FA)-adipic dihydrazide (ADH)-glycerine monostearate (GMS), was formulated and integrated into gefitinib-incorporated solid lipid nanoparticles (SLNs) to improve lipid compatibility, facilitate receptor-mediated uptake, and enable controlled drug release. GMS has been carefully oxidized using the 2,2,6,6-Tetramethylpiperidine-1-oxyl (TEMPO) process, which led to 81% oxidation. FT-IR analysis confirmed an aldehyde carbonyl stretch at 1714 cm<sup>-1</sup> and a positive 2,4-dinitrophenylhydrazine (2,4-DNPH) test. FA was conjugated to ADH via EDCI/HOBt coupling, as evidenced by amide I and II bands at 1653 and 1515 cm⁻¹. FA-ADH and GMS formed hydrazone bonds, evidenced by C=N stretching at 1635.46 cm<sup>-1</sup> and the disappearance of aldehydic signals at 1700-1725 cm<sup>-1</sup> in FTIR. The <sup>1</sup>H NMR analysis confirmed conjugation by revealing the depletion of aldehydic protons at 9.5 ppm alongside the appearance of hydrazone resonances at 8.4-8.8 ppm. LC-MS revealed a molecular ion peak of 95% purity at m/z 954.05. The fabricated SLNs exhibited pH-dependent drug release, with acidic conditions resulting in higher drug release, reaching 87.5% at pH 5.0 compared to 65% at pH 7.4 after 48 h. The release kinetics were in accordance with the Korsmeyer-Peppas model, implying a non-Fickian transport mechanism dependent on diffusion and matrix relaxation.</p> Graphical abstract <p></p>

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Synthesis and molecular characterization of a novel FA-ADH-GMS conjugated pH-responsive lipid for targeted drug delivery

  • 期刊论文

  • 发表日期：

    2026年4月26日

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  • Sai Ramya Bodagala,
  • Prasanthi Samathoti

摘要

Breast cancer therapy is often hindered by non-specific drug distribution, minimal tumor accumulation, and systemic toxicity. Gefitinib, an epidermal growth factor receptor (EGFR) and tyrosine kinase inhibitor, has shown efficacy in treating EGFR-expressing breast cancers. But, its clinical use is restricted owing to inadequate solubility and lower bioavailability, alongside off-target effects. In this study, a pH-responsive lipid conjugate, folic acid (FA)-adipic dihydrazide (ADH)-glycerine monostearate (GMS), was formulated and integrated into gefitinib-incorporated solid lipid nanoparticles (SLNs) to improve lipid compatibility, facilitate receptor-mediated uptake, and enable controlled drug release. GMS has been carefully oxidized using the 2,2,6,6-Tetramethylpiperidine-1-oxyl (TEMPO) process, which led to 81% oxidation. FT-IR analysis confirmed an aldehyde carbonyl stretch at 1714 cm-1 and a positive 2,4-dinitrophenylhydrazine (2,4-DNPH) test. FA was conjugated to ADH via EDCI/HOBt coupling, as evidenced by amide I and II bands at 1653 and 1515 cm⁻¹. FA-ADH and GMS formed hydrazone bonds, evidenced by C=N stretching at 1635.46 cm-1 and the disappearance of aldehydic signals at 1700-1725 cm-1 in FTIR. The 1H NMR analysis confirmed conjugation by revealing the depletion of aldehydic protons at 9.5 ppm alongside the appearance of hydrazone resonances at 8.4-8.8 ppm. LC-MS revealed a molecular ion peak of 95% purity at m/z 954.05. The fabricated SLNs exhibited pH-dependent drug release, with acidic conditions resulting in higher drug release, reaching 87.5% at pH 5.0 compared to 65% at pH 7.4 after 48 h. The release kinetics were in accordance with the Korsmeyer-Peppas model, implying a non-Fickian transport mechanism dependent on diffusion and matrix relaxation.

Graphical abstract