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Purpose <p>Cutaneous leishmaniasis (CL) often arises as a major neglected tropical disease leading to scars, lesions, and mental agony in the patients. Ursolic acid (UA), a pentacyclic triterpene, is fatal to the <i>Leishmania</i> species. However, UA is associated with several physicochemical limitations, including inadequate water solubility (&lt; 5.64-µg/mL), impaired permeability, hindered oral bioavailability (&lt; 3%), and higher first-pass metabolism. Therefore, in the present investigation, a laboratory-scale up of ursolic acid emulgel (UA emulgel) was carried out to augment drug delivery in <i>L. donovani</i>, the causative agent of CL.</p> Methods and Results <p>Ursolic acid nanoemulsion (UA nanoemulsion) post optimization under BBD (Box-Behnken design) illustrated a monodisperse globule-size of 24.31 ± 0.28-nm along with PDI (Polydispersity index) of 0.106 ± 0.015 and a zeta potential of -0.11 ± 0.34-mV. Next, the UA emulgel depicted exemplary textural and rheological properties comparable to those of the commercial emulgel. Additionally, the UA emulgel exhibited a 2.28-fold pronounced increase in drug release after 24&#xa0;h (85.63 ± 5.97%) as compared to UA suspension (37.45 ± 6.46%) with a significant difference (<i>p</i> &lt; 0.005). Lastly, the UA emulgel showed an IC<sub>50</sub> value of 0.02123 ± 0.000079-µg/mL against <i>L. donovani</i> promastigote infiltrated J774A cells, which was substantially lower than paromomycin (12.7 ± 0.12-µg/mL) and UA (21.99 ± 0.3-µg/mL) with a significant difference (<i>P</i> &lt; 0.0001). Molecular docking of UA displayed binding affinity for PTR1 (Pteridine reductase 1). PTR1 enzyme is an NADPH-dependent short-chain reductase accountable for the salvage of pterins in the protozoan parasite, <i>Leishmania.</i></p> Conclusion <p>UA emulgel with pronounced and extended drug release depicted excellent in-vitro leishmanicidal activity against <i>L. donovani</i> compared to paromomycin. In addition, UA emulgel exhibited a better safety profile when compared to standard paromomycin. These findings suggest that UA emulgel must be further tested in a preclinical model of CL under a set of robust parameters for translational research.</p>

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Ursolic Acid Emulgel Augmented Drug Delivery in Leishmania Donovani, A Causative Agent for Cutaneous Leishmaniasis: In Vitro Characterization and Anti-Amastigote Activity

  • 期刊论文

  • 发表日期：

    2025年10月17日

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  • Spandana Gollapalli,
  • Soyal Sayyed,
  • Soham Loharkar,
  • Atul Mourya,
  • Gopal Bajad,
  • Shristi Arya,
  • Dinesh Kumar Chandanapalli,
  • Pankaj Kumar Singh,
  • Jitender Madan

摘要

Purpose

Cutaneous leishmaniasis (CL) often arises as a major neglected tropical disease leading to scars, lesions, and mental agony in the patients. Ursolic acid (UA), a pentacyclic triterpene, is fatal to the Leishmania species. However, UA is associated with several physicochemical limitations, including inadequate water solubility (< 5.64-µg/mL), impaired permeability, hindered oral bioavailability (< 3%), and higher first-pass metabolism. Therefore, in the present investigation, a laboratory-scale up of ursolic acid emulgel (UA emulgel) was carried out to augment drug delivery in L. donovani, the causative agent of CL.

Methods and Results

Ursolic acid nanoemulsion (UA nanoemulsion) post optimization under BBD (Box-Behnken design) illustrated a monodisperse globule-size of 24.31 ± 0.28-nm along with PDI (Polydispersity index) of 0.106 ± 0.015 and a zeta potential of -0.11 ± 0.34-mV. Next, the UA emulgel depicted exemplary textural and rheological properties comparable to those of the commercial emulgel. Additionally, the UA emulgel exhibited a 2.28-fold pronounced increase in drug release after 24 h (85.63 ± 5.97%) as compared to UA suspension (37.45 ± 6.46%) with a significant difference (p < 0.005). Lastly, the UA emulgel showed an IC50 value of 0.02123 ± 0.000079-µg/mL against L. donovani promastigote infiltrated J774A cells, which was substantially lower than paromomycin (12.7 ± 0.12-µg/mL) and UA (21.99 ± 0.3-µg/mL) with a significant difference (P < 0.0001). Molecular docking of UA displayed binding affinity for PTR1 (Pteridine reductase 1). PTR1 enzyme is an NADPH-dependent short-chain reductase accountable for the salvage of pterins in the protozoan parasite, Leishmania.

Conclusion

UA emulgel with pronounced and extended drug release depicted excellent in-vitro leishmanicidal activity against L. donovani compared to paromomycin. In addition, UA emulgel exhibited a better safety profile when compared to standard paromomycin. These findings suggest that UA emulgel must be further tested in a preclinical model of CL under a set of robust parameters for translational research.