Development and evaluation of novel miltefosine-polyphenol co-loaded second generation nano-transfersomes for the topical treatment of cutaneous leishmaniasis

ABSTRACT

Objective: To test the hypothesis that miltefosine (MTF)-polyphenol co-loaded second-generation nano-transfersomes (SGNTs) can be an effective approach for the topical treatment of cutaneous leishmaniasis (CL).

Methods: The co-loaded SGNTs with various MTF-polyphenol combinations were developed, evaluated and compared for the entrapment efficiency, vesicle size, deformability index, ex-vivo permeation, cytotoxicity, and anti-leishmanial potential, using both in-vitro and in-vivo models.

Results: The co-loaded SGNTs were spherical in shape, with an average size of 119 ± 1.5 nm and a high entrapment efficiency of 73.7 ± 3.7%. The ex-vivo study displayed a 3.2-fold higher permeation of MTF when entrapped in co-loaded SGNTs, whereas cytotoxicity potential of co-loaded SGNTs was 43.2% higher than the MTF solution. A synergistic interaction was observed between MTF and apigenin (APG) among all polyphenols and an 8.0-fold lower IC₅₀ was found against amastigotes of DsRed Leishmania mexicana, compared with the plain MTF solution. Moreover, the in-vivo studies displayed a 9.5-fold reduced parasitic burden in the L. mexicana infected BALB/c mice treated with MTF-APG co-loaded SGNTs gel.

Conclusions: The potential of MTF-APG co-loaded SGNTs topical formulation is established for the first time as an effective drug delivery strategy against CL.

KEYWORDS:

• Miltefosine
• apigenin
• co-loaded second generation nano-transfersomes
• topical therapy
• macrophage targeting
• cutaneous leishmaniasis

Author contributions

Abhay R.Satoskar; Involved in the conception and design. M.Junaid Dar; Analysis and interpretation of the data. Muhammad Ijaz Khan; Drafting of the paper. Craig A.McElroy; Analysis and interpretation of LC-MS/MS data and revising the paper critically for intellectual content. Gul Majid Khan; Final approval of the version to be published. All authors agree to be accountable for all aspects of the work.

Acknowledgments

The authors are thankful to Dr. Sidra Khalid, Department of Pharmacy, Quaid-i-Azam University, Islamabad for her support during the writing of manuscript. The authors are obliged to Higher Education Commission (HEC) of Pakistan for fellowship support under the Indigenous Ph.D. Fellowship Program.

Declaration of interest

MJ Dar has a fellowship under the Indigenous Ph.D. Fellowship Program from Higher Education Commission of Pakistan (HEC), Islamabad, Pakistan. GM Khan discloses the research grant, titled; ‘Prototype and scale-up level formulation and evaluation of nanoparticles decorated transfersomes based transdermal dosage forms for the treatment of cutaneous leishmaniasis’. Project No: 6171/Federal/NRPU/R&D/HEC/2016: 04-04-2017 and ‘Design of Thiolated Polymer Coated Niosomes Gel: Promising Platform for Controlled and Targeted Drug Delivery in Leishmaniasis.’ Project No. 20-2795/R & D/HEC/14 dated: 20-6-2016 from Higher Education Commission of Pakistan (HEC), Islamabad, Pakistan. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Supplementary material

Supplemental data for this article can be accessed here.

Additional information

Funding

This paper was funded by the Higher Education Commission of Pakistan (HEC), Islamabad, Pakistan.