Utilizing liposomal encapsulation approach to address nephrotoxic challenges of colistimethate sodium through a preclinical study

Raktham Mektrirat; Noppanut Paengjun; Peerawit Chongrattanameteekul; Sonthaya Umsumarng; Suppara Cheunsri; Kornravee Photichai; Kittima Lewchalermvong; Chalutwan Sansamur; Siriporn Okonogi; Wasan Katip

doi:10.3389/fphar.2023.1282464

Utilizing liposomal encapsulation approach to address nephrotoxic challenges of colistimethate sodium through a preclinical study

Front Pharmacol. 2023 Nov 22:14:1282464. doi: 10.3389/fphar.2023.1282464. eCollection 2023.

Authors

Raktham Mektrirat^{1

2

3}, Noppanut Paengjun¹, Peerawit Chongrattanameteekul¹, Sonthaya Umsumarng^{1

2}, Suppara Cheunsri¹, Kornravee Photichai⁴, Kittima Lewchalermvong⁵, Chalutwan Sansamur^{6

7}, Siriporn Okonogi^{3

8}, Wasan Katip^{3

9}

Affiliations

¹ Department of Veterinary Bioscience and Public Health, Faculty of Veterinary Medicine, Chiang Mai University, Chiang Mai, Thailand.
² Research Center for Veterinary Biosciences and Veterinary Public Health, Faculty of Veterinary Medicine, Chiang Mai University, Chiang Mai, Thailand.
³ Center of Excellence in Pharmaceutical Nanotechnology, Faculty of Pharmacy, Chiang Mai University, Chiang Mai, Thailand.
⁴ Center of Veterinary Diagnosis and Technology Transfer, Faculty of Veterinary Medicine, Chiang Mai University, Chiang Mai, Thailand.
⁵ School of Agricultural Technology, King Mongkut's Institute of Technology Ladkrabang, Bangkok, Thailand.
⁶ Akkhraratchakumari Veterinary College, Walailak University, Nakhon Si Thammarat, Thailand.
⁷ Centre for One Health, Walailak University, Nakhon Si Thammarat, Thailand.
⁸ Department of Pharmaceutical Sciences, Faculty of Pharmacy, Chiang Mai University, Chiang Mai, Thailand.
⁹ Department of Pharmaceutical Care, Faculty of Pharmacy, Chiang Mai University, Chiang Mai, Thailand.

Abstract

The use of Colistin, a last-resort antimicrobial drug, carries the risk of acute kidney injury. The objective of the study was to assess the effectiveness of colistin-encapsulated liposomes (CL) in reducing nephrotoxicity. Additionally, a liposomal preparation of colistimethate sodium was formulated using the reverse phase evaporation method with a 3:1 ratio of phospholipids to cholesterol. The liposomal properties were evaluated using scanning electron microscopy, photon correlation spectroscopy, and release kinetic assay. The killing kinetics of the formulations on embryonic kidney cells were assessed using in vitro MTT reduction assay. The nephrotoxicity of CL and colistimethate sodium solution (CS) was evaluated in vivo by administering a dose of 20 mg/kg to rats every 12 h for 3 days, with a negative control group receiving a 0.9% saline solution (NSS). The study results revealed that monodisperses of CL showed a smooth surface and distinct boundaries, with an average size of 151.50 ± 0.46 nm and a narrow size distribution of 0.25 ± 0.01. The liposomal particles showed high entrapment efficiency of 96.45% ± 0.41%, with a ζ-potential of -60.80 ± 1.01 mV and a release rate of 50% of colistimethate sodium within the first 480 min. The CL induced nephrocytotoxicity in a concentration- and time-dependent manner. However, CS had notably lower IC₅₀ values compared to its liposome preparations at 48 and 72 h (p < 0.05). In vivo study results show that serum levels of symmetric dimethylarginine (SDMA) and total white blood cell count (WBC) were significantly lower in the CL group (SDMA = 8.33 ± 1.70 μg/dL; WBC = 7.29 ± 0.99 log₁₀ cells/mL) compared to the CS group (SDMA = 15.00 ± 1.63 μg/dL; WBC = 9.73 ± 0.51 log₁₀ cells/mL). Our study findings enhance the understanding of the safety profile of CL and its potential to improve patient outcomes through the use of liposomal colistin medication. Additional clinical studies are necessary to establish the optimal safety regiment in humans.

Keywords: acute kidney injury; antimicrobial; cytotoxicity; liposome; rat; symmetric dimethylarginine.

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This research project is supported by Thailand Science Research and Innovation (TSRI) with grant number 71689.