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Formulation and Delivery - Biomolecular

(W1130-07-43) Urolithin-A Laden Nanoparticles Attenuate Cisplatin-Induced Systemic Toxicity: A Comparative Study in Aged and Young Mice

Wednesday, November 12, 2025
11:30 AM - 12:30 PM CT
Purpose: Cisplatin remains a mainstay in cancer treatment since its approval by the FDA in 1978; however, its use is limited by multiple off-target toxicities [1]. These toxicities are both dose and age-dependent, with older patients being particularly vulnerable due to increased oxidative stress, inflammation, and impaired tissue repair capacity in the aging population[2]. While preclinical studies often use younger mice (6-12 weeks) to study cisplatin toxicities, age-related differences in drug metabolism and inflammation may increase susceptibility to cisplatin-induced liver injury, yet this area remains poorly explored, complicating treatment optimization. Urolithin-A (UA), a gut metabolite of dietary ellagic acid, offers anti-inflammatory and antioxidant benefits, but its clinical use is limited by poor oral bioavailability[3]. To address this, we formulated UA in a biodegradable polymer conjugated with the ligand gambogic acid (GA), which non-competitively binds with gut-expressed transferrin receptors. We have shown that this formulation enhanced UA’s oral bioavailability by 7-fold and reduced cisplatin-induced acute kidney injury mortality in mice by 63%[4]. Leveraging these findings, we explored the systemic protective effects of P2Ns-GA-UA against cisplatin-induced injury and assessed age-related variations in therapeutic efficacy between old and young mouse models.

Methods: UA formulations (nUA) were prepared using an oil-in-water emulsification method. Old (87-week-old) and young (11-week-old) C57BL/6 female mice (n = 5 per group) were assigned to control (healthy), cisplatin only (C), C+P2Ns-UA (no ligand), and C+P2Ns-GA-UA (ligand) groups. Single intraperitoneal injection of cisplatin (20 mg/kg) was administered to induce toxicity. P2Ns-UA and P2Ns-GA-UA were administered orally (50 mg/kg) over 7 days (as shown in Figure 1A). At study completion, mice were euthanized, and tissues were harvested. We performed biochemical and molecular analysis to assess hepatotoxicity and P2Ns-GA-UA efficacy to compare age-related susceptibility to cisplatin liver injury and evaluated the extent of protection conferred by UA treatment (nUA) in both old and young mice.

Results: nUA exhibited favorable characterization, with optimal particle size, zeta potential and spherical morphology confirmed by SEM images (Figure 1B). P2Ns-GA-UA significantly reduced cisplatin-induced hepatotoxicity in both old and young mice, though older mice showed greater susceptibility. Gross liver examination showed severe hepatic lesions, discoloration, and texture changes in cisplatin-treated older mice, compared to mild changes in young mice (Figure 2A). Hepatic enzyme levels (amylase, GGT, and ALP) were significantly elevated in the cisplatin only group, with older mice showing nearly double the levels observed in young mice (Figure 2B). Pre-euthanasia images showed physical deterioration and roughened coats in older cisplatin-treated mice as compared to young cisplatin-treated mice (Figure 2C), and survival analysis further revealed 50% mortality in this group, whereas all young mice survived in all experimental groups (Figure 2B(ii)). qPCR analysis of liver homogenates showed elevated inflammatory markers (IL-6, IL-18, NLRP3) in older mice, with levels two-fold higher than in young mice, confirming heightened inflammatory responses (Figure 3A&B). While P2Ns-UA (no ligand) confer some protection against cisplatin-induced toxicities, P2Ns-GA-UA (ligand) exhibits superior efficacy with improved survival, attenuated liver injury, suppressed inflammatory cytokine expressions, and improved liver function in both old and young mice altogether. These findings collectively highlight that older mice are more prone to cisplatin-induced hepatotoxicity, but P2Ns-GA-UA confers wide hepatoprotective effects across ages.

Conclusion: Taken together, our findings suggest that older mice are more susceptible to cisplatin-induced systemic toxicities as evidenced in heightened inflammation, severe liver damage, and a 50% mortality rate in cisplatin cisplatin-only group. However, our novel P2Ns-GA-UA significantly reduced cisplatin-induced hepatotoxicity in both old and young mice, demonstrating its robust multitarget protective effects against cisplatin-induced systemic toxicities. This highlights the critical need for age-specific strategies in optimizing cisplatin-based cancer treatments.

References: [1] D. Wang, S.J. Lippard, Cellular processing of platinum anticancer drugs, Nat Rev Drug Discov 4(4) (2005) 307-20.
[2] A. Schwandt, P.J. Harris, S. Hunsberger, A. Deleporte, G.L. Smith, D. Vulih, B.D. Anderson, S.P. Ivy, The role of age on dose-limiting toxicities in phase I dose-escalation trials, Clin Cancer Res 20(18) (2014) 4768-75.
[3] C.E. Iglesias-Aguirre, R. García-Villalba, D. Beltrán, M.D. Frutos-Lisón, J.C. Espín, F.A. Tomás-Barberán, M.V. Selma, Gut bacteria involved in ellagic acid metabolism to yield human urolithin metabotypes revealed, J Agric Food Chem 71(9) (2023) 4029-4035.
[4] D. Zou, R. Ganugula, M. Arora, M.B. Nabity, D. Sheikh-Hamad, M. Kumar, Oral delivery of nanoparticle urolithin A normalizes cellular stress and improves survival in mouse model of cisplatin-induced AKI, Am J Physiol Renal Physiol 317(5) (2019) F1255-f1264.

Acknowledgements: This study is supported by the National Institutes of Health Grant No. R01DK128597


Figure 1: A: Schematic representation of study protocol. B: (i) Tabulated particle size and zeta potential of formulations (n=3); SEM images of nanoformulation (nUA) (ii) P2Ns-UA and (iii) P2Ns-GA-UA. Scale bar =2um


Figure 2: Effect of Oral UA laden Nanoparticles on Cisplatin-induced Liver Injury. A: Gross morphology of liver architecture in old and young mice across experimental groups, showing visible differences in liver color and surface lesions; B: Liver enzyme activity (Amylase, GGT and ALP) in liver homogenates from both old and young mice; C: (i) Representative whole body images of old and young mice captured before euthanasia, showing physical differences including posture and grooming, (ii) Percentage survival plot of old mice across different experimental groups. One-way ANOVA was used for statistical analysis (*p < 0.05, **p < 0.01, ***p < 0.0001 for comparison with the cisplatin group). All values are presented as mean ± SEM.


Figure 3: Effect of UA laden Nanoparticles on Cisplatin-induced Liver Injury in Old and Young Mice. A: Gene expression levels of IL-6, IL-18, and NLRP3 in liver homogenates of old mice across experimental groups; B: Gene expression levels of IL-6, IL-18, and NLRP3 in liver tissues of young mice across experimental groups. Expression levels were normalized to β-actin. One-way ANOVA was used for statistical analysis (*p < 0.05, **p < 0.01, ***p < 0.0001 compared with the cisplatin group). All data are presented as mean ± SEM.