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. 2022 Jul 23;14(8):1536.
doi: 10.3390/pharmaceutics14081536.

Sustainable Release of Propranolol Hydrochloride Laden with Biconjugated-Ufasomes Chitosan Hydrogel Attenuates Cisplatin-Induced Sciatic Nerve Damage in In Vitro/In Vivo Evaluation

Yasmin M Ahmed  1 , Raha Orfali  2 , Doaa S Hamad  3 , Mostafa E Rateb  4 , Hanan O Farouk  3
Affiliations

Sustainable Release of Propranolol Hydrochloride Laden with Biconjugated-Ufasomes Chitosan Hydrogel Attenuates Cisplatin-Induced Sciatic Nerve Damage in In Vitro/In Vivo Evaluation

Yasmin M Ahmed et al. Pharmaceutics. .

Abstract

Peripheral nerve injuries significantly impact patients' quality of life and poor functional recovery. Chitosan-ufasomes (CTS-UFAs) exhibit biomimetic features, making them a viable choice for developing novel transdermal delivery for neural repair. This study aimed to investigate the role of CTS-UFAs loaded with the propranolol HCl (PRO) as a model drug in enhancing sciatica in cisplatin-induced sciatic nerve damage in rats. Hence, PRO-UFAs were primed, embedding either span 20 or 60 together with oleic acid and cholesterol using a thin-film hydration process based on full factorial design (24). The influence of formulation factors on UFAs' physicochemical characteristics and the optimum formulation selection were investigated using Design-Expert® software. Based on the optimal UFA formulation, PRO-CTS-UFAs were constructed and characterized using transmission electron microscopy, stability studies, and ex vivo permeation. In vivo trials on rats with a sciatic nerve injury tested the efficacy of PRO-CTS-UFA and PRO-UFA transdermal hydrogels, PRO solution, compared to normal rats. Additionally, oxidative stress and specific apoptotic biomarkers were assessed, supported by a sciatic nerve histopathological study. PRO-UFAs and PRO-CTS-UFAs disclosed entrapment efficiency of 82.72 ± 2.33% and 85.32 ± 2.65%, a particle size of 317.22 ± 6.43 and 336.12 ± 4.9 nm, ζ potential of -62.06 ± 0.07 and 65.24 ± 0.10 mV, and accumulatively released 70.95 ± 8.14% and 64.03 ± 1.9% PRO within 6 h, respectively. Moreover, PRO-CTS-UFAs significantly restored sciatic nerve structure, inhibited the cisplatin-dependent increase in peripheral myelin 22 gene expression and MDA levels, and further re-established sciatic nerve GSH and CAT content. Furthermore, they elicited MBP re-expression, BCL-2 mild expression, and inhibited TNF-α expression. Briefly, our findings proposed that CTS-UFAs are promising to enhance PRO transdermal delivery to manage sciatic nerve damage.

Keywords: chitosan–ufasomes; cisplatin; propranolol HCl; sciatic nerve; surface modification.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Response surface plot for the effect of oleic acid amount (B), cholesterol amount (C) at the middle levels of the 1st and 4th variables (Span type and sonication time) on (a) EE%, (b) particle size, (c) PDI, (d) zeta potential, and (e) Q6h of the developed UFAs’ dispersions.
Figure 2
Figure 2
Transmission electron photomicrographs of (a) PRO–UFAs and (b) PRO–CTS–UFAs.
Figure 3
Figure 3
Effect of storage on EE%, particle size, and ζ potential of (a) PRO–UFAs and (b) PRO–CTS–UFAs.
Figure 4
Figure 4
Ex vivo permeation study of PRO–CTS–UFAs compared to PRO solution and PRO–UFAs.
Figure 5
Figure 5
Effect of thirty days’ treatment with PRO solution, PRO–UFAs gel, and PRO–CTS–UFAs gel on sciatic nerve catalase activity in cisplatin-induced neuropathy. Values are mean ±  SD (n = 8). Data were analyzed by one-way ANOVA followed by Post Hoc Tukey for multiple comparisons. ANOVA; a Significant difference in comparison with the control group. b Significant difference in comparison with cisplatin positive control group c Significant difference in comparison with PRO–UFAs gel and d Significant difference in comparison with PRO–CTS–UFAs gel at (p < 0.05).
Figure 6
Figure 6
Effect of thirty days of treatment with PRO solution, PRO–UFAs gel, and PRO–CTS–UFAs gel on sciatic nerve GSH (a) and MDA (b) against cisplatin-induced neuropathy. Values are mean ± SD (n = 8). Data were analyzed by one-way ANOVA followed by Post Hoc Tukey for multiple comparisons. ANOVA; a Significant difference in comparison with the control group. b Significant difference in comparison with cisplatin positive control group. c Significant difference in comparison with PRO solution, d significant difference in comparison with PRO–UFAs gel, and e significant difference in comparison with PRO–CTS–UFAs gel at (p < 0.05.).
Figure 7
Figure 7
Effect of thirty days’ treatment with PRO solution, PRO–UFAs gel, and PRO–CTS–UFAs gel on sciatic nerve peripheral myelin 22 gene expression against cisplatin-induced neuropathy. Values are mean ± SD (n = 8). Data were analyzed by one-way ANOVA followed by Post Hoc Tukey for multiple comparisons. ANOVA; a Significant difference in comparison with the control group. b Significant difference in comparison with cisplatin positive control group at (p < 0.05).
Figure 8
Figure 8
Photomicrographs of sciatic nerve of 30-days daily dorsal application administration of PRO solution, PRO–UFAs gel, and PRO–CTS–UFAs gel against cisplatin-induced sciatic nerve injury (H&E; 25x); Top left (a) A normal control rat section showing normal histological structure of myelinated nerve fibers (black arrow); Top middle (b) An cisplatin positive control rat section showing demyelination of nerve fibers with a Wallerian degeneration coupled with significant presence of abundant edema with inflammatory cells infiltration in the surrounding tissue (black arrows); Top right (c) PRO solution group revealed numerous congested blood capillaries coupled with mild inflammation in the nerve sheath (black arrows); Bottom left (d) PRO–UFAs gel section represents demyelination and vacuolated nerve fibers (black arrows), with a numerous mononuclear inflammatory cells infiltration in the perineuronal tissue (black star); Bottom middle (e) PRO–CTS–UFAs gel investigation apparently with normal myelinated nerve fibers in several examined sections coupled with few mildly dilated of endoneurial blood vessels associated with mild inflammation in the perineuronal tissue (black arrow).
Figure 9
Figure 9
Photomicrographs of rat sciatic nerve sections (immunostained; 15×) for BCL-2 associated x showing the effect of 30-day daily dorsal application administration of PRO solution, PRO–UFAs gel, and PRO–CTS–UFAs gel against cisplatin-induced sciatic nerve injury. (1a) A normal control rat section showing normal showing negative expression of BCL-2 associated x; (1b) A cisplatin positive control rat section showing strong positive expression; additionally, both (1c) PRO solution and (1d) PRO–UFAs gel group showing moderate expression BCL-2 associated x; in contrast (1e) PRO–CTS–UFAs gel investigation revealed a mild expression. Furthermore, immunostaining myelin basic protein (MBP) revealed that (2a) MBP normal control group showed normal expression. Meanwhile, marked decreased expression was detected in nerve fibers of cisplatin positive control group (2b). Moderate expression was detected in PRO solution and PRO–UFAs gel (2c,d), while enhanced expression of MBP was observed for the PRO–CTS–UFAs gel treated group (2e). Additionally, TNF α immunostained (3a) normal control group showed an absence of its expression in sciatic nerve fibers; (3b) the cisplatin positive control group reveals a strong positive expression for TNF α in nerve fibers. While (3c,d) moderate expression was detected in PRO solution and PRO–UFAs gel, (3e) limited expression of TNF-α was observed in PRO–CTS–UFAs gel.
Figure 9
Figure 9
Photomicrographs of rat sciatic nerve sections (immunostained; 15×) for BCL-2 associated x showing the effect of 30-day daily dorsal application administration of PRO solution, PRO–UFAs gel, and PRO–CTS–UFAs gel against cisplatin-induced sciatic nerve injury. (1a) A normal control rat section showing normal showing negative expression of BCL-2 associated x; (1b) A cisplatin positive control rat section showing strong positive expression; additionally, both (1c) PRO solution and (1d) PRO–UFAs gel group showing moderate expression BCL-2 associated x; in contrast (1e) PRO–CTS–UFAs gel investigation revealed a mild expression. Furthermore, immunostaining myelin basic protein (MBP) revealed that (2a) MBP normal control group showed normal expression. Meanwhile, marked decreased expression was detected in nerve fibers of cisplatin positive control group (2b). Moderate expression was detected in PRO solution and PRO–UFAs gel (2c,d), while enhanced expression of MBP was observed for the PRO–CTS–UFAs gel treated group (2e). Additionally, TNF α immunostained (3a) normal control group showed an absence of its expression in sciatic nerve fibers; (3b) the cisplatin positive control group reveals a strong positive expression for TNF α in nerve fibers. While (3c,d) moderate expression was detected in PRO solution and PRO–UFAs gel, (3e) limited expression of TNF-α was observed in PRO–CTS–UFAs gel.
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