Bioadhesive Eudragit RL®100 Nanocapsules for Melanoma Therapy: A Repurposing Strategy for Propranolol
Abstract
Background/Objectives: Cutaneous melanoma is a potent neoplasm whose advancement is linked to catecholamine-induced angiogenesis through β-adrenergic receptors. Propranolol (PROP), a non-selective β-blocker, holds potential in oncology, but its systemic side effects restrict its viability. This study aims to nanoencapsulate PROP in Eudragit RL®100 polymeric nanocapsules for topical melanoma treatment.
Methods: Nanocapsules were created through interfacial deposition of preformed polymer and characterized in terms of particle size, zeta potential, pH, drug content, and encapsulation efficiency. In vitro evaluations include release profile, antioxidant activity, bioadhesiveness, hemolysis, cytotoxicity, and antitumor effect on melanoma cells. Additionally, migration assays were conducted.
Results: The nanocapsules displayed an acidic pH, an average size of 151 nm, and a positive zeta potential. An encapsulation efficiency of 81% was achieved, even with the hydrochloride form of the drug. The release profile exhibited sustained release of PROP, showcasing enhanced antioxidant activity in the nanoencapsulated form. The formulations also exhibited significant bioadhesion with mucin and an in vitro hemolysis rate over 50%, attributed to the cationic polymer and surfactants present. Moreover, in the cell viability assays, the NC-PROP formulations significantly reduced melanoma cell viability. In the migration assay, both the nanocapsules with and without the drug significantly inhibited cell migration, supporting the potential therapeutic benefits of these formulations.
Conclusions: The nanoencapsulation of PROP in Eudragit RL®100 presents a viable strategy for topical treatment of cutaneous melanoma, enhancing release duration and reducing systemic effects. The assessments indicated distinct physical properties and substantial therapeutic potential.
Introduction
Melanoma is considered one of the most aggressive types of skin cancer, originating from the uncontrolled proliferation of melanocytes and, if not detected early, can metastasize, drastically worsening the prognosis [1]. Metastatic melanoma poses a major clinical challenge, with nearly 50% of patients developing liver metastases [2,3]. This progression severely diminishes survival rates, dropping five-year survival to 15–20% [1,2]. Given its high metastatic potential, therapies that halt or slow tumor progression are urgently needed.
Evidence suggests a strong connection between stress-related catecholamines and tumor growth progression, mediated by β-adrenergic receptors (β-ARs), particularly the β2 subtype [4,5,6]. β-ARs are membrane receptors activated by catecholamines such as epinephrine and norepinephrine, which trigger signaling pathways associated with angiogenesis, including the nitric oxide synthase and the release of proangiogenic factors such as VEGF, PDGF, and SDF-1, contributing to melanoma progression. In solid tumors, pathological angiogenesis sustains the malignant cells nourished and vasculated [7,8,9].
Drug repurposing has emerged as a cost-effective strategy to identify new applications for approved drugs with good safety profiles, making them feasible for rapid implementation in new medical applications [10]. Propranolol (PROP), a non-selective β-blocker initially used for cardiovascular diseases, has been explored in other contexts such as essential tremor, migraines, infantile hemangiomas, wound healing in burn patients, and certain cancers, including melanoma and angiosarcoma [11,12,13,14]. Although its anti-angiogenic mechanism is still unclear, PROP appears to reduce endothelial cell proliferation and migration, inhibit vasodilation, and suppress VEGF and basic fibroblast growth factor (bFGF) expression, contributing to reduced tumor vascularization and growth [15].
Although PROP demonstrates promising pharmacological effects, its systemic use carries risks because of its ability to cross the blood–brain barrier, potentially leading to neurocognitive impacts. Furthermore, this drug can induce respiratory, cardiac and metabolic disturbances, disrupt sleep, alter behavior, and impair memory [13,16,17,18,19]. From a pharmaceutical perspective, propranolol presents multiple formulation challenges. Its high first-pass metabolism leads to low oral bioavailability, and its relatively short half-life demands frequent administration to maintain therapeutic levels [20,21,22,23]. Moreover, its hydrophilic hydrochloride salt form exhibits limited permeation through the stratum corneum when applied topically, making skin delivery particularly difficult [24]. In addition, propranolol is chemically unstable under light exposure due to its photosensitive nature, which can compromise product shelf-life and efficacy [25]. These limitations necessitate the development of innovative delivery systems that can enhance skin penetration, protect the drug from degradation, and promote sustained local release while minimizing systemic exposure.
Topical drug delivery systems offer an alternative that could overcome many of these limitations, particularly for the treatment of cutaneous melanoma. Among the advanced delivery platforms, polymeric nanocapsules (NCs) have shown great potential due to their ability to protect labile drugs, prolong release, and enhance skin penetration [26]. Nanocapsules comprise an oily core surrounded by a polymeric shell, where the drug is usually dispersed, dissolved in, or even adsorbed onto the surface [17]. Eudragit RL®100 is a biocompatible, bioadhesive, and water-insoluble polymer that offers sustained release and improved permeation profiles [27,28]. Encapsulating PROP in Eudragit RL®100 nanocapsules could enhance its physicochemical stability, prevent degradation, extend half-life, and facilitate a controlled release directly at the tumor site.
Furthermore, the cationic character of Eudragit RL®100 enables stronger interaction with the skin surface, which is predominantly anionic under physiological conditions. This electrostatic interaction favors the bioadhesion of the nanocapsules to the stratum corneum, leading to prolonged residence time and enhanced localization of the drug at the application site [29,30]. These bioadhesive formulations are especially advantageous in topical melanoma therapy because they can increase drug retention near the basal layer of the epidermis, where melanocytes reside and malignant transformation initiates. By promoting intimate and prolonged contact with the viable epidermis, bioadhesive nanocapsules may enhance local drug bioavailability, maximize therapeutic efficacy against melanoma cells, and minimize systemic absorption and associated side effects [29,31,32].
Currently, PROP is only available in oral and intravenous forms, which limits its application in localized therapies and increases the likelihood of off-target effects. While topical PROP formulations have been researched, they primarily target infantile hemangiomas and are often hydrophilic, restricting local drug effects [33,34]. This research pioneers the use of Eudragit® nanocapsules for PROP, enabling controlled release directly at the tumor site. To the best of our knowledge, only one previous study has explored Eudragit RS®-based nanoformulations of PROP; however, that study focused on nanobeads rather than nanocapsules, further underscoring the novelty and innovation of our approach [35].
In this context, the present study proposes developing and characterizing propranolol-loaded Eudragit RL®100 nanocapsules for topical application as an innovative therapeutic strategy for cutaneous melanoma. The central objective is to repurpose propranolol by overcoming its pharmacokinetic and physicochemical limitations—such as its short half-life, poor skin permeability, and systemic side effects—through encapsulation in a polymeric nanocarrier. By leveraging the bioadhesive and controlled release properties of Eudragit RL®100 nanocapsules, this formulation aims to enhance local drug retention at the tumor site, prolong drug action, and minimize systemic absorption. Ultimately, this approach seeks to improve the efficacy and safety profile of propranolol for the localized treatment of skin cancer.
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Materials
Propranolol hydrochloride (SM Empreendimentos, São Paulo, Brazil) was donated by Vicofarma (Guarapuava-PR, Brazil). Eudragit RL®100 was kindly donated by Evonik (São Paulo, Brazil). Span® 80 (sorbitan monooleate) and Tween® 80 (polysorbate 80) were purchased from Sigma Aldrich (São Paulo, Brazil). Medium-chain triglycerides (MCT) mixture was supplied by Delaware (Porto Alegre, Brazil). HPLC-grade methanol was acquired from Tedia (Rio de Janeiro, Brazil). All other solvents and reagents were analytical grade and used as received.
Mieres, N.G.; Simião, S.d.O.; Cruz, L.S.; Melo, R.C.d.; Khalil, N.M.; Bonini, J.S.; Rego, F.G.d.M.; Sari, M.H.M.; Pontarolo, R.; Lazo, R.E.L.; et al. Bioadhesive Eudragit RL®100 Nanocapsules for Melanoma Therapy: A Repurposing Strategy for Propranolol. Pharmaceutics 2025, 17, 718. https://doi.org/10.3390/pharmaceutics17060718
Read also our introduction article on Topical Excipients here:
