Development and optimization of Soluplus®/Pluronic-based polymeric micelles for bicalutamide delivery: characterization, lyophilization, stability, and cellular studies

Abstract

Polymeric micelles are promising nanocarriers for improving the solubility and therapeutic efficacy of poorly water-soluble drugs. In this study, bicalutamide (BIC)-loaded polymeric micelles were developed and optimized using central composite design (CCD) by varying two formulation factors: the Soluplus® percentage (%) and the Pluronic F127/Pluronic F68 ratio (w/w). The selected formulations exhibited favorable physicochemical properties with particle size (PS) below 100 nm, low polydispersity index (PDI) (≤ 0.066), and high encapsulation efficiencies (EE) (up to 90.6%). Transmission electron microscopy (TEM) confirmed the spherical and monodisperse structure. The micelles exhibited near-neutral zeta potentials. Lyophilization with trehalose did not significantly alter particle size or uniformity. In vitro release studies demonstrated sustained drug release profiles for 72 hours, and in vitro solubility measurements revealed a significant increase (∼161 to 335-fold) compared to free BIC. The formulations also remained colloidally stable upon dilution and were physically stable for up to 6 months at 4°C, 25°C/60% Relative Humidity (RH), and 40°C/75% RH. Cellular uptake studies in the human prostate cancer (PC-3) cell line confirmed effective internalization of the micelles. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays demonstrated a concentration- and time-dependent cytotoxicity. F7 exhibited superior cytotoxicity among the tested formulations, compared to free BIC, while its blank formulation showed no significant toxicity, indicating favorable biocompatibility. These results suggest that the developed polymeric micelle systems have potential as stable and biocompatible delivery systems for BIC, warranting further investigation.

Introduction

Prostate cancer (PCa) is the second most frequently diagnosed malignancy and the fifth leading cause of cancer-related deaths in men worldwide (Sung et al., 2021). PCa arises from the malignant transformation of glandular epithelial cells in the prostate gland and is primarily driven by the proliferative effects of androgens, mainly testosterone and dihydrotestosterone (DHT) (Chen et al., 2009). While early-stage cancer can be effectively treated with surgery, radiation, or careful monitoring, patients with advanced or metastatic disease often require systemic therapy, mainly androgen deprivation therapy (ADT) (Teo et al., 2019). Despite first responses, most patients eventually progress to castration-resistant prostate cancer (CRPC), which is associated with a poor prognosis and necessitates the use of additional pharmacological agents such as antiandrogens, taxanes, or androgen receptor inhibitors (Teo et al., 2019).

Bicalutamide (BIC; Casodex™) is a first-generation non-steroidal antiandrogen commonly used in treating PCa. It works by blocking the binding of testosterone and DHT to androgen receptors, which stops their effects on prostate tissue (Furr, 1996). Its pharmacological activity is primarily attributed to the (R)-enantiomer, which exhibits a long elimination half-life (∼4.2 days) with peak plasma concentrations (Cmax) ranging between 559 and 970 ng/mL within 15-48 hours following oral administration of a 50-70 mg dose (McKillop et al., 1993; Cockshott, 2004). In contrast, the (S)-enantiomer exhibits a shorter half-life (∼19 hours) and a substantially lower Cmax (32-66 ng/mL) within 2 to 5 hours (McKillop et al., 1993; Cockshott, 2004). BIC is often prescribed as monotherapy or in combination with luteinizing hormone-releasing hormone (LHRH) analogs due to its long elimination half-life and favorable tolerability profile. However, its therapeutic potential is restricted by extremely poor aqueous solubility (< 5 µg/mL) and highly variable oral bioavailability (∼44%), leading to inconsistent therapeutic outcomes (Cockshott, 2004; Danquah et al., 2010). Its solubility remains largely independent of pH but increases significantly in organic solvents, emphasizing a marked solubility contrast between aqueous and organic media (Volkova et al., 2022). This difference in solubility highlights the necessity of advanced formulation strategies to enhance BIC’s aqueous solubility and oral bioavailability.

Among various nanocarriers, polymeric micelles are considered to enhance the delivery of poorly water-soluble drugs (Lu and Park, 2013). Polymeric micelles are nanosized core-shell structures formed by the self-assembly of amphiphilic block copolymers above their critical micelle concentration (CMC) (Lu and Park, 2013). These systems, typically ranging from 10 to 100 nm in size, consist of a hydrophobic core that encapsulates poorly soluble drugs and a hydrophilic corona that stabilizes the structure in aqueous environments (Perumal et al., 2022). These features not only improve solubility and stability but also enable passive tumor targeting through the enhanced permeability and retention (EPR) effect (Torchilin, 2007). Most of the amphiphilic polymers used for polymeric micelle formation are generally recognized as safe (GRAS) by regulatory authorities, ensuring their safety and suitability for pharmaceutical use (FDA, 2023). Among various polymers, Soluplus®, a graft copolymer of polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol, and Pluronics (poloxamers), which contain hydrophobic poly(propylene oxide) (PPO) and hydrophilic poly(ethylene oxide) (PEO) blocks, have gained attention for their biocompatibility, low CMC values, and ability to enhance drug solubility and stability (Perumal et al., 2022; Dian et al., 2014; Akbar et al., 2018). Recent studies have further demonstrated that Soluplus®-based micellar systems can significantly improve the solubility, permeability, and anticancer efficacy of hydrophobic drugs (Pereira-Silva et al., 2024; Patel et al., 2025).

Although various nanocarrier systems have been investigated for BIC delivery, most studies have focused on single-polymer micelles, solid dispersions, or lipid-based formulations. However, the advantages of using mixed polymeric micelles, particularly those combining Soluplus® and Pluronic copolymers, have not been thoroughly explored. Mixed polymeric micelles can exhibit synergistic effects compared to single-polymer systems, such as reduced CMC, enhanced thermodynamic stability, improved drug-polymer compatibility, and more sustained drug release profiles (Wu et al., 2020). The combination of Soluplus® and Pluronics provides a balance between strong drug encapsulation by Soluplus® and steric stabilization by the PEG chains of Pluronics, resulting in improved solubilization capacity and colloidal stability.

To the best of the authors’ knowledge, no previous study has systematically optimized Soluplus®/Pluronic mixed micelles for BIC using a central composite design (CCD). Therefore, the purpose of the present study was to design, optimize, and evaluate BIC-loaded mixed polymeric micelles based on Soluplus® and Pluronic copolymers. A Design of Experiments (DoE) approach was employed to investigate formulation parameters systematically, and a CCD was selected to assess the effects of polymer composition on particle size (PS), polydispersity index (PDI), and encapsulation efficiency (EE). Following optimization, selected micelle formulations were lyophilized using trehalose as a cryoprotectant, and the polymeric micelles were comprehensively evaluated for their in vitro performance, including in vitro drug release, physicochemical stability, redispersibility, solubility enhancement, as well as cellular uptake and cytotoxicity. To assess cellular uptake and anticancer activity, PC-3 human prostate cancer cells were used. PC-3 represents an androgen-independent, castration-resistant phenotype while still expressing the androgen receptor, making it a biologically relevant model for evaluating the efficacy of antiandrogen-loaded formulations such as BIC (van Bokhoven et al., 2003).

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Materials

BIC was kindly provided by Onko&Koçsel Pharmaceuticals (Kocaeli, Turkey). Soluplus®, Pluronic F127 and Pluronic F68 were supplied by BASF (Ludwigshafen, Germany). Trehalose dihydrate (Vialose™) was obtained from Ashland (Wilmington, DE, USA). Ethanol (analytical grade), methanol, and acetonitrile (HPLC grade) were purchased from Merck (Darmstadt, Germany). All other reagents and chemicals used were of analytical grade.

Nihal Tugce Ozaksun, Tugce Tayyar, Aysun Ozdemir, Mustafa Ark, Tuba Incecayir, Development and optimization of Soluplus®/Pluronic-based polymeric micelles for bicalutamide delivery: characterization, lyophilization, stability, and cellular studies, European Journal of Pharmaceutical Sciences, 2025, 107395, ISSN 0928-0987, https://doi.org/10.1016/j.ejps.2025.107395.

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