pH-Sensitive Dextrin-Based Nanosponges Crosslinked with Pyromellitic Dianhydride and Citric Acid: Swelling, Rheological Behavior, Mucoadhesion, and In Vitro Drug Release

Abstract

Dextrin-based nanosponges (D-NS) are promising candidates for oral drug delivery due to their biocompatibility, mucoadhesive properties, and tunable swelling behavior. In this study, pH-sensitive nanosponges were synthesized using β-cyclodextrin (β-CD), GluciDex®2 (GLU2), and KLEPTOSE® Linecaps (LC) as building blocks, crosslinked with pyromellitic dianhydride (PMDA) and citric acid (CA). The nanosponges were mechanically size-reduced via homogenization and ball milling, and characterized by FTIR, TGA, dynamic light scattering (DLS), and zeta potential measurements. Swelling kinetics, cross-linking density (determined using Flory–Rehner theory), rheological behavior, and mucoadhesion were evaluated under simulated gastric and intestinal conditions. The β-CD:PMDA 1:4 NS was selected for drug studies due to its optimal balance of structural stability, swelling capacity (~863% at pH 6.8), and highest apomorphine (APO) loading (8.23%) with 90.58% encapsulation efficiency. All nanosuspensions showed favorable polydispersity index values (0.11–0.30), homogeneous size distribution, and stable zeta potentials, confirming suspension stability. Storage at 4 °C for six months revealed no changes in physicochemical properties or apomorphine (APO) degradation, indicating protection by the nanosponge matrix. D-NS exhibited tunable swelling, pH-responsive behavior, and mucoadhesive properties, with nanoparticle–mucin interactions quantified by the rheological synergism parameter (∆G′ = 53.45, ∆G″ = −36.26 at pH 6.8). In vitro release studies demonstrated slow, sustained release of APO from D-NS in simulated intestinal fluid compared to free drug diffusion, highlighting the potential of D-NS as pH-responsive, mucoadhesive carriers with controlled drug release and defined nanoparticle–mucin interactions.

Introduction

Neurodegenerative diseases, including Alzheimer’s disease (AD), Parkinson’s disease (PD), multiple sclerosis, amyotrophic lateral sclerosis, and Huntington’s disease, are progressive disorders characterized by the gradual loss of neuronal structure and function. Their global prevalence is rising, largely due to increased life expectancy and the accumulation of biological stressors such as oxidative damage, chronic inflammation, mitochondrial dysfunction, protein aggregation, and environmental factors. Despite advances in therapeutic research, effective long-term management remains challenging, particularly because many neuroprotective and symptomatic agents exhibit poor pharmacokinetic profiles and limited ability to reach the central nervous system [1,2,3,4].

Nanosized drug delivery systems have emerged as promising tools for improving therapeutic efficacy in neurodegenerative disorders [5]. Their small dimensions, tunable surface chemistry, and ability to modulate drug release make them advantageous for crossing biological barriers, including the blood–brain barrier (BBB), and for protecting labile drugs from degradation [6,7]. Among noninvasive strategies, oral delivery remains the most convenient and patient-friendly route, especially for chronic conditions [8,9]. Orally administered drugs must inevitably pass through the stomach before reaching the small intestine or colon, the primary sites of absorption. The gastrointestinal (GI) tract presents formidable physiological, enzymatic, and mechanical barriers, including wide pH variations, digestive enzymes, mucus turnover, peristalsis, and limited epithelial permeability, all of which can compromise drug absorption and stability. Consequently, many drugs suffer from degradation, poor solubility, or limited permeability, resulting in low oral bioavailability [10,11,12,13,14,15,16].

Mucoadhesive drug delivery systems offer an attractive approach to overcome these limitations. By adhering to the mucus layer that lines the GI tract, mucoadhesive polymers prolong the residence time of the formulation at the absorption site, enhance drug stability and bioavailability, and enable sustained release [17,18]. These systems can be engineered to target specific GI regions and can also facilitate transmucosal absorption, thereby bypassing hepatic first-pass metabolism [19,20]. A suitable polymeric material for mucoadhesive formulations should exhibit the following characteristics: (i) the presence of strong anionic or cationic functional groups; (ii) sufficiently high molecular weight; (iii) favorable interfacial properties for mucus penetration; (iv) high polymer chain mobility; (v) high drug-loading capability; (vi) pronounced swelling behavior in aqueous media; (vii) strong interaction with the mucosal layer; (viii) allow prolonged release of therapeutic agents; and (ix) biodegradability [21].

Hydrophilic polymers containing hydroxyl, carboxyl, or amino groups, such as chitosan, pectin, alginate, and cellulose derivatives, are commonly employed due to their capacity to interact with mucin glycoproteins through hydrogen bonding and electrostatic interactions [22]. Nevertheless, many conventional mucoadhesive polymers suffer from limitations related to pH sensitivity, poor mechanical stability, or reduced biodegradability, which may restrict their long-term applicability. As detailed by Twana Mohammed M. Way et al., although chitosan has been extensively explored as a mucoadhesive polymer, its limited solubility and reduced mucoadhesive performance at neutral and basic pH significantly constrain its effectiveness under physiological conditions. Numerous chitosan derivatives such as quaternized, thiolated, carboxymethylated, and cyclodextrin-grafted chitosans have been developed to address these limitations; however, their synthesis often involves complex chemical modifications that raise concerns regarding reproducibility, stability, and scalability, highlighting the need for alternative, more robust mucoadhesive platforms [23]. Also, chitosan, carries a high density of positive charges and may disrupt cell membranes by interacting with the negatively charged bilayer [24]. Myung-Kwan Chun et al. reported that poly(vinyl pyrrolidone) (PVP)–poly(acrylic acid) (PAA) interpolymer complexes exhibit enhanced mucoadhesion and reduced solubility under acidic conditions due to hydrogen bonding, making them suitable for gastric transmucosal drug delivery. However, their performance remains strongly pH-dependent, with limited applicability outside acidic environments, and relies on non-covalent interactions that may be destabilized under physiological conditions. In addition, rapid dissolution or erosion at higher pH and restricted control over long-term drug release limit their broader transmucosal applicability [25]. As mentioned, first-generation mucoadhesive polymers, including cationic chitosan and anionic PAA, rely on non-covalent interactions, making them highly sensitive to pH, ionic strength, and mucus turnover, which limits residence time and drug delivery efficiency. Second-generation systems, such as lectins or thiolated polymers, provide stronger, targeted adhesion via covalent or receptor-mediated interactions; however, many lectins are immunogenic or toxic, and thiomers may offer limited control over drug release due to increased crosslinking and rigidity [26]. To address these challenges, increasing attention has been directed toward polysaccharide-based carriers, particularly dextrin and cyclodextrin derivatives. These starch-based materials are biodegradable, biocompatible, and structurally versatile, enabling precise modulation of physicochemical properties through chemical modification or crosslinking [27].

Cyclodextrins (CDs) are cyclic oligosaccharides composed of α-(1,4)-linked D-glucopyranose units, characterized by a hydrophilic outer surface and a lipophilic internal cavity that enables host–guest inclusion complex formation. Linecaps (LC) and Glucidex® (GLU2) are linear dextrins (maltodextrins) derived from starch hydrolysis, consisting mainly of α-(1,4)-linked glucose units and exhibiting strong hydration, swelling, and intrinsic mucoadhesive behavior. While dextrins provide structural hydration and adhesion, CDs enhance drug solubility and protect labile compounds from oxidative or enzymatic degradation through inclusion complexation. Polymerization of cyclodextrin and dextrin units using multifunctional crosslinking agents yields cyclodextrin-based nanosponges, three-dimensional, crosslinked networks with tunable swelling, pH-responsive behavior, and high drug-loading capacity.

These combined properties make dextrin- and cyclodextrin-based nanosponges particularly suitable for oral drug delivery systems requiring controlled release, enhanced stability, and protection against harsh gastrointestinal conditions [28,29,30,31,32,33,34,35,36]. The pH-responsive behavior of these polymers arises from the presence of ionizable functional groups, such as carboxyl (–COOH) and hydroxyl (–OH) moieties. pH-responsive polymers are considered smart biomaterials, as they can be rationally designed to exhibit site-specific responses to defined pH ranges, enabling controlled drug release through pH-dependent swelling [37]. pH-responsive polymers contain ionizable functional groups, such as –COOH and –OH, which enable site-specific responses to changes in pH through swelling, thereby allowing controlled drug release. Although pH-sensitive hydrogels are widely used in drug delivery and other applications, challenges remain in achieving stable performance across acidic and basic conditions, maintaining mechanical stability during swelling, and ensuring degradation within a desired timeframe [38,39]. Apomorphine (APO), a potent dopamine agonist used in the management of Parkinson’s disease, exemplifies the challenges associated with oral delivery. The molecule is chemically unstable, undergoing rapid oxidative degradation in aqueous media, and shows extreme sensitivity to pH, temperature, and light. Moreover, APO exhibits very low oral bioavailability (<4%) due to extensive hepatic first-pass metabolism, necessitating frequent subcutaneous injections or continuous infusion. These administration strategies are burdensome for patients and may negatively affect compliance, especially in advanced stages of the disease. A mucoadhesive, pH-responsive delivery platform capable of stabilizing APO and sustaining its release through the GI tract could significantly improve therapeutic management [40,41,42].

In this context, as physiological conditions are associated with site-specific pH variations, dextrin-based nanosponges crosslinked using pyromellitic dianhydride (PMDA) and citric acid (CA) offer a promising alternative. Their hydrophilic, multifunctional network, rich in hydroxyl and carboxyl groups, supports strong swelling, water uptake, and mucoadhesion. By modulating the dextrin-to-crosslinker molar ratios, it is possible to finely tune network architecture, cross-linking density, rheological behavior, and pH sensitivity. These properties are essential for designing oral delivery carriers that can withstand gastric conditions while enabling targeted release in the intestinal environment.

This study aims to synthesize and characterize pH-sensitive dextrin-based nanosponges crosslinked with PMDA and CA and to evaluate their swelling behavior, rheological properties, mucoadhesive performance, and in vitro drug release. The goal is to establish a polymeric platform suitable for oral administration of unstable or poorly bioavailable drugs, with particular relevance to therapeutic agents used in neurodegenerative diseases such as PD.

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Materials

β-cyclodextrin (β-CD, Mw = 1134.98 g/mol), GluciDex®2 (GLU2, DE value of 2; Mw = ~200,000 g/mol), and KLEPTOSE® Linecaps (LC, Mw = ~12,000 g/mol) (kindly supplied as a gift by Roquette, Lestrem, France), are used as building blocks, whereas pyromellitic dianhydride (PMDA) and citric acid (CA) as multifunctional cross-linking agents. Anhydrous β-CD, LC, and GLU2 were kept in an oven prior to use. Pyromellitic dianhydride (PMDA, 97.00%); dimethylsulfoxide (DMSO, ≥99.90%); triethylamine (Et3N, ≥99.00%); acetone (C3H6O, ≥99.00% (GC)), sodium hypophosphite monohydrate (NaPO2H2*H2O, ≥99.00%), hydrochloric acid (HCl, 37.00%); sodium hydroxide (NaOH, pellets); mucin (from porcine stomach), chitosan (low molecular weight), sodium chloride (NaCl, ACS, ISO, Reag. Ph Eur), potassium chloride (KCl, ≥99.50% (AT)), are all purchased from Sigma-Aldrich (Darmstadt, Germany). The citric acid (C6H8O7, 99.90%) is purchased from VWR Chemicals BDH (Milano, Italy). Disodium hydrogen phosphate dodecahydrate (Na2HPO4*2H2O, 99.00%) and potassium phosphate monobasic (KH2PO4, 98.00%) are purchased from Italia Carlo Erba S. P. A (Milano, Italy). Simulated gastric fluid (SGF, pH 1.2) is prepared by dissolving 1.00 g of NaCl and adding 3.50 mL of concentrated HCl, then diluting the solution to 500 mL with deionized water. Simulated intestinal fluid (SIF, pH 6.8) is prepared by mixing 6.80 g of KH2PO4 in 250 mL of water with 0.94 g of NaOH dissolved in 118 mL of water, and then diluting the mixture to a final volume of 500 mL. Simulated intestinal fluid (SIF, pH 7.4) is prepared by dissolving 4.00 g of NaCl, 0.10 g of KCl, 0.90 g of Na2HPO4·2H2O, and 0.12 g of KH2PO4 in 500 mL of deionized water. Deionized water and water purified by reverse osmosis (MilliQ water, Millipore, Burlington, MA, USA) with a resistivity above 18.20 MΩcm−1, and dispensed through a 0.22 μm membrane filter, are used throughout the studies.

Hoti, G.; Er-Rahmani, S.; Gatti, A.; Hussein, I.; Argenziano, M.; Cavalli, R.; Anceschi, A.; Matencio, A.; Trotta, F.; Caldera, F. pH-Sensitive Dextrin-Based Nanosponges Crosslinked with Pyromellitic Dianhydride and Citric Acid: Swelling, Rheological Behavior, Mucoadhesion, and In Vitro Drug Release. Gels 2026, 12, 90. https://doi.org/10.3390/gels12010090

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