Tamoxifen is a synthetic, nonsteroidal selective estrogen receptor modulator (SERM) that has played a central role in the hormonal therapy of estrogen receptor (ER)-positive breast cancer for more than four decades (Jordan 2003; Buijs et al. 2024). In clinical practice, tamoxifen is used as adjuvant therapy for early-stage ER-positive breast cancer, in the treatment of metastatic disease, and as a means of primary chemoprevention in high-risk women (Early Breast Cancer Trialists’ Collaborative Group 2011; Kerr et al. 2022). The introduction of tamoxifen into breast cancer treatment represents one of the most significant breakthroughs in oncological pharmacotherapy of the 20^th century, as its adjuvant use significantly reduces recurrence rates and mortality in hormone-sensitive tumors (Amjad et al. 2023). Data from large-scale randomized trials show that continuing adjuvant therapy with tamoxifen for up to 10 years leads to a further reduction in late recurrences and mortality in patients with ER-positive breast cancer (Davies et al. 2013). Although tamoxifen therapy has proven clinical efficacy, it is associated with significant interindividual variability due to its complex hepatic metabolism and pharmacogenetic factors. Its biotransformation into active metabolites, primarily endoxifen, depends on CYP2D6 activity, which partially explains the differences in therapeutic response (Sanchez-Spitman et al. 2019). However, tamoxifen itself retains antiestrogenic and antiproliferative activity, although the major hydroxylated metabolites, endoxifen and 4-hydroxytamoxifen, exhibit substantially greater potency (de Vries Schultink et al. 2017). Therefore, nanoformulation should not be regarded as a strategy that inherently bypasses CYP2D6-dependent metabolic activation. Furthermore, prolonged exposure to tamoxifen is associated with an increased risk of serious adverse events, including endometrial carcinoma and thromboembolic complications, which necessitates a careful assessment of the benefit–risk ratio in long-term therapy (Perez 2007). Tamoxifen poses a challenge due to its high lipophilicity and low water solubility (intrinsic solubility of approximately 1.60 × 10^–2 mM), which may limit its dissolution and affect its bioavailability (Shangguan et al. 2017). In recent years, a variety of drug delivery systems have been developed, including lipid- and polymer-based nanoformulations, designed to improve the solubility, pharmacokinetic profile, and therapeutic efficacy of the molecule (Day et al. 2020).

The aim of this review is to examine recent technological developments in tamoxifen nanoformulation, with a special focus on chemically modified chitosan-based nanoparticles, including their synthesis, functionalization, drug-loading capacity, release behavior, and potential impact on targeted breast cancer therapy.

From a technological perspective, tamoxifen has an unfavorable biopharmaceutical profile, which significantly complicates its incorporation into various dosage forms. The molecule is highly lipophilic (log P ≈ 6–7), and its solubility is pH-dependent due to the presence of a tertiary amine group with a pKa of approximately 8.8–9.0 (Knox et al. 2024). According to the Biopharmaceutical Classification System (BCS), drug substances with low solubility and high permeability are classified as Class II, in which the dissolution rate is a limiting factor for absorption (Amidon et al. 1995). A further limitation is its stable crystal structure. It is well established that drugs with a stable crystal lattice exhibit lower thermodynamic solubility compared with their amorphous forms (Pudipeddi and Serajuddin 2005). Clinically used dosage forms contain tamoxifen citrate, which provides improved solubility compared with the free base; however, dissolution remains a potentially rate-limiting step in oral administration (Clemons et al. 2002). Poor water solubility, combined with high lipophilicity, can lead to variability in the extent and rate of absorption, which potentially affects the drug’s pharmacokinetic profile. As a BCS Class II drug, tamoxifen exhibits dissolution-limited bioavailability, whereby improving solubility leads to a significant increase in systemic exposure (Jena et al. 2014). Given these physicochemical and biopharmaceutical limitations, conventional formulation approaches such as micronization or modification of the salt form are often insufficient to optimize solubility and control drug release. This has led to increased interest in the development of advanced drug delivery systems, including lipid- and polymer-based nanoformulations, which, through encapsulation or conjugation, can improve the dispersibility, stability, bioavailability, and pharmacokinetic profile of the molecule (Avramović et al. 2020).

The development of nanotechnology-based drug delivery systems represents a modern, multidisciplinary approach with the potential to overcome the limitations inherent in a number of anticancer drugs with unfavorable physicochemical and biopharmaceutical properties (Peer et al. 2007; Shi et al. 2017). The above-mentioned physicochemical properties of tamoxifen suggest that nanoformulations represent an effective approach for improving the solubility, stability, and pharmacokinetic profile of the active ingredient, thereby increasing its bioavailability and therapeutic efficacy (Avramović et al. 2020). One of the main mechanisms by which nanoparticles improve solubility is the increase in specific surface area and the reduction in the thickness of the diffusion layer, which, according to the Noyes–Whitney equation, accelerates the dissolution process. Furthermore, reducing the size to the nanoscale can increase the saturation solubility (Cs) due to the increased curvature of the particles (Kelvin effect), which is particularly important for sparingly soluble substances (Jog and Burgess 2017). Beyond improving solubility, nanoformulations offer the possibility of precise control over drug release. Controlled release can be achieved by adjusting the structural characteristics of the carrier system, including molecular weight, degree of crystallinity, hydrophilic–lipophilic balance, and degree of cross-linking. In polymer nanoparticles, release is typically determined by a combination of diffusion processes and erosion of the polymer matrix, which allows for sustained and predictable release (Danhier et al. 2012; Eker et al. 2024). This aspect is of critical importance in tamoxifen treatment, where long-term therapy is necessary for optimal clinical efficacy; accumulated data indicate that prolonged exposure leads to a significant reduction in the risk of recurrence and mortality in patients with ER-positive breast cancer (Davies et al. 2013). In cancer pharmacotherapy, nanoparticles offer the potential for selective accumulation in tumor tissue through the enhanced permeability and retention (EPR) effect. Tumor vasculature is characterized by disrupted architecture and increased permeability, as well as a lack of effective lymphatic drainage, which allows for the passive accumulation of nanoparticles in the interstitial space. Although the effectiveness of this mechanism may vary depending on tumor type, disease stage, and individual physiological characteristics, the EPR effect remains a fundamental principle in the design of nanomedicine systems (Wu 2021). Nanotechnology platforms also enable the implementation of active targeting strategies through the functionalization of particle surfaces. By conjugating specific ligands—such as monoclonal antibodies, peptides, sugars, or vitamins—it is possible to achieve selective interaction with receptors that are overexpressed on tumor cells, leading to increased intracellular accumulation of the drug and potentially enhanced therapeutic efficacy (Dastidar et al. 2022). The influence of nanoformulations on the pharmacokinetics and biotransformation of drug substances is another important aspect. Encapsulating active compounds in nanocarriers can result in prolonged circulation time, reduced premature biotransformation, and controlled release, which ultimately leads to a more predictable pharmacokinetic profile (Shi et al. 2017). A further benefit of nanoparticles is the ability to integrate therapeutic and diagnostic functions (known as “theranostics”), as well as to co-deliver multiple active substances with different mechanisms of action. These strategies allow for a synergistic enhancement of the therapeutic effect and lay the groundwork for the development of personalized anticancer therapies and real-time monitoring of the therapeutic response (Freire et al. 2025). Despite the wide range of nanoformulations that have been developed, the selection of a suitable carrier remains a critical factor determining the efficacy of the drug delivery system. Polymer nanoparticles attract significant interest due to the possibility of precise control over their physicochemical properties, release kinetics, and surface functionalization. Their structural flexibility allows adaptation to the specific characteristics of the drug substance, including the high lipophilicity and pH-dependent behavior of tamoxifen. Therefore, polymeric nanocarriers represent a logical platform for the development of advanced tamoxifen delivery systems, which necessitates a more in-depth comparative analysis of the various polymeric approaches. Key biopharmaceutical limitations of tamoxifen and the potential advantages of modified chitosan nanocarriers are schematically presented in Fig. 1.

The encapsulation of tamoxifen in modified chitosan nanocarriers allows several key limitations of the molecule to be addressed simultaneously. On the one hand, the presence of hydrophobic domains in the carrier’s structure facilitates the incorporation of the lipophilic drug and increases its apparent solubility. On the other hand, the structural characteristics of the nanoparticles allow for controlled and often pH-dependent release, which is important for achieving a more stable pharmacokinetic profile. Furthermore, surface functionalization and the nanoscale size of the systems contribute to improved cellular penetration and potential selective accumulation in tumor tissue. These effects act synergistically and account for the increased therapeutic efficacy of tamoxifen delivered using nanostructured carriers.

Polymer nanocarriers represent one of the most extensively studied platforms for the delivery of antitumor drugs, including tamoxifen, due to their high structural flexibility, biocompatibility, and ability to precisely control the physicochemical properties of the system. Depending on the polymer used and the method of preparation, these systems can be designed to improve the solubility, stability, pharmacokinetic profile, and control of the release of the incorporated active substance (Behdarvand et al. 2020; Beach et al. 2024). Among the polymers commonly used to create nanoparticles, poly(lactide-co-glycolide) (PLGA)—a biocompatible and biodegradable copolymer approved by regulatory authorities for medical use—stands out. PLGA-based nanoparticles enable effective encapsulation of various active substances, including lipophilic molecules such as tamoxifen, and provide controlled and sustained release, which can improve the pharmacokinetic profile and reduce dosing frequency. However, their relatively hydrophobic nature and the possibility of an initial “burst release” represent limitations that require further optimization of the system (Sun et al. 2024). Polyethylene glycol (PEG) and PEG-conjugated systems are widely used in nanomedicine; their primary role is to enhance colloidal stability and prolong circulation time by reducing opsonization and elimination by the reticuloendothelial system. PEGylation of nanoparticles leads to the creation of so-called “stealth” systems, in which the hydrophilic polymer layer shields the surface and limits interactions with plasma proteins and cells of the mononuclear phagocytic system, allowing prolonged circulation in the systemic circulation and potentially increased accumulation in tumor tissue. However, PEG alone does not constitute a carrier matrix but rather a surface modifier, which limits its standalone application (Suk et al. 2016; López-Estevez et al. 2024). Alginate, as a natural anionic polysaccharide, has also been extensively studied as a drug delivery vehicle due to its biocompatibility, low toxicity, and ability to form hydrogels in the presence of divalent cations. Alginate nanoparticles and microparticles enable a relatively gentle encapsulation process suitable for sensitive molecules, as well as controlled and sustained release of the incorporated active substances. Nevertheless, their limited mechanical stability and variability in the release profile under different physiological conditions pose challenges that require further optimization of the system (Lee and Mooney 2012; Fleten et al. 2022). Recently, there has been growing interest in lipid–polymer hybrid nanoparticles, which combine the advantages of polymer and lipid systems. These nanostructures typically consist of a polymer core, which provides mechanical stability and controlled drug release, surrounded by a lipid layer that enhances biocompatibility and facilitates interaction with biological membranes. Due to this architecture, hybrid systems demonstrate enhanced stability, high encapsulation efficiency, and the ability to optimize the pharmacokinetic profile and targeted delivery of active substances (Liu 2024).

Despite significant progress in the development of various polymeric nanocarriers, each of these systems has specific limitations related to solubility, stability, release control, or functionalization capabilities. This necessitates the search for alternative or modified polymer platforms that combine the favorable characteristics of existing systems while overcoming their shortcomings. In this context, chitosan—a natural cationic polymer with unique properties—attracts particular attention, offering additional opportunities for modification and targeted drug delivery.

Chitosan is a natural polysaccharide obtained through partial or complete deacetylation of chitin—the second most abundant biopolymer in nature after cellulose. Chitin is found primarily as a structural component of the exoskeletons of crustaceans (shrimp, crabs, and lobsters) and insects, as well as in the cell walls of certain fungi and microorganisms. Industrial production of chitosan typically uses chitin isolated from waste materials from the fish processing industry, making it particularly attractive from the perspective of sustainable resource use (Baharlouei and Rahman 2022). Chitosan is a linear cationic polysaccharide composed of β-(1→4)-linked units of D-glucosamine (GlcN) and N-acetyl-D-glucosamine (GlcNAc), with the ratio between these monomers being influenced by the degree of deacetylation (DDA). This structural variability—resulting from different DDA profiles as well as the random distribution of GlcN and GlcNAc in the polymer chain—leads to significant heterogeneity in the physicochemical properties and functional characteristics of commercially available and laboratory-produced forms of chitosan. The presence of primary amino groups at the C-2 position of the glucosamine residues accounts for the unique cationic nature of chitosan among natural polysaccharides. At an acidic pH, these amino groups become protonated, which imparts a positive charge to the polymer chain and explains the pH-dependent solubility of chitosan in weak organic acids. This structural feature underlies its mucoadhesive properties, electrostatic interactions with biological membranes, and ability to form polymer complexes and nanostructures (Aranaz et al. 2021). Beyond its physicochemical parameters, such as the degree of deacetylation and molecular weight, chitosan possesses numerous biological properties, including biocompatibility and antimicrobial activity, which are closely linked to the polymer’s structure and solubility. These biological functions are influenced by the polymer’s physicochemical characteristics and contribute to the wide range of applications of chitosan in medicine and pharmaceuticals, including drug delivery systems and antibacterial agents (Akdaşçi et al. 2025). The combination of variable molecular weight, heterogeneity in the degree of deacetylation, and the presence of reactive functional groups (–NH₂ and –OH) makes chitosan an extremely flexible material for chemical modification and the design of functionalized nanocarriers. These structural features form the basis for the subsequent development of chitosan nanoparticles, hydrogels, and polymer complexes for targeted and controlled drug delivery (Wang et al. 2020).

Chitosan possesses a number of features that make it particularly attractive as a carrier in anticancer drug delivery systems. One of its most significant properties is its cationic nature, which facilitates interaction with negatively charged cell membranes and can improve the cellular uptake of nanoparticles, thereby potentially increasing the intracellular accumulation of drugs (Piotrowska et al. 2025). This feature is particularly beneficial for lipophilic antitumor agents such as tamoxifen, for which intracellular accumulation is a key factor in therapeutic efficacy. It has been shown that chitosan-based nanoparticles can increase the cellular uptake and intracellular concentration of tamoxifen, leading to an enhanced antitumor effect and the induction of apoptosis in tumor cells (Vivek et al. 2013). Chitosan’s mucoadhesive properties constitute a substantial advantage, particularly for oral administration. Through electrostatic interaction with mucosal glycoproteins, chitosan can prolong the retention time of the dosage form in the gastrointestinal tract and improve the absorption of the active ingredient it contains (Porfiryeva et al. 2026). Chitosan is capable of inducing reversible opening of the tight junctions between epithelial cells, which further facilitates the paracellular transport of drugs. This mechanism is highly relevant for increasing the bioavailability of poorly soluble compounds (Choukaife et al. 2022). Chitosan enables the production of nanoparticles through relatively simple and gentle methods, such as ionotropic gelation and self-assembly, which can be carried out without the use of aggressive organic solvents. This offers a significant benefit in the design of formulations for sensitive or unstable drug substances. Moreover, the ability to precisely control the size, surface charge, and morphology of chitosan nanoparticles allows for the optimization of their in vivo behavior, including circulation time, cell interaction, and tissue distribution, which is crucial for achieving effective and selective delivery of antitumor agents (Yanat and Schroën 2021; Bavel et al. 2023). Despite the favorable physicochemical and biological properties of chitosan, its use in a non-functionalized form is accompanied by a number of drawbacks that significantly restrict its applicability in modern pharmaceutical and targeted drug delivery systems. These limitations stem both from the material’s structural characteristics and from its behavior under physiological conditions and upon systemic administration (Mourya and Inamdar 2008; Pellis et al. 2022).

One of the main limitations of chitosan is its limited and highly pH-dependent solubility, which hinders the maintenance of stable dosage forms at physiological pH. Under neutral and slightly alkaline conditions, the deprotonation of the amino groups leads to reduced solubility, aggregation, and changes in the system’s rheological properties, which can compromise both the stability and predictability of drug release (Sogias et al. 2008; Sirviö et al. 2021). The variability of chitosan as a natural polymer is also a major issue; this variability manifests itself in the form of differences in molecular weight, degree of deacetylation, and distribution of acetyl groups. This heterogeneity leads to significant differences in physicochemical properties, mucoadhesion, and biological behavior, which hinders standardization, reproducibility, and regulatory evaluation (Kasaai 2010; Egorov et al. 2023; Žigrayová et al. 2024). In addition, non-functionalized chitosan offers limited possibilities for precise control over drug loading and release, especially in the case of water-soluble active ingredients. In the absence of specific polymer–drug interactions, a pronounced initial release (“burst release”) is often observed, which poses a limitation in the development of sustained-release and targeted drug delivery systems (Sinha et al. 2004; Guadarrama-Escobar et al. 2023). Upon systemic administration, an additional challenge is posed by the nonspecific electrostatic interactions between cationic chitosan and plasma proteins and cell membranes, which can lead to rapid clearance, off-target accumulation, or altered biodistribution (Aggarwal et al. 2009; Shaheen et al. 2021). In the absence of functionalization, chitosan offers limited possibilities for selective targeting, as it lacks native structural moieties that enable specific recognition of cellular or tissue targets. Therefore, its application in the context of active targeting and precise drug delivery typically requires additional functionalization or combination with other targeting strategies (Kesharwani et al. 2024; Omidian et al. 2024). Despite its favorable biocompatibility, biodegradability, and mucoadhesive properties, native chitosan presents several formulation-related limitations that may restrict its performance as a nanocarrier. Its pH-dependent solubility, hydrolytic instability in aqueous environments, and batch-to-batch variability in molecular weight and degree of deacetylation can influence nanoparticle characteristics, drug-loading capacity, and release behavior. These limitations provide a strong rationale for the chemical modification of the chitosan backbone, with approaches such as carboxymethylation, quaternization, and thiolation being explored to improve solubility, stability, mucoadhesion, and overall drug delivery performance (Stefanache et al. 2025). Within the scope of modern drug delivery systems, these limitations restrict the ability to achieve precise and predictable therapeutic effects. Thus, the functionalization of chitosan is emerging as an essential tool for the targeted control of its properties and its adaptation to the requirements of targeted and nanoscale drug delivery.

Although chitosan is widely used in drug delivery systems, studies focusing specifically on the incorporation of tamoxifen into chitosan nanoparticles remain relatively limited. Available data indicate that native chitosan may be limited in its ability to incorporate highly lipophilic molecules such as tamoxifen, which is attributed to the predominantly hydrophilic nature of the polymer and the limited hydrophobic interactions with the drug. These factors could contribute to lower encapsulation efficiency and a less controlled release profile. Within this scenario, the chemical modification of chitosan—particularly through the introduction of hydrophobic or amphiphilic groups—is considered a key strategy for improving formulation characteristics and enhancing the efficacy of drug delivery systems (Mikušová and Mikuš 2021). Such formulations enable the effective incorporation of lipophilic drugs such as tamoxifen through hydrophobic interactions and result in increased encapsulation efficiency compared with native chitosan (Cheung et al. 2015). In the study by Thotakura et al., a chemically functionalized chitosan derivative was developed through covalent conjugation with stearic acid, leading to the formation of an amphiphilic chitosan–stearic acid copolymer (CS-SA) capable of self-assembling into polymeric micelles for the delivery of tamoxifen. The conjugation was confirmed by Fourier-transform infrared (FT-IR) spectroscopy and nuclear magnetic resonance (NMR) spectroscopy, and the resulting micelles were characterized in terms of morphology, drug loading, and surface properties. The developed system demonstrated increased tamoxifen loading, controlled release, and significantly enhanced cytotoxicity against MCF-7 cells compared with the free drug. Furthermore, in vivo pharmacokinetic studies showed a significant increase in the area under the concentration–time curve (AUC), prolonged half-life, and reduced clearance, confirming the ability of lipid-modified chitosan micelles to optimize systemic exposure and the therapeutic efficacy of tamoxifen (Thotakura et al. 2017). Other experimental research indicates that graft polymerization of chitosan with PLGA enables the production of copolymer micelles with improved stability, cellular uptake, and antitumor activity, highlighting the importance of covalent modification in controlling the structural and functional properties of the nanocarrier. According to Thakur et al., chitosan-modified PLGA micelles containing tamoxifen exhibited an entrapment efficiency (EE) of 89.78 ± 7.31% and a drug loading (DL) of 45 ± 4.24%, providing quantitative evidence that covalent/hybrid modification of chitosan-based systems can improve tamoxifen loading. The same system also exhibited a lower IC₅₀ compared with the free drug, as well as higher dermokinetic parameters in the epidermis and dermis (Thakur et al. 2016). Furthermore, the development of oleic acid-grafted carboxymethylated chitosan demonstrates that combining hydrophilic and hydrophobic functionalization results in amphiphilic micellar systems with enhanced ability to deliver hydrophobic antitumor agents, highlighting the potential of such derivatives for delivering molecules with physicochemical properties similar to those of tamoxifen. Taken together, these studies indicate that hydrophobic functionalization and graft polymerization of chitosan represent promising strategies for tamoxifen delivery but remain limited in terms of the diversity of derivatives and their systematic investigation (Kumar et al. 2020). Recent Quality by Design (QbD) studies on polycaprolactone (PCL)–chitosan hybrid nanocomposites demonstrate that incorporation of chitosan into PCL-based nanocarriers provides positively charged nanoscale systems capable of encapsulating hydrophobic drugs such as tamoxifen and sustaining their release. An optimized tamoxifen-loaded PCL–chitosan formulation exhibited an entrapment efficiency of approximately 47%, together with a biphasic release profile characterized by an initial burst followed by prolonged release. However, despite promising anticancer activity against MCF-7 and 4T1 breast cancer cells, biological evaluation remained limited to in vitro models, with in vivo tumor validation yet to be established (Hammouda et al. 2025). Surface modification provides an alternative strategy for controlling the properties of tamoxifen-loaded chitosan nanoparticles, in which no covalent modification of the chitosan backbone occurs. A direct comparison between uncoated and alginate-coated chitosan nanoparticles reveals that alginate increases the particle size and changes the surface charge from positive to negative, while generally reducing the encapsulation efficiency of tamoxifen. However, this trade-off is accompanied by significantly improved control over drug release: the initial release of tamoxifen under acidic conditions decreases from approximately 10–18% for uncoated nanoparticles to only 2–3% after alginate coating, followed by a more controlled, pH-dependent release profile. These results indicate that the benefits of chitosan functionalization should not be evaluated solely on the basis of particle size or encapsulation efficiency but rather in relation to the intended route of administration and therapeutic goal. In this case, the alginate layer appears particularly advantageous for oral administration, where protection of the chitosan-based carrier in the gastric environment and subsequent drug release in the intestine are desirable (Waqas et al. 2022).

Although various chitosan derivatives—such as carboxymethylated and thiolated forms—are widely used in the development of drug delivery systems, their application in the incorporation of highly lipophilic compounds remains relatively limited, as confirmed by the existing body of literature. The reason is that these modifications are primarily aimed at improving solubility and mucoadhesive properties rather than enhancing hydrophobic interactions with the drug substance (Sivanesan et al. 2021). Regarding tamoxifen, these modifications facilitate the encapsulation of the hydrophobic molecule and allow for the formation of stable nanostructures capable of increasing drug loading and improving its bioavailability. Moreover, carboxymethylated chitosan exhibits pH-dependent behavior, including swelling and controlled diffusion, which can be utilized for stimulus-sensitive drug release in the tumor microenvironment (Poovi and Damodharan 2020). This mechanism combines improved solubility with the potential for selective delivery and optimization of the drug’s pharmacokinetic profile (Jena et al. 2017). PEGylation of chitosan has been used to prolong systemic circulation and reduce recognition by the reticuloendothelial system due to the formation of a hydrated surface shell and reduced opsonization of nanoparticles (Popova et al. 2020). In the delivery of tamoxifen, PEGylated systems can improve the pharmacokinetic profile, ensure controlled release, and increase tumor accumulation through the EPR effect (Popova et al. 2020; Megahed et al. 2022). Moreover, PEG-modified chitosan nanocarriers enable the effective encapsulation of hydrophobic drugs through the formation of amphiphilic structures with high loading efficiency, which is particularly relevant for tamoxifen (Megahed et al. 2022; Fahmy et al. 2026). Notwithstanding the significant advantages of PEGylation, this strategy also has a number of shortcomings that should be taken into account when developing nanocarriers. One of the primary issues is the so-called accelerated blood clearance (ABC) effect, associated with the formation of anti-PEG antibodies upon repeated administration, which can reduce therapeutic efficacy. Furthermore, while the PEG coating provides a stealth effect, it can also limit cellular uptake and intracellular delivery—a phenomenon known as the “PEG dilemma.” Thus, the hydrophilic PEG coating may act as a diffusion barrier and delay drug release, while the potential immunogenicity and limited biodegradability of PEG raise concerns regarding long-term safety. These challenges motivate the development of alternative strategies, including degradable stealth polymers and stimulus-responsive PEG linkages (Knop et al. 2010).

The differences between native and modified chitosan in terms of their ability to encapsulate tamoxifen are schematically illustrated in Fig. 2.

The choice of method for producing the nanoparticles is essential for the successful incorporation of tamoxifen, given its highly lipophilic nature and low water solubility. These attributes necessitate the use of formulation strategies that ensure effective distribution of the drug within the nanoparticle structure and minimize the risk of crystallization.

Ionotropic gelation is one of the most commonly used methods for preparing chitosan nanoparticles, based on electrostatic interactions between positively charged chitosan and multivalent anions such as tripolyphosphate (TPP). Although simple and free of organic solvents, this method presents limitations when incorporating highly lipophilic molecules such as tamoxifen, which often results in lower encapsulation efficiency and uneven distribution of the drug within the nanoparticles (Calvo et al. 1997; Sacco et al. 2021). Nanoparticle formation occurs via ionotropic gelation, in which the protonated amine groups of the polymer chains interact electrostatically with multivalent polyanions, leading to physical cross-linking and the formation of a three-dimensional polymer network. The resulting structures are submicrometer-sized particles whose size, compactness, and surface charge are determined by the synthesis parameters, including polymer concentration, polymer–cross-linking agent ratio, pH, and ionic strength of the medium. These physicochemical factors determine the morphology, internal organization, and colloidal stability of the system (Jonassen et al. 2012). The primary advantages of the method include technological simplicity, high biocompatibility, good encapsulation efficiency, and scalability. The drawbacks are related to potential polydispersity, limited mechanical stability, and sensitivity to pH and ionic strength, which may affect the stability of the resulting nanoparticles (Desai 2016). The main parameters affecting the size of chitosan nanoparticles produced by ionotropic gelation are summarized in Table 1.

Self-assembly is a method for obtaining chitosan nanoparticles based on the spontaneous self-assembly of polymer chains, induced by noncovalent interactions such as electrostatic forces, hydrogen bonds, and hydrophobic effects. Using functionalized chitosan, this process leads to the formation of stable nanocarriers with a micelle-like structure suitable for drug delivery (Quiñones et al. 2018). Self-assembly is often induced by chemically modifying chitosan with hydrophobic substituents, leading to the formation of amphiphilic derivatives that, in an aqueous environment, are able to form nanoparticles through the association of the hydrophobic segments and stabilization by the hydrophilic chains (Wang et al. 2008; de Oliveira Pedro et al. 2018). The size and stability of self-assembled nanoparticles depend on the characteristics of the polymers, the degree of modification, the concentration, and the environmental conditions—including pH and ionic strength—and these parameters allow for the modulation of the morphology, encapsulation, and release of the active substances (Rusu et al. 2020). The main obstacles include dependence on the critical concentration for self-assembly and potential destabilization in biological environments. Through appropriate chemical modification and combined stabilization strategies, these obstacles can be mitigated (Gaucher et al. 2005; Bravo-Anaya et al. 2018).

Emulsion techniques are commonly applied methods for the preparation of chitosan nanoparticles, in which the polymer phase is dispersed in a continuous phase to form emulsion droplets, followed by their stabilization through cross-linking or solvent removal. This approach allows for the modulation of the size, morphology, and encapsulation characteristics of the resulting nanoparticles (Mikušová and Mikuš 2021). In emulsion-based approaches for chitosan, emulsification followed by cross-linking is most widely utilized, in which a chitosan solution is emulsified in an organic phase and stabilized through chemical or ionic cross-linking (e.g., glutaraldehyde or TPP). The resulting droplets function as microreactors in which nanoparticles are formed (Agnihotri et al. 2004). Emulsification–solvent evaporation is a method for producing polymer nanoparticles, in which an organic solution of a polymer and a drug is emulsified in an aqueous phase, followed by solvent evaporation and polymer precipitation. The method is mainly used for the encapsulation of lipophilic drugs (Reis et al. 2006). Emulsion techniques may involve the use of organic solvents and cross-linking agents, which requires subsequent purification steps; however, process optimization and the selection of safer stabilizing systems can improve the biocompatibility of the resulting nanoparticles (Rizeq et al. 2019).

Nanospray drying is a method for producing chitosan nanoparticles based on the atomization of a polymer solution into a stream of hot air, resulting in rapid evaporation of the solvent and the formation of dry particles. The process is characterized by scalability, reproducibility, and the ability to produce stable dry nanocarriers (Vehring 2008). Nanospray drying is widely used for the encapsulation of drug substances in chitosan matrices, providing high encapsulation efficiency and improved drug stability, including for hydrophobic compounds. In addition, the process allows for the production of particles with a narrow size range and controlled release profiles (Sosnik and Seremeta 2015; Spindler et al. 2021). The characteristics of spray-dried chitosan particles are determined by the composition of the formulation and the process parameters, including polymer concentration, drying conditions, and feed rate; these factors allow for the modulation of the size, morphology, and encapsulation properties of the resulting systems (Guo et al. 2022; Narayanan et al. 2022). The main limitations of this method are related to the potential thermal degradation of sensitive drug substances and the need for careful optimization of the process parameters. Nevertheless, through the use of protective matrices and optimization of spray-drying conditions, it remains a powerful tool for the production of chitosan nanocarriers (Sosnik and Seremeta 2015; Spindler et al. 2021).

The technique of producing nanoparticles via polyelectrolyte complexes represents an effective and gentle approach to the formulation of drug carriers, applicable to the encapsulation of hydrophobic active substances such as tamoxifen. It is based on the spontaneous interaction between oppositely charged polymers, such as cationic chitosan and anionic gellan gum, which form a stable complex through electrostatic interactions, hydrogen bonds, and hydrophobic forces. As a consequence, a three-dimensional polymer network is formed in which tamoxifen can be effectively encapsulated and protected while ensuring controlled and sustained drug release. The resulting nanocapsules are characterized by good biocompatibility and low toxicity, and in vitro studies on the MCF-7 cell line show increased cytotoxicity of the tamoxifen-loaded nanocapsules compared with the free drug, which is associated with more effective cellular uptake and increased intracellular concentration (Kathle et al. 2018).

EE and DL are key parameters that determine the feasibility of using chitosan nanoparticles for tamoxifen delivery. Due to the highly lipophilic nature of the molecule, its effective incorporation into the polymer matrix depends directly on the presence of hydrophobic domains in the carrier’s structure, which form an internal core capable of incorporating water-insoluble drugs through hydrophobic interactions (Liu et al. 2011). Using unmodified chitosan often results in limited encapsulation efficiency, which is attributed to the lack of distinct hydrophobic domains in the polymer’s structure and, consequently, limited hydrophobic interactions with the drug. As a result, lipophilic compounds tend to distribute unevenly within the polymer matrix, leading to lower encapsulation efficiency and less stable drug delivery systems (Soppimath et al. 2001). Experimental data show that amphiphilic chitosan derivatives can achieve significantly higher EE and DL values compared with the native polymer, which is due to the introduction of hydrophobic domains into the carrier structure, facilitating the incorporation of lipophilic drugs (Bernal-Mercado et al. 2022; Zhang et al. 2025).

Nokhodi et al. conducted an experiment in which hyaluronic acid-coated chitosan nanoparticles were used; for tamoxifen, an EE of 55% was achieved, while for chitosan-modified PLGA micelles, the EE reached 89.78 ± 7.31% and the DL was 45 ± 4.24%. Although these findings suggest that amphiphilic or hybrid architectures may favor tamoxifen incorporation, direct quantitative comparison should be interpreted cautiously because the values were obtained using different formulations and experimental conditions (Thakur et al. 2016; Nokhodi et al. 2022). Chitosan–stearic acid-based systems have demonstrated improved drug loading and a high degree of encapsulation, which is explained by the formation of an amphiphilic copolymer with a hydrophobic core that favors the inclusion of lipophilic molecules such as tamoxifen. The hydrophobic interactions between the stearic acid chains and the drug, as well as possible hydrogen bonds and van der Waals forces, contribute to the effective retention of the active substance within the micellar structure. Consequently, the system exhibits significantly increased encapsulation efficiency (over 90%) and improved drug loading, highlighting the potential of fatty acid-modified chitosan as a carrier for hydrophobic antitumor agents (Thotakura et al. 2017).

The release of tamoxifen from polymer nanoparticles is a complex process determined by a combination of diffusion, relaxation, and degradation of the polymer matrix, as well as interactions between the drug and the carrier. A biphasic release profile is typically observed, characterized by an initial “burst release” due to the desorption of drug molecules from the surface of the nanoparticles, followed by sustained and controlled release driven by diffusion through the polymer matrix and its gradual erosion (Maji et al. 2014; Altmeyer et al. 2016). The initial phase is associated with drug release localized near the surface of the nanoparticles, while the subsequent phase is controlled by diffusion through the polymer matrix and gradual erosion of the system. This two-phase release profile is characteristic of polymeric drug delivery systems, in which the initial rapid release is followed by a diffusion-controlled process described by models such as the Higuchi model (Costa and Sousa Lobo 2001). In modified chitosan derivatives with increased hydrophobicity, stronger drug retention is observed, which leads to a reduction in the initial burst effect and prolongation of drug release. This is explained by the formation of hydrophobic cores within the self-assembled nanostructures, which stabilize the lipophilic molecules and limit their rapid diffusion to the surface (Quiñones et al. 2018). Additionally, amphiphilic chitosan systems provide more sustained and controlled release through a diffusion-regulated process from the hydrophobic core to the aqueous medium (Kim et al. 2006). Beyond modification of the chitosan backbone itself, surface engineering of hybrid carriers can also substantially alter tamoxifen release. Haidary et al. demonstrated that tamoxifen was completely released from unmodified porous silicon carriers within 6 h, whereas chitosan coating reduced drug release by approximately 30%. Interestingly, silica xerogel coating alone provided little additional release control, while a hybrid chitosan/silica xerogel coating prolonged complete tamoxifen release to approximately 7 days. This direct comparison suggests that release behavior is determined not only by the properties of the individual carrier components but also by their combination within the delivery architecture, where complementary material properties may provide substantially greater control over drug release (Haidary et al. 2016). The kinetic behavior of these systems is often described using models such as the Higuchi and Korsmeyer–Peppas models, which allow for a quantitative assessment of the release mechanism and the degree of diffusion control. In particular, the Korsmeyer–Peppas model uses the exponent n to distinguish between Fickian diffusion, non-Fickian transport, and other release mechanisms. Non-Fickian transport is frequently observed in amphiphilic chitosan systems, reflecting the combined mechanism of diffusion and relaxation of the polymer matrix (Korsmeyer et al. 1983; Yarce et al. 2016). The controlled release of tamoxifen is particularly important for maintaining stable plasma concentrations and reducing variability in exposure, which is critical for long-term therapeutic efficacy, especially given the need for prolonged use in the treatment and prevention of breast cancer (Jordan 2003).

In vitro studies indicate that chitosan-based nanoparticles significantly improve the cellular uptake of tamoxifen and enhance its antiproliferative effect, which is due to the increased solubility and stability of the drug upon encapsulation, as well as the cationic nature of chitosan, which facilitates interaction with cell membranes and endocytosis (Gonciarz et al. 2025). In tumor cell lines, including MCF-7, increased cytotoxicity has been observed when using nanoformulations compared with free tamoxifen, which is attributed to increased intracellular accumulation of the drug as a result of its effective cellular uptake (Nokhodi et al. 2022). Importantly, these findings should not be interpreted as evidence that nanoencapsulation circumvents CYP2D6-dependent tamoxifen metabolism. Instead, enhanced cellular uptake and intracellular exposure to the parent drug may themselves contribute to the increased antiproliferative activity observed in vitro.

In vivo studies indicate that polymeric nanocarriers of tamoxifen may improve its antitumor efficacy and provide a more prolonged therapeutic effect compared with the free drug, which is associated with improved tissue distribution and increased exposure in tumor tissue (Ghayoumipour and Ghafouri 2025; Torchelsen et al. 2026). To enhance tamoxifen chemosensitivity and potentially overcome treatment resistance, recent studies have explored combining natural polyphenols such as phloretin with tamoxifen using chitosan-based nanoparticles. In 7,12-dimethylbenz[a]anthracene (DMBA)-induced breast cancer mouse models, phloretin-loaded chitosan nanoparticles combined with tamoxifen produced synergistic anti-inflammatory and antiproliferative effects, including reductions in IL-6 and cyclin D1, together with improved histopathological features and increased tumor-cell apoptosis. However, although individual phloretin–chitosan nanoparticle and tamoxifen treatment groups were included, the specific contribution of the chitosan carrier itself was not isolated through comparison with blank chitosan nanoparticles (Ageeli and Mohamed 2025).

Despite these promising results, the available in vivo data remain limited, and direct comparative studies between different types of modified chitosan systems are often lacking, which underscores the need for more in-depth and standardized experimental approaches.

A comprehensive analysis of the available studies indicates that hydrophobic functionalization and graft polymerization of chitosan represent promising strategies for tamoxifen delivery but remain limited in terms of the variety of derivatives used and the extent of their systematic investigation.

From a comparative perspective, the available evidence is not equally strong across the different chitosan modification strategies. Hydrophobic and amphiphilic modifications, particularly fatty acid-conjugated and graft-polymer systems, currently provide the most direct experimental evidence for improved tamoxifen incorporation, controlled release, and enhanced biological performance. In contrast, the potential advantages of other chitosan derivatives, including carboxymethylated, thiolated, and PEGylated systems, are supported predominantly by studies with other hydrophobic drugs or by general properties of these derivatives, while direct evidence for tamoxifen remains limited. Moreover, differences in nanoparticle composition, preparation methods, drug-to-polymer ratios, release conditions, and biological models preclude reliable quantitative comparison across studies. Therefore, the apparent superiority of a particular modification strategy cannot yet be established, and direct head-to-head studies under standardized experimental conditions are required.

Although there have been isolated experimental studies demonstrating the successful delivery of tamoxifen via hydrophobically modified or graft-polymerized chitosan systems, the literature suggests that research has focused primarily on a limited set of chemical modifications, such as fatty acid conjugates and simple copolymer structures. Simultaneously, other widely used chitosan derivatives, including carboxymethylated, thiolated, or alternatively graft-polymerized systems, remain underexplored in the context of tamoxifen delivery.

Furthermore, there is a lack of systematic comparative studies evaluating the impact of various chemical modifications on key technological and biopharmaceutical parameters, such as encapsulation efficiency, colloidal stability, release mechanism, and tumor selectivity. This gap is particularly significant for amphiphilic hydrophobically modified derivatives, which possess the potential for self-assembly and effective encapsulation of highly lipophilic molecules such as tamoxifen.

An additional limitation is the heterogeneity of the available experimental evidence. Differences in particle characterization, encapsulation efficiency determination, release media and kinetic analysis, as well as in vitro models and exposure conditions, make cross-study comparisons difficult. Consequently, differences in reported performance cannot be attributed solely to the type of chitosan modification.

Currently, a gap exists between formulation optimization and clinical trials. Although increasingly complex surface modifications and hybrid carriers can improve tamoxifen incorporation, colloidal properties, and release control, these physicochemical advantages do not necessarily lead to improved therapeutic efficacy. Therefore, future studies must go beyond the characterization of nanoparticles and in vitro release tests and focus on a systematic evaluation of cellular uptake, pharmacokinetics, biodistribution, tumor accumulation, and antitumor efficacy in vivo. Establishing such relationships will be essential for determining whether the technological advantages of modified chitosan systems provide significant biopharmaceutical and therapeutic benefits.

As such, the development of new functionalized chitosan nanocarriers, including acylated and other chemically modified derivatives, should be accompanied by systematic comparative and biological evaluation. Such an approach represents an important avenue for future research and may help establish rational structure–performance relationships for the optimization of tamoxifen delivery.

Despite its long history of clinical use, tamoxifen remains a drug with a number of biopharmaceutical limitations, including low water solubility, variable bioavailability, and dependence on metabolic activation. This review demonstrates that nanotechnology-based drug delivery systems and, in particular, modified chitosan nanoparticles represent a promising approach for addressing physicochemical and drug delivery limitations, although they do not inherently eliminate CYP2D6-dependent metabolic variability.

Available experimental data suggest that hydrophobic, amphiphilic, and hybrid modification of chitosan can improve the incorporation of tamoxifen and may provide more controlled drug release. Enhanced cellular uptake and improved antiproliferative activity have also been demonstrated in several in vitro models, while evidence for pharmacokinetic and antitumor benefits in vivo remains considerably more limited. Thus, the physicochemical and in vitro advantages of these systems are better established than their in vivo therapeutic superiority and clinical relevance.

Despite these promising results, a review of the literature reveals significant limitations, including a limited number of systematic comparative studies between different types of modified chitosan carriers, a lack of standardized approaches for assessing release kinetics, and insufficient in vivo and clinical data. This hinders direct comparison between different strategies and limits the potential for translation into clinical practice.

In the future, the development of rationally designed amphiphilic and targeted chitosan systems, combined with a systematic analysis of structure–function–effect relationships, will be essential for optimizing the delivery of tamoxifen. Particular attention should be paid to integrating pharmacokinetic, pharmacodynamic, and pharmacogenetic aspects to develop personalized therapeutic approaches.

In conclusion, modified chitosan nanocarriers represent a promising but still underexplored platform for improving the therapeutic profile of tamoxifen, and their further development requires coordinated efforts in the fields of pharmaceutical technology, nanomedicine, and clinical pharmacology.