MF contains two hydroxylated aromatic rings, with four hydroxyl groups located on carbons 1, 3, 6, and 7; a xanthone ring, which includes a carbonyl group, and a glucose moiety (pyranose group) attached to carbon 2 (Figure 1). Consequently, the hydroxyl groups on C3, C6, and C7 are the primary target sites for synthesizing MF derivatives. Some substitution reactions may involve the hydrogen atom on C8, as well as C-C enzymatic cleavage at C2. The hydroxyl group on carbon atom C1 is hindered by steric effects from the pyranosyl group and forms an intramolecular hydrogen bond with the adjacent carbonyl group (Gómez-Zaleta et al., 2006). However, in a strongly basic medium, it may be possible to bond the oxygen atom of the C1-hydroxyl group.

The synthesis of MF derivatives using alkyl halides at 60°C, with dimethylformamide (DMF) as the solvent at pH = 8, has led to the formation of nine derivatives, as illustrated in Figure 2 (Turkar et al., 2024). Notably, the substitution with a decyloxy group at positions C3, C6, and C7 (derivative 6 in Figure 2) exhibited the highest inhibition ratio (100%), compared to MF, indicating a significant enhancement in antidiabetic activity due to this novel derivative. Similarly, a positive outcome was observed with acetyl derivatives, which were created by esterifying the four hydroxyl groups in the pyranosyl group. This method produced acetic, propionic, and butyric derivatives that demonstrated greater antidiabetic activity than MF (Figure 3). Additionally, various modifications such as acetylation, benzylation, cinnamoylation, and methylation were conducted to develop different MF derivatives aimed at increasing antioxidant activity (Figure 4). The antioxidant capabilities of the synthesized derivatives were assessed through the DPPH test and by evaluating the inhibition of lipid peroxidation. The results indicated a significant improvement in the antioxidant activity of the acetylated MF derivative (compound 2, Figure 4).

The synthesis of aryl and alkyl halide MF derivatives has been reported to enhance its analgesic properties (Khare and Shanker, 2016). However, no significant differences in analgesic effects were observed (Figure 5). Patil et al. (2022) reported the synthesis of novel esterified and alkylated aryl amine derivatives of MF aimed at improving its in vitro antioxidant and antitumor effects (Figure 6). Some of these derivatives had higher cytotoxic effects than MF against the breast cancer cell line MDA-MB-231. Liu et al. (2017) found comparable results using xanthones in the same cancer cell line.

The synthesis of glycosylated derivatives of MF is regarded as a promising strategy for enhancing its biological effects, although it has not been extensively documented in the literature. One approach involved creating MF-fructosyl derivatives through biotransformation using Arthrobacter nicolianae and dextrasucrase, specifically targeting the C6 position of the pyranosyl group (He et al., 2015; Septiana et al., 2020). This method was associated with claims of treating antitumor-related diseases. In a similar effort to increase the antioxidant activity of MF, researchers used a recombinant maltogenic amylase to produce MF-glucosyl-α-(1→6)-MF and maltosyl-α-(1→6), resulting in a 5500-fold increase in water solubility compared to MF. Nevertheless, the MF glucosides exhibited similar DPPH free radical scavenging activity (Wu et al., 2021). Additionally, Lee et al. (2022) reported the synthesis of an MF-glucosyl-α-(1→4) derivative through glucosyl transferase from Thermoanaerobacter sp. This derivative was formulated with β-cyclodextrin to create an inclusion complex, achieving a remarkable 5093-fold increase in water solubility and demonstrating significantly higher anti-inflammatory activity than MF.

Five new derivatives of MF were identified in the extract of mango stem bark, which have not been documented previously (Figure 7) (Núñez-Sellés et al., 2020). The underlying hypothesis suggests that the biological effects observed in plant extracts containing MF may result from a synergistic combination of MF, glycosylated MF derivatives, galloylated MF derivatives, and benzoylated MF derivatives. Moreover, computational techniques have been employed to profile the interaction of MF at the atomic level against nine selected molecular targets with clinical relevance in tumorigenesis. In an attempt to investigate the potential of MF as a viable starting point for synthetic exploration of MF-based analogs, extensive structural modifications have been explored, which need to be realized experimentally (Taiwo et al., 2018). Several studies have been conducted on QSAR studies for MF derivatives focused on antimicrobial (Nortje et al., 2025) or antidiabetic (da Silva-Lopes et al., 2024), but there is a lack of information about the antitumor effects of MF derivatives.

In summary, alkylation and acylation reactions at positions C3, C6, and C7 resulted in MF derivatives with improved antidiabetic and antioxidant activities, respectively. Additionally, esterification and aryl-alkylation reactions, particularly at position C6, produced MF derivatives that exhibited greater cytotoxicity against a breast cancer cell line compared to free MF. However, not all MF derivatives synthesized through these chemical reactions demonstrated improved biological activity over MF, which underscores the necessity for quantitative structure-activity relationship (QSAR) studies focused on the biological effects of MF derivatives (Benard and Chi, 2015). A promising strategy for developing antitumor agents from MF includes creating derivatives with oxygenated radicals, such as acetylated, benzoylated, glycosylated, and galloylated, attached to both the xanthone ring and the pyranosyl group.

Nanoparticle carriers are considered one of the most promising methods for enhancing the bioavailability of MF in cancer treatment, as extensively reviewed by Barakat et al. (2022). Among these carriers, Nanostructured Lipid Carriers (NLCs) represent a second generation of lipid-based carriers developed to address the limitations of earlier solid lipid carriers (SLCs) (Viegas et al., 2023). NLCs consist of a mixture of biocompatible solid and liquid lipids (in a 7:3 ratio), along with a surfactant, offering higher drug loading capacity and stability compared to SLCs. The MF-NLC formulation has been utilized for ocular delivery, as reported by Santonocito et al. (2022), using 888ATO as the solid lipid and miglyol as the liquid lipid. This formulation was found to be non-irritating to the eyes and demonstrated a significant increase in the antioxidant activity of MF. Khurana et al. (2017a) prepared MF-NLC by refluxing various molar ratios of MF and Phospholipon 90G (1:1, 1:2, 1:3) before incorporating them into the NLC formulation, which consisted of Compritol and Labrafil M2125. They achieved a controlled release formulation that lasted up to 10 h, resulting in a fivefold increase in MF plasma concentration. Additionally, MF-SLC was successfully developed using Labrafil M 2130 CS as the lipid carrier and Tween 80 as the surfactant, which enhanced antidiabetic activity in Wistar rats with streptozocin-induced diabetes (Foudah et al., 2024).

A noteworthy approach in the treatment of lung cancer has involved the use of a system based on transferrin (Tf) and MF, capitalizing on the overexpression of Tf in lung cancer cell receptors (Zhou et al., 2023). The Tf-MF-SLN was created using the emulsification-solvent evaporation method with DSPE-PEG2000-Tf (where DSPE stands for 1.2-Distearoyl-sn-glycero-3-phosphoethanolamine). The release of MF, MF-SLN, and MF-SLN-Tf was investigated in a specific lung cancer cell line using confocal microscopy. It was observed that MF-SLN-Tf was internalized by the cells within 2 h, whereas free MF and MF-SLN were not detected. Additionally, the benefits of MF-SLN-Tf were evident in terms of cell cytotoxicity and the inhibition of cell proliferation.

Nanoemulsions serve as versatile carriers for the delivery of lipophilic, hydrophilic, and amphiphilic bioactives, enhancing the bioavailability of poorly absorbed drugs (Mohammad et al., 2017; Dhumal et al., 2022). A self-assembly method of MF using phosphatidylcholine and chitosan has achieved a complete release of MF within 60 min for oral administration (Duyen and Duy, 2024). Self-assembled phospholipidic nanomicelles of MF, co-delivered with vitamin E, enhanced the cytotoxicity and cellular uptake on MCF-7 and MDA-MB-231 breast cancer cell lines, resulting in a higher and faster uptake by the cells (Khurana et al., 2018). Carbon dots (CDs) have been developed as organic carriers, but they also have photoluminescent and chemical structures that may be adapted for several pharmaceutical applications (Magdy et al., 2023). A water-soluble CD nanoemulsion containing MF (MF-CD) has demonstrated an increase in pharmacokinetic parameters, especially showing a 1.6-fold increase in the area under the curve for the maximum blood concentration in normal rats. This finding presented a novel approach for developing MF formulations with enhanced bioavailability (Kong et al., 2024).

A specific study investigated polyethylene glycol linked to carbon nanotubes (PEG-CNTs) as carriers for methotrexate (MT) in brain cancer treatment (Harsha et al., 2019). Cytotoxicity studies conducted on the U-87 brain cancer cell line showed a 1.28-fold decrease in the IC50 dose compared to MTX alone. This suggests that PEG-CNTs may be a promising approach to enhance the antitumor effects of MTX. Nanoparticles of MTX combined with hyaluronic acid (HA) have been synthesized using a self-assembly method to reduce the toxicity of MTX in cancer treatment (Wang et al., 2023). The MF-HA-MTX nanoparticles specifically inhibited the K7 cancer cell line while exhibiting lower toxicity compared to traditional MTX chemotherapy. A similar study by Meng et al. (2019) reported the assembly of an ionic peptide (RADA16-I) with MTX. The RADA16-I-MF-MTX nanoparticles demonstrated a significantly greater inhibition of colorectal adenocarcinoma cells (DLD-1) and colon cancer cells (KYSE 30) compared to MTX alone after 24, 48, and 72 h. MF has also been used as a carrier for delivering antitumor drugs (Zheng et al., 2025). The MF carrier consists of four components: i. a modulator for the tumor’s inflammatory environment, ii. an inducer of ferroptosis, iii. a tumor-penetrating agent, and iv. MF itself, which together form a self-assembled MF amphiphile that incorporates the antitumor drug (paclitaxel). The anticancer efficacy of the MF-carried formulation against paclitaxel-resistant breast tumors was confirmed in both in vitro and in vivo studies, demonstrating the effectiveness of this new cancer treatment approach.

In summary, organic carriers have been widely used to enhance the biological effects of MF. Among these, NLCs appear to be the most promising option for improving MF bioavailability when combined with specific tumor-targeting agents. Additionally, CyDs, CDs, and carbon nanotubes have been recently introduced as organic carriers for MF. These carriers have demonstrated favorable properties for cancer treatment due to their low toxicity in cancer cell lines.

Gold nanoparticles (AuNPs) with anti-microbial, anti-viral, and anti-tumor properties have gained attention in prostate cancer, as summarized in a recent review by Mitri et al. (2023). In addition to their cytotoxic effects on cancer cell lines, particularly prostate cancer cells, AuNPs can effectively target tumor cells by delivering antibodies and ligands that specifically eliminate prostate tumors (Khoobchandani et al., 2021). The synthesis of MF-loaded gold nanoparticles (MF-AuNPs) and their effects on the MCF-10A breast cancer cell line have been reported by Patra et al. (2018). Their study noted the cleavage of the C-C bond of the pyranose moiety along with the oxidation of the phenolic hydroxyl groups (C1, C3, C6, and C7) during the formation of MF-AuNPs. Furthermore, Aboyewa et al. (2021) indicated that MF-AuNPs could be beneficial in the cotreatment of colorectal cancer when used alongside doxorubicin, showing effectiveness in the Caco 3 cancer cell line and HT-29 (colorectal adenocarcinoma), as well as in MDA-321 (breast cancer) cell lines (Aboyewa et al., 2022).

Radioactive gold (¹⁹⁸Au) nanoparticles loaded with MF (MF-¹⁹⁸AuNPs) have been shown to enhance radiotherapy for prostate cancer (Al-Yasiri et al., 2017). The intratumoral delivery of MF-¹⁹⁸AuNPs demonstrated that over 80% of the injected dose remained in prostate tumors for up to 24 h. Additionally, there was a five-fold reduction in tumor volume after 3 weeks of treatment compared to the control group, which received a saline solution. Moreover, MF-¹⁹⁸AuNPs have led to efficient endocytosis of prostate tumor cells, via the MF pyranose moiety, in SCID mice implanted with prostate tumor (PC-3) xenografts (Katti et al., 2017; Katti et al., 2018).

Zinc oxide (ZnO) has recently been utilized as an encapsulating agent for various antitumor drugs due to its cytotoxic effects associated with compounds produced during the synthesis of ZnO nanoparticles (Hamrayev et al., 2020; Razura-Carmona et al., 2022; 2023; Wang Y. et al., 2022; Missier et al., 2024; Shubha et al., 2024). Extracts from Mangifera indica (mango) containing MF have been encapsulated in ZnO nanoparticles and tested against the A549 lung cancer cell line (Rajeshkumar et al., 2018). The cytotoxic effect of the ZnO-microencapsulated mango extract increased with higher concentrations of the formulation and was comparable to that of the positive control, cyclophosphamide, at lower doses.

Mesoporous silica (Syloid^® XDP 3050) has been reported to form MF complexes following rotary mill mixing with MF in a 1:1 ratio (Baán et al., 2019), leading to enhanced water solubility; however, no biological data were provided. MF magnetic microspheres (MF-MG-MS) have been identified as potential carriers for cancer treatment (Xiao et al., 2021). The MF-MG-MS carrier was synthesized using iron acetylacetonate in phenyl ether, incorporating oleic acid and oleylamine. Additionally, copolymers (PCL-PEG-PCL) were created through the ring-opening of ε-caprolactone, and MF-MG-MS were produced by the solvent diffusion method.

Polymer-based carriers are micro- or nano-particle spherical matrices that deliver bioactive molecules. These carriers can be created using one or more types of polymers (Lu et al., 2021). They have been utilized in various applications, including bone and cartilage tissue engineering (Zhou et al., 2023), cancer treatment formulations (Yan et al., 2018), ocular drug delivery (Naik et al., 2020), insulin delivery (Mansoor et al., 2019), and vaccine delivery systems (Lambricht et al., 2017), among others. Various polymer-based carriers have been employed to enhance the bioavailability of MF, as discussed in a review by Morozkina et al. (2021).

Chitosan, a polysaccharide derived from acid hydrolysis of chitin, and chitosan-modified polymers have attracted the scientific community as drug carriers for several applications (Ghaz-Jahanian et al., 2015; Demeyer et al., 2021; Saeedi et al., 2022; Goyal et al., 2024; Athipornchai et al., 2024; Lv et al., 2024). Samadarsi and Dutta (2020) utilized MF-chitosan nanoparticles (MF-Chi-NPs) with tripolyphosphate as a crosslinker to enhance the antioxidant effects of MF. In addition to exhibiting a greater free radical scavenging effect, as compared to free MF, the MF-Chi-NPs demonstrated a synergistic effect on the antioxidant enzymes catalase and peroxidase. This led to improved protection against protein oxidation and enhanced inhibition of lipid peroxidation. The effectiveness of MF carboxymethyl chitosan on the MG63 osteosarcoma cell line has been shown to inhibit cell growth, with IC50 values ranging from 7.8 to 15.6 μg/mL. In comparison, MF required significantly higher concentrations (Yusri et al., 2020). Additionally, MF has been incorporated into alginate-grafted N-succinyl chitosan (MF-Chi-NSC) to lower glucose, cholesterol, and triglyceride levels (Wang Y. et al., 2022). In vivo experiments demonstrated a reduction in glucose levels from 300 to 90 mg/mL with MF-Chi-NSC (300–180 mg/mL with MF); cholesterol levels decreased by approximately 37% (compared to 1%–36% with MF), and triglyceride levels dropped by around 60% (10%–40% with MF).

The research conducted by Pipattanawarothai et al. (2019) investigated the loading of MF into various blending systems, including binary systems composed of polyvinyl alcohol (PVA) and chitosan (CHI), as well as ternary systems that combine PVA, CHI, and gelatin. The study revealed that MF can form hydrogen bonds with the amide groups of chitosan and the hydroxyl groups of polyvinyl alcohol in homopolymer matrices. Notably, MF exhibited a stronger tendency to form intermolecular hydrogen bonds with the hydroxyl groups of chitosan compared to those of polyvinyl alcohol. Consequently, as the content of chitosan in the polymer-based carrier increases, the release of MF decreases.

The enhancement of brain bioavailability for MF has been achieved using polylactic-glycolic acid (PLGA) nanoparticles coated with polysorbate 80, administered via intranasal delivery in rats through an ischemia-induced model (Ahmad et al., 2024). The absorption of MF was higher than 80%, with a controlled release lasting 8 h. Additionally, MF-β-LG nanoparticles were formulated with β-lactoglobulin using tripolyphosphate as a cross-linker, demonstrating an 80% release in simulated colonic fluid within 8 h and only 9% release in simulated gastric fluid. This suggested that these nanoparticles could be a promising system for targeted MF delivery in oral formulations (Samadarsi and Dutta, 2019). However, there is a risk that the nanoencapsulation with β-lactoglobulin could reduce the biological properties of MF, which may affect its oral bioavailability.

Targeted polymeric nanoparticles have been developed to deliver MF with a high loading content of 6.86% ± 0.60%. These nanoparticles demonstrate excellent blood circulation and exhibit missile-like delivery to the pancreas (Wang M. et al., 2022). A pancreas-targeting agent, GLP-1, was immobilized on the copolymer polyethylene glycol-polycaprolactone (PEG-PCL) to create GLP-1-PEG-PCL (GLPP). These nanoparticles were self-assembled with MF, resulting in MF-GLPP nanoparticles that exhibited a higher concentration in the pancreas compared to free MF formulations in vivo. MF particles loaded with PGE have been evaluated concerning the inhibition of the enzyme α-glucosidase, which showed a more effective inhibition, around 95.42%, when compared to the free-form MF (90.42%) (Bezerra et al., 2019).

Recently, there has been a review of alternatives to forming macromolecular organic carriers with an inhibitor to enhance cell permeability (Skwarecki et al., 2020). Once these conjugates are internalized into the cell, either through direct translocation or endocytosis, they can release the active compound and target intracellular sites. Polymer-based carriers for the bioactive compound have demonstrated their high structural versatility, making them an appealing option for delivery. Modifying these carriers using homopolymers, copolymers, peptides, or proteins can facilitate specific targeting of therapeutic or diagnostic active sites. This targeting potentially increases the efficacy and sensitivity of the treatment. Table 2 summarizes the MF-drug carriers that enhance MF’s water solubility and permeability.