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Review

Bile Acid: Drivers, Carriers and Trojan Horses in Cancer Research

by
Silvia Vázquez-Gómez
1,
Julio A. Seijas
2,
Francisco Meijide
3,
M. Pilar Vázquez-Tato
2,
Francisco Fraga
4 and
José Vázquez Tato
3,*
1
Department of Pharmacy, Vigo University Hospital Complex, Estrada de Clara Campoamor 341, 36312 Vigo, Spain
2
Department of Organic Chemistry, Faculty of Sciences, University of Santiago de Compostela, 27002 Lugo, Spain
3
Department of Physical Chemistry, Faculty of Sciences, University of Santiago de Compostela, 27002 Lugo, Spain
4
Department of Applied Physics, Faculty of Sciences, University of Santiago de Compostela, 27002 Lugo, Spain
*
Author to whom correspondence should be addressed.
Targets 2026, 4(2), 18; https://doi.org/10.3390/targets4020018
Submission received: 10 November 2025 / Revised: 13 May 2026 / Accepted: 19 May 2026 / Published: 22 May 2026
Browse Figures
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Abstract

Composed of a steroid nucleus, widely distributed in the animal and plant kingdoms, containing various hydroxyl and methyl groups, and a carboxyl side chain, bile acids (BAs) appear to be the result of an irreversible evolution in nature. BAs are involved in numerous vital processes, such as enterohepatic circulation, recognition and transport by various proteins, and their role as “clients” of the farnesoid X receptor, suggesting that they could be used as carriers, transporters, or Trojan horses to deliver a drug to its target. Pioneers of this approach include Ehrlich, Ho, and Kramer, who conceived of “magic bullet” concepts and designed what are now known as conjugated BAs or drug–BA complexes. This review focuses on articles that apply these concepts to the broad and complex field of cancer research. Most of the reviewed studies follow a common trajectory encompassing the design and synthesis of BA conjugates, the in vitro evaluation of their anticancer activity in various cell lines, and their subsequent in vivo assessment. More than 250 compounds have been taken into consideration.

Graphical Abstract

1. Introduction

Current chemical knowledge allows, a priori, the design of a molecule that meets desired specifications, but new designs have a high risk of not working. Biological mechanisms have had millions of years to evolve (and will likely never be truly emulated) [1], and, during this evolution, nature has learned to distinguish what works from what does not. Therefore, to respond to the demands of a given biological challenge, rather than tackling the design and synthesis of a product from zero, one can choose what nature has already achieved in its evolution as the starting point.
Bile acids (BAs) have a hydrocarbon skeleton, cyclopentanoperhydrophenanthrene [2], known as the “steroid nucleus”. This group and its conformation seem to be an optimal solution that nature has achieved due to its wide distribution in plants [3] and animals [4]. It appears in hormones, natural antibiotics [5,6,7], BAs, and cholesterol [8]. It has been proposed that BAs evolved from cholesterol-derived alcohols toward C24 cholanoic acids such as cholic (CA) and chenodeoxycholic (CDCA) acids [9].
This information leads us to conclude that BAs are an excellent starting point for designing new molecules to obtain either new physicochemical [10,11,12] or new biological properties. Their derivatization requires straightforward procedures, making them attractive building blocks for the design of novel pharmaceutical formulations and systems for the delivery of drugs [13,14]. Multifaceted applications of bile salts in pharmacy have been comprehensively discussed by Elnaggar [15]. A huge variety of derivatives, with or without therapeutic applications, have been synthesized.
In BAs the steroid nucleus possesses three rings (A, B and C) of six carbon atoms and a fourth ring (D) of five carbon atoms (Figure 1). In mammals, BAs have a 5β hydrogen, leading to a cis configuration for the A and B rings. Functional groups of BAs are limited to hydroxyl groups on the steroid nucleus and a side chain bearing a terminal carboxylic group. In addition, BAs have methyl groups attached to the C10 and C13 positions. The hydroxyl groups are located at C3 (from cholesterol reduction) and at C7, resulting from the fact that cholesterol 7-hydroxylase is the rate-limiting enzyme in BA synthesis. A third hydroxyl group is located at C12 (for example, in primates) although in rodents and pigs it is located at C6. In the nomenclature of bile salts, prefixes such as deoxy- are used to indicate the absence of a hydroxyl group. CA and deoxycholic (DCA) acids (the 7-deoxy derivative of the former) are representative examples and are present in many mammalian species. Cheno- and urso- prefixes are used to denote the stereochemistry of the C7 hydroxyl group [16]. Excellent schematic diagrams depicting the biochemical synthesis of BAs have been published [17].
BAs are reference examples of bifacial molecules. In CA, the three hydroxyl groups are located on the α side of the molecule (hydrophilic side), while the methyl groups are located on the β side (hydrophobic side). This bifacial polarity explains the BAs’ behavior in aqueous media; since they are surfactants and above a critical concentration (cac or cmc), they form aggregates by self-association, commonly called micelles. Some of the most important physiological properties of bile salts, such as lipid transport, derive from this amphipathic nature. Below the critical concentration, bile salts behave as strong 1:1 electrolytes and do not show any association process [18,19]. The aggregation number of bile salts is small compared to the aggregation number of classical alkyl surfactants, and trihydroxy derivatives tend to form trimers while dihydroxy derivatives tend to form hexamers. The fraction of counterions is commonly 1/3 [20]. Based on results obtained using nitroxide stearic acid spin probes, Kawamura et al. [21] concluded that the common micellar structure is likely disk-like, consistent with the primary micelles proposed by Small [22]. An alternative model for the structure of micelles has been proposed by Giglio et al. [23].
The enterohepatic circulation of BAs plays very important physiological functions [24] and has been extensively reviewed [25,26,27]. The process involves numerous transport proteins, including the Na+-taurocholate cotransporting polypeptide (NTCP), organic anion-transporting polypeptides (OATPs) [28,29], the apical sodium-dependent bile acid transporter (ASBT), organic cation transporters (OCTs), the bile salt export pump (BSEP), multidrug resistance-associated protein 3 (MRP3), and the organic solute transporter α/β (OSTα/β) [30,31,32,33,34,35,36,37]. The structures of human drug transporters OATP1B1 and OATP1B3 have been published [38]. Transmembrane transport has been reviewed by Gyimesi and Hediger [39]. Drug delivery techniques that are reshaping cancer therapy have recently been reviewed by Imtiaz et al. [40]. Obviously, transporters are required partners for the delivery of drugs conjugated with BAs [17,34,41].
Targeted drug delivery is an approach closely related to the “magic bullet” envisioned a century ago by Ehrlich [42]. The development of the concept is particularly useful when attempting the reduction in the undesired chemotherapy-related systemic side effects. This may be achieved by using vectors that selectively deliver the cytotoxic agent to tumor cells, thus sparing healthy cells [43]. BA–drug conjugates are still recognized as unmodified BA and are translocated by the transporter [44]. In other words, these modified BAs play the role of “Trojan horses” [45] to deliver a drug molecule, particularly into the liver and the biliary system.
As early as 1987, Ho [46] proposed that BAs could serve as molecular carriers for drug delivery by exploiting active BA transport mechanisms. Based on transport requirements, he suggested that the C17 side chain with a terminal carboxylic group should be preserved, while derivatization should be performed at the C3-OH position.
Using tritium-labeled derivatives (3-tosyl-, 3-benzoyl-, and 3-iodocholic acids; Figure 2), Ho demonstrated that C3-modified BAs and their analogs may act as effective molecular delivery systems for intestinal and liver-targeted absorption. The results obtained by Kolhatkar and Polli [47] suggest that drug conjugation to the C3 hydroxyl group, rather than C7, may enhance targeting to BA transport pathways, particularly ASBT and NTCP. However, as discussed below, other positions of CA derivatives have also been explored for drug conjugation.
The present review concentrates on BA derivatives formed through covalent bonds, restricting itself to those which have been tested in cancer research. The reviewed compounds can be grouped into three categories, the first one being, by far, the most numerous:
(i)
BAs are directly linked to the drug or via a small bridge. Unmodified BAs will not be reviewed here, although we would like to remark that, despite extensive research, the role of primary and secondary BAs in cancer remains controversial. A comprehensive overview is provided by Fu et al. [48].
(ii)
BAs are linked to a polymer (natural or synthetic) or to a lipid, allowing the formation of nanomicelles (NMs) or, more generally, nanoparticles (NPs). Typically, the drug is covalently bound to the other end of the polymer. While this review was being prepared, a review on biopolymers containing BA derivatives by Acik and Altinkok was published [49].
(iii)
BAs are linked to the polymer to form NPs, but the drug is loaded onto them without covalent bonds.
Finally, since the preparation by Conacher et al. [50] of bilosomes, bile salt-incorporating vesicles, many examples have been published about their use as potential carriers for the enhancement of drugs on cancer cells. But, as covalent modification to the BAs’ structure is not required, bilosomes are not systematically reviewed here. However, a few examples have been considered in the Supplementary Materials. Many of the works discussed below present a long journey from the design and synthesis of a specific derivative to its in vivo distribution in multiple organs of animal models, through to its in vitro influence on multiple cancer cell lines. Ignoring any of these aspects of the work in question limits our understanding of the underlying effort required and the significant achievements.
This review includes more than 250 conjugates with BAs, as well as their structures and the main steps of their synthesis (see Supplementary Materials). Most of them have been evaluated in vitro for their anticancer potential across a wide range of cancer cell lines, and many have also been tested in vivo in animal models. More than 90 cell lines are explicitly reported in the reviewed studies. The Supplementary Materials document contains 76 Figures and 14 Tables.

2. Method

Before starting this review, we had a personal database with more than 9000 references, accumulated over the years, which was the core of the articles cited in the work. Despite this, we also conducted bibliographic searches avoiding rigid design filters and instead pursued a broad and inclusive search strategy. We have consulted PubMed, Web of Science, Scopus, and Scifinder from the earliest foundational reports to the middle of 2025. Typical search terms were “bile acid”, “bile acid conjugates” combined with “anticancer agents”, and “target cancer cell”, as well as “bile acid-drug conjugates” and “bile acid-polymer conjugates”. Specifically, names of cancer drugs were also used as research items. Around 450 additional papers were consulted. After an exhaustive full-text review, all this literature was reduced to that included in the bibliography. Exclusions were non-English-language papers, patents, and conference abstracts, as well as papers without biological cancer studies (either in vitro or in vivo).

3. BA–Drug Conjugates

The rich functional groups present in the structure of BAs allow them to bind to the drug through simple chemical reactions, provided that the drug itself possesses the appropriate functional groups.
Kramer et al. [51,52] proposed using the hydroxyl group at the C3 position of the steroid ring as a binding site for BA, thereby preserving the carboxyl group. This position has been used to form the conjugate via ether, ester, amide, and thiosemicarbazone bonds, either directly or through linkers. For the drug–BA conjugate of dihydroartemisinin (DHA), Huang et al. [53] have observed that it is more effective against a hepatocellular carcinoma (HCC) cell line than a mixture of DHA and ursodeoxycholic acid (UDCA) at a 1:1 molar ratio, demonstrating that the covalent linkage between UDCA and DHA is important for enhancing anticancer activity. For DHA conjugates, it has been observed that derivatives with a direct bond to C3 exhibit greater activity than those using linkers [54]. The type of bond and the orientation of the substitution (α or β) influence the observed IC50 values [55]. For artemisinin conjugates, the 3α-orientation of the CA skeleton in both ester and amide hybrids contributed to the enhancement of the cytotoxicity.
Although other positions on the steroid nucleus have been utilized [56], the C24 position is perhaps the most used, with esters or amides being the most sought-after functional groups, whether or not linkers are employed. The length of the alkyl chain spacer also affects cytostatic activity [57,58]. For a given drug, BA influences cytotoxicity and cytoselectivity, as has been demonstrated for Paclitaxel (PTX) derivatives conjugated with CDCA or UDCA [59].
Furthermore, the vast majority of derivatives exhibit a 1:1 stoichiometric ratio between BA and the drug. However, derivatives with 2:1 and 3:1 stoichiometries have also been synthesized. Tamoxifen (Tam) derivatives are clear examples [60], with the CA-Tam3-Am derivative having been observed to be the most active conjugate, irrespective of the estrogen receptor status (+ve and −ve) of human epithelial breast adenocarcinoma (MCF-7) cells, demonstrating both intrinsic and extrinsic pathways of apoptosis. It has been proposed that the enhanced anticancer activity of this derivative is due to favorable irreversible electrostatic interactions and the intercalation of these conjugates into the hydrophobic core of membrane lipids, causing an increase in membrane fluidity. Following treatment with CA-Tam3-Am, the down-regulation of anti-apoptotic protein levels (Bcl-2 and Bcl-XL) and up-regulation of pro-apoptotic proteins (Bax, Bid, Bad, and caspase 8), without any change in the expression of caspase 9, were observed.
There are also examples where the opposite relationship holds true. In the case of chlorambucil, it has been observed that activity decreases as the number of sterol units is reduced [61].
The formation of a drug–BA conjugate only makes sense if the conjugation offers benefits for the action of the drug. This effect can be achieved by specifically directing the drug to a particular organ, such as the liver. Already for the first conjugates of chlorambucil, synthesized by Kramer [51], preferential drug release in the liver was observed. This fact is closely related to the involvement of BA transporters such as NTCP and OATP [62]. A notable liver-targeted effect of an oxaliplatin–CA conjugate LLC-202 (see Supplementary Materials, SM) was observed, as oxaliplatin alone is mainly localized in the kidney but LLC-202 was mainly distributed in the liver [63]. Similar results were obtained for the CA–carboplatin (CP) conjugate [64].
Studies carried out on the conjugation of cisplatin with BA, forming derivatives known as Bamets, are particularly illustrative. The uptake of cisplatin by the cell occurs primarily through passive diffusion across the membrane. It also requires its conversion into aqueous species through the displacement of chlorine, thereby forming the active forms of the compound that ultimately bind to DNA [65]. Transport systems involved in cellular handling of platinum derivatives have been reviewed [66].
The cytostatic activity of Bamet-H2 was already demonstrated in 1997 [67]. Bamet-R2 inhibited cell growth in all tested cell lines [68]. It was shown that this Bamet has cholephilic characteristics typical of BAs [69]. It was observed that the antitumor activity of Bamet-UD2 was similar to that of cisplatin, but without its side effects. Furthermore, both Bamet-UD2 and Bamet-R2 reached liver concentrations several times higher than cisplatin.
Highly significant is that transport systems OATP-A, OATP-C, NTCP, OCT1 and OCT2 mediated Bamet-R2 and Bamet-UD2 uptake [70]. This mediated transport is affected by the presence of typical substrates of the involved transporters. As cisplatin is not transported by any of these carriers, the BA moiety in Bamets is crucial for the transportation by the mentioned carriers. Therefore, the drug conjugation with BAs is essential to target it toward liver tumor cells. This liver accumulation was observed for other conjugates, such as camptothecin linked to DCA [71]. For this conjugate, competitive inhibition experiments by DCA suggested that BA transporters are involved.
Kinetic studies showed that the uptake efficiency of OATP and OCT were higher for Bamet-UD2 than for Bamet-R2, the most significative difference corresponding to OCT1. The analysis of different systems suggests that the conjugation of the side chain and location and orientation of hydroxy groups influence the affinity for the transporters of a BA (free or conjugated with a drug). No correlation has been observed between the efficiency and hydrophobicity of BAs. Therefore, it seems that the most plausible explanation for the observed differences between Bamet-R2 and Bamet-UD2 is due to the differences in the dissociation mechanisms of Bamets in water, which would also be the origin of the differences in the cytostatic activities of Bamet-R1 and Bamet-UD2 [72]. Bamet-UD2 may be transported by ASBT [73], and it also induced marked Lt-OATP1B3 inhibition [74].
Bamet-R2 was loaded into liposomes [75], resulting in a higher drug amount accumulated in cells. This enhanced the cytostatic activity. Bamet-R2 and Bamet-UD2 were also encapsulated into phospholipids liposomes. Bamets were able to overcome cisplatin resistance in tested cell lines [76].
The conjugate retains the antitumor activity of the drug, but normally the specificity in targeting the liver increases, as was shown for Cytarabine–CA conjugates [77], OATP-mediated uptake being involved [78]. Depending on the characteristics of the drug or of a drug derivative, the conjugate forms stable micelles, as was shown for a piperidine derivative of Docetaxel (DTX) conjugated with LCA [79].
The drug binding to the C24 position (tail) of the BA allows for free hydroxyl groups, particularly that at the C3 position (head). Thus, they can be functionalized with neutral, negatively charged or positively charged groups. This action modifies the physicochemical characteristics of the starting BA, such as its cmc and its lipophilicity [80]. Logically, this action also affects its biological activity. Yadav et al. [81] have synthesized eight LCA–Tam conjugates with different cationic charged head groups. The drug was inserted at the carboxylic group as an amide with the charge head group at C3. The activity of these LCA–Tam amphiphiles is highly dependent on the nature of the charged head group, as hard-charged amphiphiles exhibit strong membrane interactions and enhanced anticancer activity compared to soft-charged amphiphiles.
These substitutions allow for the introduction of additional features. Thus phosphocholine (PC) and Tam were linked at C3 and C24 of LCA, respectively [82]. The derivative (LCA-Tam-PC) is stable at both stomach and intestinal media conditions, providing a possible new platform for oral delivery. In vivo biodistribution studies confirmed the increased circulatory and tumor-site drug concentrations as compared to the parent drug. A reduction in the tumor volume and tumor weight, reduced hepatotoxicity, and a significant increase in median survival were observed as well.
Commonly, several conjugates are obtained for a given drug. Harikandei et al. [83] have synthesized twenty noscapinoid–BA conjugates via amide bond formation between noscapine (as secondary amine) derivatives and BAs (LCA, DCA, CDCA, and dehydrocholic acids, DHCAs). The activity against cancer cell lines depends on both BA and noscapine derivatives. The importance of the BA moiety, already demonstrated for Bamets, was also observed for curcumin (CUR) conjugates (as C24 ester derivatives) with CA and DCA [84].
In a new strategy, CA was conjugated to monoclonal antibodies (mAb). This novel technology is named ChAcNLS, Accum or “cell accumulator” [85,86,87]. Here, we will maintain the acronym ChAc for CA which was used at the original papers. Via an N-terminal cysteine, ChAc was coupled to the peptide CGYGPKKKRKVGG, which contains the nuclear localization sequence (NLS) from simian virus SV-40 large T-antigen. Then, the conjugate ChAcNLS was conjugated to the mAb 7G3 [85]. The final compound, 7G3ChAcNLS, maintains the nanomolar affinity for the cell-surface leukemic antigen interleukin-3 receptor-α (IL-3Rα). 7G3-ChAcNLS effectively escapes endosome entrapment and degradation.
In a following paper, Paquette et al. [86] constructed 64Cu-A14-ChAcNLS, which contains the mAb A14 that is specific against the interleukin-5 receptor α-subunit (IL-5Rα), which is a vital component for driving muscle invasive bladder cancer (MIBC) progression. The radioisotope 64Cu allows the evaluation of nuclear and intracellular accumulation by radioactivity counting. 64Cu-A14-ChAcNLS had nanomolar affinity for IL-5Rα. 64Cu-A14-NLS and 64Cu-A14 were also constructed. It was demonstrated that 64Cu-A14-ChAcNLS had improved targeting of MIBC tumor relative to 64Cu-A14 and that 64Cu-A14-NLS had poor tumor targeting due to extremely rapid clearance.
Similarly, the antibody–drug conjugate trastuzumab–emtansine (T-DM1) was modified with ChAcNLS [87]. The modified T-DM1 significantly enhanced cytotoxic efficacy in the human epidermal growth factor receptor 2 (HER2)-positive breast cancer system (SKBR3). The efficacy was dependent on the nuclear transport receptor importin-7.
Steroidal 1,2,4,5-tetraoxanes have been obtained for checking their antimalarial and antimycobacterial activities [88], but many of them have antiproliferative properties as well. Around 50 compounds have been published and tested against more than 60 cell lines [89,90,91]. The series include cis and trans bis-steroidal tetraoxanes with different BA moieties, all linked by their C3 carbon atom. Some tetraoxanes induced apoptosis, as confirmed by morphological analysis; others are highly specific compounds; and inhibition on a submicromolar scale occasionally at <10 nM was observed for some derivatives.
Several deoxynucleoside–BA conjugates linked through a 1,2,3-triazole ring have been obtained [92,93,94]. Most of the compounds have linked the nucleoside at C3 (α-orientation) [92] but C24 has been used as well [94], the BAs being CA, DCA, CDCA, UDCA and tauroursodeoxychoclic acid (TUDCA). Even nor-derivatives (with C23 as the linked carbon atom) have been obtained [93]. Adenosine′, guanosine′, 2′-deoxyadenosine′, 2′-deoxyguanosine′, 2′-deoxyuridine′, 5′-deoxy-2′′,3′-O-isopropylideneadenosine-5′-yl′, and 5′-deoxy-2′′,3′-O-isopropylideneuridine-5′-yl have been used as nucleosides. More than 50 derivatives have been synthesized and tested against different cell lines. The highest cytotoxicity was observed for 2′-deoxyadenosine-CDCA (dA-CDCA) on human chronic myelogenous leukemia (K562) cell lines, with IC50 = 8.51 μM [92], Click-3 on the MCF-7 cell line (IC50 = 8.08 μM), and Click-13 on the human neuroblastoma (IMR-32) cell line (IC50 = 8.71 μM) [94].
NO photodonor 4-nitro-2-(trifluoromethyl)aniline was conjugated with UDCA and CDCA, through a 4-alkyl-1,2,3-triazole moiety [95] (Figure S54). Photocage-UDC was the best candidate to highlight the cytotoxic effect of light, resulting in the production of NO, toward human colorectal carcinoma (HTC116) cells, but no comparative results (dark and light experiments) were given. However, the percent of growth inhibition observed for a 50 μM solution of photocage-SdAdo (a photodonor 2′-deoxyadenosine derivative) upon irradiation was around twice that observed in the dark.
Amide derivatives of BAs are very common compounds. In fact, common glyco- and tauro- conjugates of BAs belong to this family. Thus, it should not be surprising that many other amides have been prepared and tested as anticancer drugs. This is the case of the products obtained by Im et al. [96,97,98], named HS-1030, HS-1183, HS-1199 and HS-1200. The activity depends on the derivative and the cell line. Yee et al. [99] assessed the in vivo efficacy of HS-1200 in human glioblastoma (U87MG) cells inoculated into non-obese diabetic and severe combined immunodeficient (NOD/SCID) mice. Treatment with HS-1200 delayed tumor onset, reduced tumor burden, and improved survival.

4. BA–Polymer–Drug Conjugates

This section covers conjugates in which the BA binds to a polymer, a macromolecule or a lipid, whilst the drug is covalently bonded to the polymer as well. These conjugates tend to self-assemble, forming aggregates known as NPs or NMs.
DCA or TCA and Deferoxamine (DFO) were linked to hyaluronic acid (HA) [100] obtaining seven polymeric conjugates which form self-assembled spherical NPs. Ferritin reduction studies indicated that the conjugation of DFO to TCA-HA did not compromise its chelation efficiency. Compared to the free drug DFO, the conjugate TCA9-HA-DFO showed an enhanced permeation of DFO and was also less cytotoxic to cells.
DTX NMs made up of two components have been designed [101]. In one component, named PC-LCA-DTX, LCA was linked (ester bond) to DTX by its C24 carboxylic group, while the C3 hydroxyl group was bonded to PC. In the second component (PEG-LCA) LCA was conjugated to polyethylene glycol (PEG) by the C3 hydroxyl group. Stable NMs (with hydrophobic core and hydrophilic outer shell) are obtained when the two components are mixed in 1:1 and 1:2 proportions. The carboxylesterases expressed at the tumor site can cleave the ester group, thus releasing the drug. These DTX NMs showed better anticancer efficacy than Taxotere®.
In a similar approach [102], the component PC-LCA-DTX was maintained, but the second component incorporated the antiangiogenic combretastatin A4, linked as amide at C24 of LCA, and the ester bond at C24 with PEG was kept. Mixing the two components leads to the formation of NMs. The release of DTX and CA4 from the NMs in the presence of esterase, facilitated by acidic conditions, was confirmed. NMs effectively inhibit the tumor growth in syngeneic and xenograft colorectal cancer models.

5. BA–Polymer Conjugates

The presence of the polymer allows for different approaches for drug release. For instance, GCA was linked to a poly(lactic acid)−PEG copolymer [103]. The synthetic polymers were used to prepare micelles exhibiting relatively uniform spherical structure and good loading capacities of gemcitabine (Gem). Fluorescence studies were indicative of a heightened interaction between GCA-modified micelles and ASBT receptors. In mice, the antitumor activity of oral Gem-PPG was superior to that of free drug injection in a xenograft model. Park et al. [104] have developed a PTX carrier based on chitosan chemically modified with DCA or LCA as hydrophobic groups. In an aqueous environment, the BAs induce self-association to form aggregates which effectively encapsulate PTX. The antitumor activity of the PTX-loaded NPs was demonstrated in vivo.
Due to the reductive properties of the disulfide bond and the higher glutathione (GSH) levels in tumor cells than in normal cells [105], redox-sensitive hyaluronic acid–DCA (HA-ss-DCA) conjugates have been developed [106]. The conjugates self-assembled into micelles which are stable under normal physiological conditions but undergo rapid disassembly in the presence of 20 mM GSH, resulting in intracellular drug release. In tumor-bearing mice, HA-ss-DCA micelles had much higher tumor targeting capacity as compared to the insensitive control. A similar approach was developed by using PEG as the polymer, while CA was linked by an amide bond [107]. PTX, located in the core of the NP, is protected from degradation in gastrointestinal and blood circulation. Again, PTX release occurred in the strong reduction environment of tumor cells. Competitive inhibition experiments with TCA in human colorectal adenocarcinoma (Caco-2) cells demonstrated that ASBT was responsible for the absorption of PEGylated PTX.
A different approach was carried out by Mehnath et al. [108]. Two different polymers were obtained: (i) a CA-grafted polymer (CA-PCPP) and (ii) Poly(bis(carboxyphenoxy)phosphazene)–poly(diallyldimethylammonium chloride) (PDADMAC) were functionalized with sodium cholate through an ionic interaction. Sonication of mixed solutions of both compounds leads to the formation of micelles which were loaded with PTX. The release of PTX from micelles was pH dependent, being faster at low pH values. So, the system would be able to release more drug in the tumor cell environment and, consequently, the IC50 values (MCF-7 cells) increase when increasing the pH of the environment.
Similarly, pH-responsive drug release was observed for a DCA conjugated to carboxymethylated–curdlan conjugate (DCMC). Epirubicin (EPB) was physically loaded into DCMC self-assembled NPs [109]. No side effects were observed for DCMC, meaning it could be used as a safe drug carrier. In vitro studies showed that the drug release occurs in two steps; the fast initial step was followed by a slow and sustained release for a prolonged period. As indicated for other systems, the release is accelerated by decreasing the pH of the medium. In vivo distribution studies showed that the order of Area Under the Curve (AUC) was liver > tumor ≥ spleen > kidney > blood > heart > lung for EPB-loaded DCMC NPs (EDNs) and liver > kidney > spleen > heart ≥ tumor > blood > lung for free EPB. This pH-responsive drug release behavior was also observed for amphiphiles in which pyrenebutyric acid (Pyr) or CA (or DHCA) were linked to the terminal groups of methoxy PEG [110]. The conjugates form NPs and were tested for the delivery of loaded doxorubicin (DOX).
A biocompatible amphiphilic telodendrimer, PEG5k-CA8, composed of PEG, CA and lysine has been synthesized [111]. In aqueous media, the telodendrimer self-aggregates to form micellar NPs. The NPs themselves were not responsible for the cytotoxicity. They were loaded with PTX. In subcutaneous and orthotopic intraperitoneal murine models of ovarian cancer, these loaded NPs achieved superior toxicity profiles and antitumor effects compared to Taxol® and Abraxane® at equivalent PTX doses. Another CA telodendrimer (OA02-PEG5k-CA8) was obtained by conjugating an OA02 peptide at the distal terminus of the PEG by using click chemistry [112]. NPs were prepared by mixing OA02-PEG5k-CA8 and PEG5k-CA8 in a 1:1 (w/w) ratio and loaded with PTX, forming PTX-OA02-NPs. The OA02 peptide enhanced the intracellular delivery in cancer cells (human ovarian adenocarcinoma, SKOV-3, and human ovarian clear cell carcinoma, ES-2 cells) that overexpress α-3 integrin.
NPs composed of quercetin (Qu)-modified liposomes (QL) coated with a GCA–chitosan oligosaccharide conjugate have been designed [113]. The NPs were loaded with PTX. GCA functionalization contributed to the enhanced endocytosis of NPs via the ASBT-mediated pathway since inhibition by TCA of endocytosis efficiency was observed. The oral bioavailability of PTX-loaded GCA-NPs was increased 19-fold compared to that of oral Taxol®, and a better antitumor efficacy and prolonged absorption time in the intestine were also demonstrated.
Nanoliposomes were obtained after the conjugation of CA with an amino derivative of soybean phosphatidylcholine–PEG [114]. The nanoliposomes were loaded with silybin as a model drug. The cellular uptake was facilitated by ASBT and NTCP. CA reduced the expression of both transporters. Hepatic distribution data demonstrated that the amount of silybin delivered by drug-loaded nanoliposomes to the liver was significantly greater than by both free silybin solution and silybin-loaded nontargeted nanoliposomes.

6. Conclusions

In the revision, only those compounds in which a BA moiety is covalently linked to another residue have been considered. In any case, the synthesis of the conjugates follows standard organic chemistry procedures involving reactions such as esterification, hydrolysis, amidation, etc. For a given BA and drug pair, different stoichiometries have been obtained.
The second residue may be a drug which is currently used in clinical anticancer treatments, an organic molecule, a metal complex, a polymer, a macromolecule, or a lipid. The BA is linked to the residue either directly or through a spacer. For each cell line studied, there is at least one conjugate that exhibits improved anticancer activity compared to the unconjugated drug, and, in general, these conjugates exhibit greater selectivity toward cancer cells than toward normal cells. Some compounds exhibit a strong specificity for a given cell line.
The formation of a BA–drug conjugate only makes sense if the conjugation offers benefits for the action of the drug. The conjugate must retain the antitumor activity of the drug, and some examples unequivocally show an enhancement of the anticancer activity of the drug by the BA–drug conjugate over a simple mixture of both components. The advantageous effects extend to the reduction in side effects and to the increment in specificity in targeting a given organ (mainly the liver). Apart from the drug itself, the activity depends on the spacer and its length, BA, link location to the BA backbone (commonly C3 or C24), and orientation (α or β) at C3 of the substituent. The drug substitution at C3 has been used for the introduction of additional features of the conjugate through the C24 carbon atom of the side alkyl chain of the BA.
The enhancement of activity is associated with increased drug accumulation in cells and organs, which in turns is associated with the transportation of conjugates by BA transporters. This carrier-mediated transport is influenced by the presence of typical substrates of these transporters, such as BAs themselves.
In numerous cases, drug distribution in tissues and organs has been studied. The liver often represents a preferential organ for drug accumulation and release. In vivo studies frequently demonstrate significant reductions in the tumor volume and weight. Reduced hepatotoxicity and a significant increase in median survival are observed as well.
The ability of BA–polymer conjugates to form self-assembled spherical NPs has been advantageously used to exploit significant differences between normal and cancerous cells. The higher glutathione (GSH) levels in tumor cells compared with normal cells have been used to disassemble the NPs formed by conjugates carrying disulfide bonds, thereby releasing the drug intracellularly. Similarly, NP disassembly, induced by a decrease in pH in the tumor cell environment, has been used for the enhancement of the drug release, as well as to design BA-derived amphiphiles with stability under gastric pH conditions for oral administration.
Finally, new research projects and concepts offer a promising future for the conjugation of bile acids to antibodies.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/targets4020018/s1. Figure S1. Structures of chlorambucil, and CA conjugates obtained by Kramer et al. Figure S2. Chlorambucil umbrella conjugates obtained by Vijayaraghavan et al. Figure S3. Metallo-Drugs in Cancer Therapy.Figure S4. Structure of Bamets and analogs: Bamet-R2, Bamet-R1, Bamet-UD2, Bamet-H2, Bamet-D3, [PtCl(UDC)(en)] complexes E1 and E2, [Pt(UDC)2(en)], and trans-[PtII(GC)2(NH3)2] Figure S5. Structure of Bamet-A1 synthesized by Criado et al. Figure S6. Structure and synthesis of platinum-conjugates obtained by Paschke et al. Figure S7. Scheme of the synthesis of carboplatin conjugate obtained by Paschke et al. Figure S8. Structure and syntheses of steroidal thiosemicarbazones-Pt(II) complexes obtained by Huang et al. Figure S9. Structure and synthesis of the conjugates obtained by Seroka et al. Figure S10. Structure of LLC-202 obtained by Jiang et al. Figure S11. Structure and synthesis of the cholic acid-carboplatin conjugate CP-CA obtained by Lan et al. Figure S12. Platinum conjugate obtained by Hryniewicka et al. Figure S13. Structure of Paclitaxel. Figure S14. Structure and synthesis of the BA-Paclitaxel and Paclitaxel-PB conjugates obtained by Melloni et al. Figure S15. Hyaluronic acid-deoxycholic acid (HA-ss-DOCA) conjugates obtained by Li et al. Figure S16. Structures of the polymers PEG3k-PTX (MPP) and CAC24-PEG3k-PTX (CPP) obtained by Lu et al. The disulfide bond was introduced as published previously and the amide bond was obtained by standard procedures. Figure S17. Amphiphilic telodendrimer PEG5k-CA8 synthesized by Wang et al. Figure S18. Chemical structure of OA02 peptide functionalized PEG5K-CA8 telodendrimer OA02-PEG5k-CA8 obtained by Xiao et al. Figure S19. Chitosan-BA conjugates obtained by Park et al. Figure S20. Synthesis and structure of poly(bis(carboxyphenoxy)phosphazene) (CA-PCPP), and polymeric micelles CA-PCPP– PDADMAC-CA obtained by Mehnath et al. Figure S21. Structure of Docetaxel. Figure S22. Structures and synthesis process of LCA-DTX-PC and LCA-PEG obtained by Sreekanth et al. Figure S23. Structure and synthesis of the polymer PEG-LCA-CA4 carried out by Yadav et al. Figure S24. Conjugate formed by piperidine, LCA and DTX (PIP-LCA-DTX) obtained by Mehta et al. Copper-mediated click chemistry was used as indicated in the Figure. Figure S25. Structure of Tamoxifen. Figure S26. Series of Tam-BA conjugates synthesized by Sreekanth et al. Figure S27. Synthesis of Tam-BA conjugates having free carboxylic group a C24 (top) or bearing amine head group attached (bottom). Figure S28. Structure and synthesis of LCA-Tam conjugates obtained by Yadav et al. Figure S29. Structure and synthesis of the conjugates LCA-Tam-PC and the fluorophore LCA-Tam-NBD-PC. Figure S30. Structure and synthesis of cholic acid-cytarabine conjugates with different linkers between both residues obtained by Chen et al. Figure S31. BA conjugates of of cytarabine syntheszed by Zhang et al. Figure S32. Structure of Doxorubicin. Figure S33. BA conjugates obtained by Pan et al. Figure S34. Structure of CPT and its DCA conjugate G2 obtained by Xiao et al. Figure S35. Structure of Gemcitabine. Figure S36. Synthesis of the GCA-polymer conjugate PLGA10k-PEG5k-GCA obtained by Zang et al. Figure S37. Structure of twenty BA-noscapine derivatives obtained by Harikandei et al. Figure S38. Structure of DFO and synthesis of the conjugate TCA-HA-DFO carried out by Agboluaje et al. Figure S39. Structure and synthesis of products Art-1/Art-9 obtained by Letis et al. Figure S40. Structure and synthesis of DHA-BA conjugates obtained by Marchesi et al. Figure S41. Structure of DHA-BA conjugates obtained by Zou et al. Figure S42. BA-curcumin conjugates synthesized by Rathod et al. Figure S43. Structure of the PIP. Figure S44. Structure of silybin. Figure S45. Structure of DSPE-PEG-CA conjugate synthesized by Li and Zhu. Figure S46. (top) Cholic acid (ChAc) was coupled to the peptide CGYGPKKKRKVGG containing the nuclear localization sequence (NLS) to give ChAcNLS. This compound ChAcNLS was conjugated to the monoclonal antibody mAb 7G3 to form 7G3ChAcNLS, according to Beaudoin et al. (Bottom) Schematic representation of ChAcNLS conjugated to surface lysines via the cross-linker sulfo-SMCC, according to Paquette et al. Figure S47. Structure and synthesis of tetraoxanes obtained by Opsenica et al. Figure S48. Structure and synthesis of tetraoxanes obtained by Opsenica et al. Figure S49. Structure and syntheis of tetraoxanes obtained by Terzic et al. Figure S50. Tetraoxanes studied by Zizak et al. Figure S51. Example of a deoxyadenosine BA conjugate. In this example the starting BA was the methyl ester of chenodeocholic acid. Figure S52. Synthesis of nucleoside-BA conjugates carried out by Navacchia et al. Figure S53. General structure of compounds synthesized by Agarwal et al. Figure S54. BA conjugate NO photodonor obtained by Navacchia et al. Figure S55. Structure of the conjugates obtained by Im et al. Figure S56. Structure and synthesis of conjugates of LCA and CDCA with piperazine derivatives obtained by El Kihel et al. Figure S57. Acetilated BA conjugates with piperazine and rhodamine obtained by Brandes et al. Figure S58. Structure of BA conjugates with piperazinyl derivatives obtained by Brossard et al. Figure S59. Structure of the BA-aryl conjugates obtained by Brossard et al. Figure S60. Structure of some CDCA conjugates obtained by Agarwal et al. Figure S61. Structure and synthesis of BA conjugates obtained by Vallejo et al. Figure S62. Structure of BA conjugates CAC3-FUa obtained by Qian et al. Figure S63. Structure of floxuridine glutamic acid-CDCA conjugates obtained by Vivian and Polli. Figure S64. Structure of the BA-heterocycle conjugates obtained by He et al. Figure S65. BA conjugates obtained by Wang et al. Figure S66. Deoxycholic conjugates obtained by Popadyuk et al. Figure S67. Epoxy intermediate obtained by Popadyuk et al. Figure S68. Structure of compounds obtained by Salomatina et al. Figure S69. Structure of amides conjugates obtained by Salomatina et al. Figure S70. Strucuture of deoxycholic acid derivatives obtained by Salomatina et al. Figure S71. Structure of BA-α-cyanostilbenes conjugates obtained by Agarwal et al. Figure S72. Structures of mirin and tautomers of the cholic acid-mirin conjugate obtained by Tassone et al. Figure S73. Structure of the cholic acid-hymecromone (CA-Hym) obtained by Erdagi. Figure S74. BA conjugates obtained by Kuhajda et al. Figure S75. BA–polyaminocarboxylate conjugates containing NE3TA obtained by Chong et al. Figure S76. Fluorescent cholic acid conjugate NBD-CA-NE3TA obtained by Chong et al. Table S1. Summary of Chlorambucil-bile acid conjugates. Table S2. Summary of cisplatin–Bamet conjugates. Table S3. Summary of other platin conjugates. Table S4. Summary of Paclitaxel-bile acid conjugates. Table S5. Summary of Docetaxel-bile acid conjugates. Table S6. Summary of Tamoxifen-bile acid conjugates. Table S7. Summary of Cytarabine-bile acid conjugates. Table S8. Summary of Doxorubicin-bile acid conjugates. Table S9. Summary of Artemisinin-bile acid conjugates. Table S10; Summary of Tetraoxanes-bile acid conjugates. Table S11. Summary of Click-bile acid conjugates. Table S12. Summary of HS1300, HS-1183, HS-1199, HS-1200 conjugates. Table S13. Summary of heterocycle-bile acid conjugates. Table S14. Summary of aminoacids and polyaminocarboxylate conjugates

Author Contributions

The authors have contributed equally to the work necessary to bring this review to completion. The original draft preparation and final version are due to J.V.T. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

No new data were created or analyzed in this study. Data sharing is not applicable to this article.

Acknowledgments

The authors thank Targets Editorial for their facilities in submitting this review.

Conflicts of Interest

The authors declare no conflicts of interest.

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Figure 1. Structure and names of common BAs [16].
Figure 1. Structure and names of common BAs [16].
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Figure 2. Structure of 3-tosylcholic acid, 3-benzoylcholic acid, and 3-iodocholic acid, synthesized by Ho [46].
Figure 2. Structure of 3-tosylcholic acid, 3-benzoylcholic acid, and 3-iodocholic acid, synthesized by Ho [46].
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MDPI and ACS Style

Vázquez-Gómez, S.; Seijas, J.A.; Meijide, F.; Vázquez-Tato, M.P.; Fraga, F.; Tato, J.V. Bile Acid: Drivers, Carriers and Trojan Horses in Cancer Research. Targets 2026, 4, 18. https://doi.org/10.3390/targets4020018

AMA Style

Vázquez-Gómez S, Seijas JA, Meijide F, Vázquez-Tato MP, Fraga F, Tato JV. Bile Acid: Drivers, Carriers and Trojan Horses in Cancer Research. Targets. 2026; 4(2):18. https://doi.org/10.3390/targets4020018

Chicago/Turabian Style

Vázquez-Gómez, Silvia, Julio A. Seijas, Francisco Meijide, M. Pilar Vázquez-Tato, Francisco Fraga, and José Vázquez Tato. 2026. "Bile Acid: Drivers, Carriers and Trojan Horses in Cancer Research" Targets 4, no. 2: 18. https://doi.org/10.3390/targets4020018

APA Style

Vázquez-Gómez, S., Seijas, J. A., Meijide, F., Vázquez-Tato, M. P., Fraga, F., & Tato, J. V. (2026). Bile Acid: Drivers, Carriers and Trojan Horses in Cancer Research. Targets, 4(2), 18. https://doi.org/10.3390/targets4020018

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